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PMID:6121 | Biochemical differentiation of mechanically dissociated mammalian brain in aggregating cell culture. | Mouse and rat brain cells were dissociated by a simple mechanical sieving technique and studied in culture for the formation of aggregates and the activities of choline acetyltransferase, acetylcholinesterase, glutamic acid decarboxylase, tyrosine 3-monooxygenase, aromatic L-amino acid decarboxylase, catechol methyltransferase, and monoamine oxidase. Cells from fetal and neonatal tissue formed aggregates but not cells from tissue older than two days after birth. The pattern of development of enzyme activities in these aggregates varied with the age of starting tissue. The highest levels of specific activity for the neuron-specific enzymes were found after 3-4 weeks in culture for aggregates of cells derived from relatively undeveloped brains. | Biochemical differentiation of mechanically dissociated mammalian brain in aggregating cell culture. Mouse and rat brain cells were dissociated by a simple mechanical sieving technique and studied in culture for the formation of aggregates and the activities of choline acetyltransferase, acetylcholinesterase, glutamic acid decarboxylase, tyrosine 3-monooxygenase, aromatic L-amino acid decarboxylase, catechol methyltransferase, and monoamine oxidase. Cells from fetal and neonatal tissue formed aggregates but not cells from tissue older than two days after birth. The pattern of development of enzyme activities in these aggregates varied with the age of starting tissue. The highest levels of specific activity for the neuron-specific enzymes were found after 3-4 weeks in culture for aggregates of cells derived from relatively undeveloped brains. | [
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PMID:6124 | Stimulation of tyrosine hydroxylase activity by cyclic AMP in synaptosomes and in soluble striatal enzyme preparations. | Dibutyryl cyclic AMP (dB-cAMP) elicits a concentration-dependent stimulation of tyrosine hydroxylase activity in the striatal and mesolimbic synaptosomes. The per cent of stimulation is significantly higher in the mesolimbic synaptosomes than in the striatal synaptosomes. dB-cAMP and depolarizing agents (ouabain or veratridine) have an additive effect on synaptosomal tyrosine hydroxylase activity, indicating that they stimulate tyrosine hydroxylase activity by different mechanisms. cAMP does not stimulate soluble striatal tyrosine hydroxylase activity unless it is added in combination with ATP and Mg2+, compounds required for the activity of cAMP-dependent protein kinase. The cAMP elicited per cent stimulation of soluble tyrosine hydroxylase activity is dependent upon the concentration of added protein kinase and upon the pH of the reaction. dB-cAMP has the same effect on the kinetic state of tyrosine hydroxylase in synaptosomes as cAMP on the soluble tyrosine hydroxylase. The nucleotide does not alter the apparent Km for tyrosine, reduces the Km for the pteridine cofactor and increases the Ki for dopamine. Thus, cAMP increases the affinity of tyrosine hydroxylase for the pteridine cofactor and concomitantly decreases the affinity for the end-product inhibition. | Stimulation of tyrosine hydroxylase activity by cyclic AMP in synaptosomes and in soluble striatal enzyme preparations. Dibutyryl cyclic AMP (dB-cAMP) elicits a concentration-dependent stimulation of tyrosine hydroxylase activity in the striatal and mesolimbic synaptosomes. The per cent of stimulation is significantly higher in the mesolimbic synaptosomes than in the striatal synaptosomes. dB-cAMP and depolarizing agents (ouabain or veratridine) have an additive effect on synaptosomal tyrosine hydroxylase activity, indicating that they stimulate tyrosine hydroxylase activity by different mechanisms. cAMP does not stimulate soluble striatal tyrosine hydroxylase activity unless it is added in combination with ATP and Mg2+, compounds required for the activity of cAMP-dependent protein kinase. The cAMP elicited per cent stimulation of soluble tyrosine hydroxylase activity is dependent upon the concentration of added protein kinase and upon the pH of the reaction. dB-cAMP has the same effect on the kinetic state of tyrosine hydroxylase in synaptosomes as cAMP on the soluble tyrosine hydroxylase. The nucleotide does not alter the apparent Km for tyrosine, reduces the Km for the pteridine cofactor and increases the Ki for dopamine. Thus, cAMP increases the affinity of tyrosine hydroxylase for the pteridine cofactor and concomitantly decreases the affinity for the end-product inhibition. | [
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PMID:6125 | Choline acetyltransferase, glutamate decarboxylase and tyrosine hydroxylase in the cochlea and cochlear nucleus of the guinea pig. | Activities of choline acetyltransferase (ChAC), glutamate decarboxylase (GAD) and tyrosine hydroxylase (TH), enzymes catalyzing the synthesis of acetylcholine (ACh), gamma-aminobutyric acid (GABA) and catecholamines, respectively, were measured in the cochlea and cochlear nucleus of the guinea pig. ChAc activity in the organ of Corti, third turn, was 1270 pmole ACh formed/min/mg protein (ChAc, 1270) and was higher than in turn 4 (ChAc, 543). ChAc activity was higher when the preparation included the inner hair cell region than when not. GAD activity in samples of turn 3 and 4 combined was low, 0.17 nmole GABA formed/min/mg protein (GAD, 0.17). All 3 enzymes were low in auditory nerve: ChAc, 1.7, GAD, 0.10 and TH, 1.0 pmole DOPA formed/min/mg protein. In the cochlear nucleus, the values were: ChAc, 129, GAD, 1.70 and TH, 2.7. The findings on the distribution of ChAc activity in the organ of Corti fit the hypothesis that the olivocochlear nerve fibers are cholinergic. Because of low GAD in the cochlea, GABA is unlikely to be transmitter in the organ of Corti. Similarly, it is unlikely that ACh, GABA or a catecholamine is a transmitter between the auditory nerve and the cochlear nucleus. | Choline acetyltransferase, glutamate decarboxylase and tyrosine hydroxylase in the cochlea and cochlear nucleus of the guinea pig. Activities of choline acetyltransferase (ChAC), glutamate decarboxylase (GAD) and tyrosine hydroxylase (TH), enzymes catalyzing the synthesis of acetylcholine (ACh), gamma-aminobutyric acid (GABA) and catecholamines, respectively, were measured in the cochlea and cochlear nucleus of the guinea pig. ChAc activity in the organ of Corti, third turn, was 1270 pmole ACh formed/min/mg protein (ChAc, 1270) and was higher than in turn 4 (ChAc, 543). ChAc activity was higher when the preparation included the inner hair cell region than when not. GAD activity in samples of turn 3 and 4 combined was low, 0.17 nmole GABA formed/min/mg protein (GAD, 0.17). All 3 enzymes were low in auditory nerve: ChAc, 1.7, GAD, 0.10 and TH, 1.0 pmole DOPA formed/min/mg protein. In the cochlear nucleus, the values were: ChAc, 129, GAD, 1.70 and TH, 2.7. The findings on the distribution of ChAc activity in the organ of Corti fit the hypothesis that the olivocochlear nerve fibers are cholinergic. Because of low GAD in the cochlea, GABA is unlikely to be transmitter in the organ of Corti. Similarly, it is unlikely that ACh, GABA or a catecholamine is a transmitter between the auditory nerve and the cochlear nucleus. | [
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PMID:6128 | An evaluation of L-glutamate as the transmitter released from optic nerve terminals of the pigeon. | The possibility was investigated that L-glutamic acid is the excitatory transmitter released from the optic nerve terminals of the pigeon optic tectum. (1) Superficial layers of the tectum contained high levels of endogenous glutamate and accumulated L-[3H]glutamate by a high affinity uptake process. (2) Subcellular and autoradiographic studies indicated that 10-30% of the exogenously accumulated L-[3H]glutamate was localized within synaptosomes, and that 11-15% of the synaptosomes had been labelled. (3) The glutamate-accumulating synaptosomes sedimented to the same isopycnic density as pinched-off optic nerve terminals. (4) GABA-and noradrenaline-accumulating synaptosomes were also associated with this subcellular population. (5) Retinal ablation did not change endogenous glutamate concentrations or the high affinity uptake of glutamate. The results are discussed in relation to a possible role for L-glutamate as the 'optic nerve transmitter' and in the context of previous evidence implicating glutamate as an excitatory transmitter. | An evaluation of L-glutamate as the transmitter released from optic nerve terminals of the pigeon. The possibility was investigated that L-glutamic acid is the excitatory transmitter released from the optic nerve terminals of the pigeon optic tectum. (1) Superficial layers of the tectum contained high levels of endogenous glutamate and accumulated L-[3H]glutamate by a high affinity uptake process. (2) Subcellular and autoradiographic studies indicated that 10-30% of the exogenously accumulated L-[3H]glutamate was localized within synaptosomes, and that 11-15% of the synaptosomes had been labelled. (3) The glutamate-accumulating synaptosomes sedimented to the same isopycnic density as pinched-off optic nerve terminals. (4) GABA-and noradrenaline-accumulating synaptosomes were also associated with this subcellular population. (5) Retinal ablation did not change endogenous glutamate concentrations or the high affinity uptake of glutamate. The results are discussed in relation to a possible role for L-glutamate as the 'optic nerve transmitter' and in the context of previous evidence implicating glutamate as an excitatory transmitter. | [
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PMID:6130 | [Hemodynamic modifications induced by hypoxia in the dog]. | In non hypercapnic hypoxia (inhalation of a 4,5% O2 mixture during 10 minutes) blood pressure, heart rate, cardiac output, femoral and carotid blood flow inhance so that, in less extent, vertebral blood flow. Such a reaction is consequent with an hypoxic stimulation of adrenal glands. | [Hemodynamic modifications induced by hypoxia in the dog]. In non hypercapnic hypoxia (inhalation of a 4,5% O2 mixture during 10 minutes) blood pressure, heart rate, cardiac output, femoral and carotid blood flow inhance so that, in less extent, vertebral blood flow. Such a reaction is consequent with an hypoxic stimulation of adrenal glands. | [
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PMID:6131 | [Respiratory stimulant effect of S 2620 in the dog anesthetized with pentobarbital]. | In the dog under pentobarbitone anesthesia, the intravenous injection of 1 mg/kg S 2620 is followed by a significant increase in respiratory rate, PaO2 and pHa and by a large decrease in PaCO2. Cervical vagotomy and chemoreceptor denervation reduced and even abolished these effects. They can be induced again by a second intravenous injection or by direct instillation in the fourth ventricle. These results suggest a central action of the drug. | [Respiratory stimulant effect of S 2620 in the dog anesthetized with pentobarbital]. In the dog under pentobarbitone anesthesia, the intravenous injection of 1 mg/kg S 2620 is followed by a significant increase in respiratory rate, PaO2 and pHa and by a large decrease in PaCO2. Cervical vagotomy and chemoreceptor denervation reduced and even abolished these effects. They can be induced again by a second intravenous injection or by direct instillation in the fourth ventricle. These results suggest a central action of the drug. | [
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PMID:6132 | Modification of the regulatory properties of pyruvate kinase of Neurospora by growth at elevated temperatures. | Pyruvate kinase (EC 2.7.1.40) was isolated from Neurospora crassa mycelium grown at 28 degrees C (PK-28) and at 42 degrees C (PK-42). The regulatory properties, particularly the response towards the allosteric effector fructose 1,6-diphosphate (FDP), was different in the two enzymes. PK-28 showed an activation by FDP but PK-42, under comparable conditions, appeared to be activated by low concentrations of FDP and inhibited by higher ones. For PK-28, complex formation with FDP results in a lowering of the isoelectric point from 6.40 to 5.50, representing the pI of the unliganded enzyme and that of the complex, respectively. In contrast to this, PK-42 exhibits a weak binding to FDP as suggested by a lack of decrease in the isoelectric point on treatment with comparable concentrations of FDP. Studies with quenching of aromatic residue fluorescence of PK-28 and PK-42, following binding of FDP, indicate that although this ligand binds to both types of enzymes the affinity for the two is vastly different. Dissociation constants of 9.3 muM and 0.1 mM were calculated for the binding of FDP to PK-28 and PK-42, respectively. It is concluded that growth at elevated temperatures induced a conformational change in the pyruvate kinase leading to partial desensitization of the allosteric site. The nature of the factor(s) responsible for this change is not understood at present. | Modification of the regulatory properties of pyruvate kinase of Neurospora by growth at elevated temperatures. Pyruvate kinase (EC 2.7.1.40) was isolated from Neurospora crassa mycelium grown at 28 degrees C (PK-28) and at 42 degrees C (PK-42). The regulatory properties, particularly the response towards the allosteric effector fructose 1,6-diphosphate (FDP), was different in the two enzymes. PK-28 showed an activation by FDP but PK-42, under comparable conditions, appeared to be activated by low concentrations of FDP and inhibited by higher ones. For PK-28, complex formation with FDP results in a lowering of the isoelectric point from 6.40 to 5.50, representing the pI of the unliganded enzyme and that of the complex, respectively. In contrast to this, PK-42 exhibits a weak binding to FDP as suggested by a lack of decrease in the isoelectric point on treatment with comparable concentrations of FDP. Studies with quenching of aromatic residue fluorescence of PK-28 and PK-42, following binding of FDP, indicate that although this ligand binds to both types of enzymes the affinity for the two is vastly different. Dissociation constants of 9.3 muM and 0.1 mM were calculated for the binding of FDP to PK-28 and PK-42, respectively. It is concluded that growth at elevated temperatures induced a conformational change in the pyruvate kinase leading to partial desensitization of the allosteric site. The nature of the factor(s) responsible for this change is not understood at present. | [
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PMID:6133 | Modified 5'-nucleotides resistant to 5'-nucleotidase: isolation of 3-(3-amino-3-carboxypropyl) uridine 5'-phosphate and N2, N2-dimethylguanosine 5'-phosphate from snake venom hydrolysates of transfer RNA. | A procedure for the quantitative measurement of the O2'-methylnucleoside constitutents of RNA has recently been developed in this laboratory (Gray, M.W. Can. J. Biochem. 53, 735-746 (1975)). This assay method is based on the resistance of O2'-methylnucleoside 5'-phosphates (pNm) (generated by phosphodiesterase hydrolysis of RNA) to subsequent dephosphorylation by venom 5'-nucleotidase (EC 3.1.3.5). In the present investigation, two base-modified 5'-nucleotides, each displaying an unusual resistance to 5'-nucleotidase, have been identified. These compounds have been characterized by a variety of techniques as N2, N2-dimethylguanosine 5'-phosphate (pm2/2G) and 3-(3-amino-3-carboxypropyl)uridine 5'-phosphate (p4abu3U). Because of their resistance to 5'-nucleotidase, pm2/2G and p4abu3U are isolated along with the pNm in the mononucleotide fraction of venom hydrolysates of transfer RNA. Under hydrolysis conditions, the stability of p4abu3U is comparable to that of a pNm, allowing quantitative assay of the nucleotide. The proportion (mean +/- SD) of p4abu3U in venom hydrolysates of wheat embryo and Escherichia coli tRNA has been determined to be 0.35 +/- 0.03 (n=5) and 0.14 +/- 0.02 (n=4) mol%, respectively. The absence of p4abu3U in venom hydrolysates of yeast tRNA implies the absence of the corresponding nucleoside in yeast tRNA, in agreement with existing data. The variable recovery of pm2/2G from venom hydrolysates of wheat embryo and yeast tRNA indicates that under hydrolysis conditions, this base-modified nucleotide is only partially resistent to 5'-nucleotidase. The complete absence of pm2/2G in venom hydrolysates of E. coli tRNA is consistent with the known absence of N2, N2-dimethylguanosine in this RNA. These observations demonstrate that resistance to 5'-nucleotidase is a necessary but not sufficient criterion for concluding that a 5'-nucleotide is O2'-methylated. When applied to wheat embryo ribosomal RNA, the analytical methods described in this report failed to reveal any compound having the distinctive charge properties of p4abu3U. It therefore appears that 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine, recently characterized as a constituent of the 18 S rRNA of Chinese hamster cells (Saponara, A.G. & Enger, M.D. Biochim. Biophys. Acta 349, 61-77 (1974)), may not be present in wheat embryo ribosomal RNA. | Modified 5'-nucleotides resistant to 5'-nucleotidase: isolation of 3-(3-amino-3-carboxypropyl) uridine 5'-phosphate and N2, N2-dimethylguanosine 5'-phosphate from snake venom hydrolysates of transfer RNA. A procedure for the quantitative measurement of the O2'-methylnucleoside constitutents of RNA has recently been developed in this laboratory (Gray, M.W. Can. J. Biochem. 53, 735-746 (1975)). This assay method is based on the resistance of O2'-methylnucleoside 5'-phosphates (pNm) (generated by phosphodiesterase hydrolysis of RNA) to subsequent dephosphorylation by venom 5'-nucleotidase (EC 3.1.3.5). In the present investigation, two base-modified 5'-nucleotides, each displaying an unusual resistance to 5'-nucleotidase, have been identified. These compounds have been characterized by a variety of techniques as N2, N2-dimethylguanosine 5'-phosphate (pm2/2G) and 3-(3-amino-3-carboxypropyl)uridine 5'-phosphate (p4abu3U). Because of their resistance to 5'-nucleotidase, pm2/2G and p4abu3U are isolated along with the pNm in the mononucleotide fraction of venom hydrolysates of transfer RNA. Under hydrolysis conditions, the stability of p4abu3U is comparable to that of a pNm, allowing quantitative assay of the nucleotide. The proportion (mean +/- SD) of p4abu3U in venom hydrolysates of wheat embryo and Escherichia coli tRNA has been determined to be 0.35 +/- 0.03 (n=5) and 0.14 +/- 0.02 (n=4) mol%, respectively. The absence of p4abu3U in venom hydrolysates of yeast tRNA implies the absence of the corresponding nucleoside in yeast tRNA, in agreement with existing data. The variable recovery of pm2/2G from venom hydrolysates of wheat embryo and yeast tRNA indicates that under hydrolysis conditions, this base-modified nucleotide is only partially resistent to 5'-nucleotidase. The complete absence of pm2/2G in venom hydrolysates of E. coli tRNA is consistent with the known absence of N2, N2-dimethylguanosine in this RNA. These observations demonstrate that resistance to 5'-nucleotidase is a necessary but not sufficient criterion for concluding that a 5'-nucleotide is O2'-methylated. When applied to wheat embryo ribosomal RNA, the analytical methods described in this report failed to reveal any compound having the distinctive charge properties of p4abu3U. It therefore appears that 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine, recently characterized as a constituent of the 18 S rRNA of Chinese hamster cells (Saponara, A.G. & Enger, M.D. Biochim. Biophys. Acta 349, 61-77 (1974)), may not be present in wheat embryo ribosomal RNA. | [
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PMID:6134 | Kinetic effect of some aliphatic amines on yeast alcohol dehydrogenase. | Initial rate studies of ethanol oxidation catalyzed by yeast alcohol dehydrogenase (EC 1.1.1.1) were carried out in the presence of varying concentrations of aliphatic amines over the pH range from 8.0 to 10.5. Aliphatic amines either activate or inhibit the enzyme depending on whether the pH is greater or less than 9.5 suggesting that the protonated amines activate and the nonprotonated amines inhibit the enzyme. Aliphatic amines activate yeast alcohol dehydrogenase by decreasing Kb while they inhibit the enzyme by increasing both Ka and Kia. When both protonated and nonprotonated amines are present in solution, either overall activation or inhibition will be observed depending on the relative concentration of the two amine species. | Kinetic effect of some aliphatic amines on yeast alcohol dehydrogenase. Initial rate studies of ethanol oxidation catalyzed by yeast alcohol dehydrogenase (EC 1.1.1.1) were carried out in the presence of varying concentrations of aliphatic amines over the pH range from 8.0 to 10.5. Aliphatic amines either activate or inhibit the enzyme depending on whether the pH is greater or less than 9.5 suggesting that the protonated amines activate and the nonprotonated amines inhibit the enzyme. Aliphatic amines activate yeast alcohol dehydrogenase by decreasing Kb while they inhibit the enzyme by increasing both Ka and Kia. When both protonated and nonprotonated amines are present in solution, either overall activation or inhibition will be observed depending on the relative concentration of the two amine species. | [
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PMID:6135 | Purine catabolism in man: characterization of placental microsomal 5'-nucleotidase. | Human placental microsomal 5'-nucleotidase (EC 3.1.3.5) was prepared free of alkaline phosphatase by isoelectric focusing. A total of seven electrophoretic variants were isolated during the preparation of six placentas. Only three to six variants were found in a single placenta. The isoelectric pH's were 6.70, 6.44, 6.23, 6.02, 5.76, 5.63 and 5.44. These were found to be composed of variable quantities of a large, medium and low molecular weight form. The apparent molecular weights of the medium and light form of the enzyme were 86 500 and 43 500, respectively, as estimated from Stokes radius and sedimentation velocity determinations. The electrophoretic variants were not distinguishable with respect to specific activity and Michaelis constants for AMP, GMP or CMP or inhibition by ATP, CTP or adenosine. These electrophoretic variants appeared to be pseudoisozymes based upon different states of aggregation of a common primary sequence. There was a wide range of substrate specificity among nucleoside 5'-monophosphates which included 2-deoxyribose compounds. With AMP as 100, substrate activity was: CMP, 122; NMN, 74; GMP, 68: IMP, 63; XMP, 28 and UDP-glucose, 68. The Michaelis constants for AMP, GMP and CMP ranged from 12-18 muM, from 33-67 muM and from 170-250 muM, respectively. Although 5'-nucleotidase was active in the absence of divalent cation, 5 mM MgCl2 stimulated the enzyme activity to 234% of control and shifted the pH optimum of 9.8 to a plateau from pH 7.4-9.8. | Purine catabolism in man: characterization of placental microsomal 5'-nucleotidase. Human placental microsomal 5'-nucleotidase (EC 3.1.3.5) was prepared free of alkaline phosphatase by isoelectric focusing. A total of seven electrophoretic variants were isolated during the preparation of six placentas. Only three to six variants were found in a single placenta. The isoelectric pH's were 6.70, 6.44, 6.23, 6.02, 5.76, 5.63 and 5.44. These were found to be composed of variable quantities of a large, medium and low molecular weight form. The apparent molecular weights of the medium and light form of the enzyme were 86 500 and 43 500, respectively, as estimated from Stokes radius and sedimentation velocity determinations. The electrophoretic variants were not distinguishable with respect to specific activity and Michaelis constants for AMP, GMP or CMP or inhibition by ATP, CTP or adenosine. These electrophoretic variants appeared to be pseudoisozymes based upon different states of aggregation of a common primary sequence. There was a wide range of substrate specificity among nucleoside 5'-monophosphates which included 2-deoxyribose compounds. With AMP as 100, substrate activity was: CMP, 122; NMN, 74; GMP, 68: IMP, 63; XMP, 28 and UDP-glucose, 68. The Michaelis constants for AMP, GMP and CMP ranged from 12-18 muM, from 33-67 muM and from 170-250 muM, respectively. Although 5'-nucleotidase was active in the absence of divalent cation, 5 mM MgCl2 stimulated the enzyme activity to 234% of control and shifted the pH optimum of 9.8 to a plateau from pH 7.4-9.8. | [
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PMID:6136 | Ethanol metabolism by the rat heart and alcohol dehydrogenase activity. | Rat hearts perfused with oxygenated buffer containing [1-14C]ethanol metabolized small amounts of the ethanol to carbon dioxide. Very sensitive techniques are required to separate the resulting 14CO2 from the ethanol. This metabolism is not inhibited by levels of pyrazole which markedly inhibit NAD dependent liver alcohol dehydrogenase (EC 1.1.1.1). In vitro studies suggest that NADP functions as a cofactor for the rat heart alcohol dehydrogenase activity of crude heart homogenates. The kinetics parameters, the specific activity, and the pH dependence of the enzyme activity measured in these experiments suggest that it may have a minor role in ethanol metabolism by the rat. | Ethanol metabolism by the rat heart and alcohol dehydrogenase activity. Rat hearts perfused with oxygenated buffer containing [1-14C]ethanol metabolized small amounts of the ethanol to carbon dioxide. Very sensitive techniques are required to separate the resulting 14CO2 from the ethanol. This metabolism is not inhibited by levels of pyrazole which markedly inhibit NAD dependent liver alcohol dehydrogenase (EC 1.1.1.1). In vitro studies suggest that NADP functions as a cofactor for the rat heart alcohol dehydrogenase activity of crude heart homogenates. The kinetics parameters, the specific activity, and the pH dependence of the enzyme activity measured in these experiments suggest that it may have a minor role in ethanol metabolism by the rat. | [
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PMID:6137 | The effect of pH on rabbit atrial response to histamine. | The chorontropic response of isolated rabbit atria in normal Tyrode's medium increases monotonically with increasing doses of histamine (9 X 10-7 -9 X 10-4 M). Plots of the inverse of response against the inverse of concentration were linear; and from these plots were derived values fro the theoretical maximum response at 'infinite' dose and for pH histamine concentration required to evoke a half maximum response. Alteration of pH by changing (HCO3-) at a constant pCO2, (Na) and osolality did not appreciably affect the response to histamine in the range pH 7.0-7.6. However, at pH below 7.0 the magnitude of histamine response was reduced at all concentrations of histamine tested. In the pH range 7.0-7.6, additions of NaHCO3 at constant pCO2 increased the spontaneous rate of rabbit atria (in the absence of histamine); however, there was little effect of changing pH (in this range) by altering (HCO3-) at constant pCO2 when (Na+) and osmolaity were kept constant. Immersion in solutions at pH's less than 7.0 led to decline in spontaneous rate and force contraction. It is probable that depression of adenyl cyclase activity rather than a specific change in ionization of histamine receptor is responsible for a decreased response to histamine at pH 6.9. | The effect of pH on rabbit atrial response to histamine. The chorontropic response of isolated rabbit atria in normal Tyrode's medium increases monotonically with increasing doses of histamine (9 X 10-7 -9 X 10-4 M). Plots of the inverse of response against the inverse of concentration were linear; and from these plots were derived values fro the theoretical maximum response at 'infinite' dose and for pH histamine concentration required to evoke a half maximum response. Alteration of pH by changing (HCO3-) at a constant pCO2, (Na) and osolality did not appreciably affect the response to histamine in the range pH 7.0-7.6. However, at pH below 7.0 the magnitude of histamine response was reduced at all concentrations of histamine tested. In the pH range 7.0-7.6, additions of NaHCO3 at constant pCO2 increased the spontaneous rate of rabbit atria (in the absence of histamine); however, there was little effect of changing pH (in this range) by altering (HCO3-) at constant pCO2 when (Na+) and osmolaity were kept constant. Immersion in solutions at pH's less than 7.0 led to decline in spontaneous rate and force contraction. It is probable that depression of adenyl cyclase activity rather than a specific change in ionization of histamine receptor is responsible for a decreased response to histamine at pH 6.9. | [
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PMID:6138 | Selective enrichment of Shigella in the presence of Escherichia coli by use of 4-chloro-2-cyclopentylphenyl beta-D-galactopyranoside. | A procedure involving the use of citrate-buffered lactose broth (pH 6.5) containing an analogue of a beta-galactoside (4-chloro-2-cyclopentylphenyl beta-D-galactopyranoside) has been developed for the enrichment of Shigella in competition with a 100-fold higher population of Escherichia coli. The system makes use of the beta-galactosidase activity of E. coli which hydrolyzes the phenolic derivative of beta-galactoside to galactose and an aglycone moiety (4-chloro-2-cyclopentylphenol) which is toxic to E. coli but is tolerated by Shigella. The procedure is particularly effective in the enrichment of S. sonnei and S. flexneri; S. dynsenteriae and S. boydii are enriched to a lesser extent. | Selective enrichment of Shigella in the presence of Escherichia coli by use of 4-chloro-2-cyclopentylphenyl beta-D-galactopyranoside. A procedure involving the use of citrate-buffered lactose broth (pH 6.5) containing an analogue of a beta-galactoside (4-chloro-2-cyclopentylphenyl beta-D-galactopyranoside) has been developed for the enrichment of Shigella in competition with a 100-fold higher population of Escherichia coli. The system makes use of the beta-galactosidase activity of E. coli which hydrolyzes the phenolic derivative of beta-galactoside to galactose and an aglycone moiety (4-chloro-2-cyclopentylphenol) which is toxic to E. coli but is tolerated by Shigella. The procedure is particularly effective in the enrichment of S. sonnei and S. flexneri; S. dynsenteriae and S. boydii are enriched to a lesser extent. | [
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PMID:6139 | Adsorption, desorption, and activity of glucose oxidase on selected clay species. | The adsorption of the enzyme glucose oxidase (EC 1.1.3.4) to clays followed the pattern described for other proteins as being pH dependent. Maximum adsorption occurred at or below the isoelectric point of the enzyme. The amount of enzyme adsorbed to clay was influenced by the type of clay used, and also the saturating cations. Initially adsorbed enzyme showed low specific activities, and as amounts of enzyme adsorbed approached maximum stauration of clay, specific activities increased approaching that determined for free enzyme. The adsorption of glucose oxidase involved a temperature-independent cation-exchange mechanism, and enzyme adsorbed to surfaces of clay could be desorbed in active form by elevation of pH of suspending solution. This was followed by a slower temperature-dependent fixation, probably by hydrogen bonding, which resulted in protein being irreversibly adsorbed to clay surfaces. It is proposed that on adsorption of glucose oxidase to clay surfaces unravelling of the protein structure occurred, which allowed penetration of protein into the interlamellar spaces of montmorillonite. This proposal was based on the observed expansion of montmorillonite to 23 A, and the decreases in amount of a second-protein lysozyme adsorbed with extended incubation times of glucose oxidase - clay complexes at pH 4.5. | Adsorption, desorption, and activity of glucose oxidase on selected clay species. The adsorption of the enzyme glucose oxidase (EC 1.1.3.4) to clays followed the pattern described for other proteins as being pH dependent. Maximum adsorption occurred at or below the isoelectric point of the enzyme. The amount of enzyme adsorbed to clay was influenced by the type of clay used, and also the saturating cations. Initially adsorbed enzyme showed low specific activities, and as amounts of enzyme adsorbed approached maximum stauration of clay, specific activities increased approaching that determined for free enzyme. The adsorption of glucose oxidase involved a temperature-independent cation-exchange mechanism, and enzyme adsorbed to surfaces of clay could be desorbed in active form by elevation of pH of suspending solution. This was followed by a slower temperature-dependent fixation, probably by hydrogen bonding, which resulted in protein being irreversibly adsorbed to clay surfaces. It is proposed that on adsorption of glucose oxidase to clay surfaces unravelling of the protein structure occurred, which allowed penetration of protein into the interlamellar spaces of montmorillonite. This proposal was based on the observed expansion of montmorillonite to 23 A, and the decreases in amount of a second-protein lysozyme adsorbed with extended incubation times of glucose oxidase - clay complexes at pH 4.5. | [
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PMID:6140 | Inhibition of growth, iron, and sulfur oxidation in Thiobacillus ferrooxidans by simple organic compounds. | Iron and sulfur oxidation by Thiobacillus ferrooxidans as well as growth on ferrous iron were inhibited by a variety of low molecular weight organic compounds. The influences of chemical structure of the organic inhibitors, pH, temperature, physical treatment of cells, and added inhibitory or stimulatory inorganic ions and iron oxidation suggest that a major factor contributing to the inhibitory effects on iron oxidation is the relative electronegativity of the organic molecule. The data also suggest that inhibitory organic compounds may (i) directly affect the iron-oxidizing enzyme system, (ii) react abiologically with ferrous iron outside the cell, (iii) interfere with the roles of phosphate and sulfate in iron oxidation, and (iv) nonselectively disrupt the cell envelope or membrane. | Inhibition of growth, iron, and sulfur oxidation in Thiobacillus ferrooxidans by simple organic compounds. Iron and sulfur oxidation by Thiobacillus ferrooxidans as well as growth on ferrous iron were inhibited by a variety of low molecular weight organic compounds. The influences of chemical structure of the organic inhibitors, pH, temperature, physical treatment of cells, and added inhibitory or stimulatory inorganic ions and iron oxidation suggest that a major factor contributing to the inhibitory effects on iron oxidation is the relative electronegativity of the organic molecule. The data also suggest that inhibitory organic compounds may (i) directly affect the iron-oxidizing enzyme system, (ii) react abiologically with ferrous iron outside the cell, (iii) interfere with the roles of phosphate and sulfate in iron oxidation, and (iv) nonselectively disrupt the cell envelope or membrane. | [
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PMID:6141 | Regulation of acetyl-CoA synthetase of Saccharomyces cerevisiae. | Acetyl-coenzyme A synthetase (EC 6.2.1.1) activity of Saccharomyces cerevisiae was determined by a radioactive assay procedure. The activity in vitro was inhibited significantly by NADPH, NADH, or AMP and to a lesser extent by NADP, NAD, or ADP. Glutamic acid and alpha-ketoglutaric acid were not inhibitory. The enzyme level was repressed when the cells were grown in a complex nutrient medium as opposed to the minimal medium. However, a glutamic acid auxotroph glul, when grown in excess glutamic acid, demonstrated a fivefold increase of acetyl-CoA synthetase. | Regulation of acetyl-CoA synthetase of Saccharomyces cerevisiae. Acetyl-coenzyme A synthetase (EC 6.2.1.1) activity of Saccharomyces cerevisiae was determined by a radioactive assay procedure. The activity in vitro was inhibited significantly by NADPH, NADH, or AMP and to a lesser extent by NADP, NAD, or ADP. Glutamic acid and alpha-ketoglutaric acid were not inhibitory. The enzyme level was repressed when the cells were grown in a complex nutrient medium as opposed to the minimal medium. However, a glutamic acid auxotroph glul, when grown in excess glutamic acid, demonstrated a fivefold increase of acetyl-CoA synthetase. | [
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PMID:6142 | beta-Galactosidase from Bacillus stearothermophilus. | Several strains of thermophilic aerobic spore-forming bacilli synthesize beta-galactosidase (EC 3.2.1.23) constitutively. The constitutivity is apparently not the result of a temperature-sensitive repressor. The beta-galactosidase from one strain, investigated in cell-free extracts, has a pH optimum between 6.0 and 6.4 and a very sharp pH dependence on the acid side of its optimum. The optimum temperature for this enzyme is 65 degrees C and the Arrhenius activation energy is about 24 kcal/mol below 47 degrees C and 16 kcal/mol above that temperature. At 55 degrees C the Km is 0.11 M for lactose and 9.8 X 10(-3) M for 9-nitrophenyl-beta-D-galactopyranoside. The enzyme is strongly product-inhibited by galactose (Ki equals 2.5 X 10(-3) M). It is relatively stable at 50 degrees C, losing only half of its activity after 20 days at this temperature. At 60 degrees C more than 60% of the activity is lost in 10 min. However, the enzyme is protected somewhat against thermal inactivation by protein, and in the presence of 4 mg/ml of bovine serum albumin the enzyme is only 18% inactivated in 10 min at 60 degrees C. Its molecular weight, estimated by disc gel electrophoresis, is 215 000. | beta-Galactosidase from Bacillus stearothermophilus. Several strains of thermophilic aerobic spore-forming bacilli synthesize beta-galactosidase (EC 3.2.1.23) constitutively. The constitutivity is apparently not the result of a temperature-sensitive repressor. The beta-galactosidase from one strain, investigated in cell-free extracts, has a pH optimum between 6.0 and 6.4 and a very sharp pH dependence on the acid side of its optimum. The optimum temperature for this enzyme is 65 degrees C and the Arrhenius activation energy is about 24 kcal/mol below 47 degrees C and 16 kcal/mol above that temperature. At 55 degrees C the Km is 0.11 M for lactose and 9.8 X 10(-3) M for 9-nitrophenyl-beta-D-galactopyranoside. The enzyme is strongly product-inhibited by galactose (Ki equals 2.5 X 10(-3) M). It is relatively stable at 50 degrees C, losing only half of its activity after 20 days at this temperature. At 60 degrees C more than 60% of the activity is lost in 10 min. However, the enzyme is protected somewhat against thermal inactivation by protein, and in the presence of 4 mg/ml of bovine serum albumin the enzyme is only 18% inactivated in 10 min at 60 degrees C. Its molecular weight, estimated by disc gel electrophoresis, is 215 000. | [
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PMID:6144 | Transient inhibition of cell proliferation in rat glioma monolayer cultures by cortisol. | The effect of 3 muM cortisol on cell proliferation in rat glioma (strain C6) monolayer cultures was investigated. Cell density measurements showed that cortisol-treated C6 cells continued to proliferate at maximum log phase rates for 1 to 2 days. Then cell proliferation ceased as growth in control cultures continued into stationary phase. A 2-day period of growth inhibition followed during which cell densities were 30 to 50% lower relative to controls. Growth resumed subsequently, and final cell densities were similar to those of controls. The presence of epicortisol (the biologically inactive isomer of cortisol) in the culture medium did not alter the rate of log phase growth relative to controls. During the initial period of continued growth after exposure to cortisol, the pH of the medium decreased at the same rate in control and treated cultures. During the growth-inhibitory period, erythrosin B dye was excluded equally well (greater than 94%) by control and treated cells, and no morphological differences were detected by phase contrast microscopy. When the culture medium was replaced daily, the control cells at elevated densities continued to proliferate at a reduced rate. In cortisol-treated cultures, the period of growth inhibition commenced 3 days after the cells were exposed initially to cortisol. A 2-day period of growth inhibition followed during which the pH of the 1-day-old media from both control and treated cultures decreased from 7.4 to 6.9. Growth resumed subsequently in the treated cultures to produce elevated cell densities similar to those of controls. These results demonstrate that cortisol at concentrations considered chemotherapeutic in vivo exerts a transient inhibitory effect on C6 glioma cell proliferation. | Transient inhibition of cell proliferation in rat glioma monolayer cultures by cortisol. The effect of 3 muM cortisol on cell proliferation in rat glioma (strain C6) monolayer cultures was investigated. Cell density measurements showed that cortisol-treated C6 cells continued to proliferate at maximum log phase rates for 1 to 2 days. Then cell proliferation ceased as growth in control cultures continued into stationary phase. A 2-day period of growth inhibition followed during which cell densities were 30 to 50% lower relative to controls. Growth resumed subsequently, and final cell densities were similar to those of controls. The presence of epicortisol (the biologically inactive isomer of cortisol) in the culture medium did not alter the rate of log phase growth relative to controls. During the initial period of continued growth after exposure to cortisol, the pH of the medium decreased at the same rate in control and treated cultures. During the growth-inhibitory period, erythrosin B dye was excluded equally well (greater than 94%) by control and treated cells, and no morphological differences were detected by phase contrast microscopy. When the culture medium was replaced daily, the control cells at elevated densities continued to proliferate at a reduced rate. In cortisol-treated cultures, the period of growth inhibition commenced 3 days after the cells were exposed initially to cortisol. A 2-day period of growth inhibition followed during which the pH of the 1-day-old media from both control and treated cultures decreased from 7.4 to 6.9. Growth resumed subsequently in the treated cultures to produce elevated cell densities similar to those of controls. These results demonstrate that cortisol at concentrations considered chemotherapeutic in vivo exerts a transient inhibitory effect on C6 glioma cell proliferation. | [
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PMID:6145 | Effects of Tumor-like assay conditions, lonizing radiation, and hyperthermia on immune lysis of tumor cells by cytotoxic T-lymphocytes. | Cytotoxic T-lymphocytes (CTL's) harvested from mixed splenic lymphocyte cultures (DBA/2 + C57BL) were tested for their ability to lyse allogeneic P815 mastocytoma cells under various tumor-like assay conditions, with or without previous exposure to ionizing radiation or hyperthermia (43 degrees). There was little or no decrease of immune cytolysis when CTL's were assayed by 51Cr release under tumor-like conditions (plateau-phase target cells, low pH, or anoxia) or after irradiation, but cytolytic activity was greatly reduced when CTL's were exposed to heat; 45 min of hyperthermic treatment decreased activity by greater than or equal to 99% while reducing the apparent cell viability (as indicated by trypan blue exclusion) by only 30%. When the P815 target cells rather than the CTL's were exposed to heat their susceptibility to immune lysis was not affected even after treatment times that were lethal to the tumor cells. Despite the dissimilar heat sensitivities of CTL and P815 cells, the dose-response curves for inhibition of protein synthesis by heat, as indicated by [3H]leucine incorporation, were similar for both cell types: neither the depression of protein synthesis in heated CTL's nor the decreased cytolytic ability of these cells was reversed within 3 hr. When irradiated or heated P815 cells were incubated with CTL's, the resulting survival curves were always additive, indicating that neither irradiation nor heat treatment affected the susceptibility of the tumor cells to immune attack. The extreme heat sensitivity of cytotoxic T-lymphocytes raises important questions about the possible effects of hyperthermic treatment on the immune competence of cancer patients. | Effects of Tumor-like assay conditions, lonizing radiation, and hyperthermia on immune lysis of tumor cells by cytotoxic T-lymphocytes. Cytotoxic T-lymphocytes (CTL's) harvested from mixed splenic lymphocyte cultures (DBA/2 + C57BL) were tested for their ability to lyse allogeneic P815 mastocytoma cells under various tumor-like assay conditions, with or without previous exposure to ionizing radiation or hyperthermia (43 degrees). There was little or no decrease of immune cytolysis when CTL's were assayed by 51Cr release under tumor-like conditions (plateau-phase target cells, low pH, or anoxia) or after irradiation, but cytolytic activity was greatly reduced when CTL's were exposed to heat; 45 min of hyperthermic treatment decreased activity by greater than or equal to 99% while reducing the apparent cell viability (as indicated by trypan blue exclusion) by only 30%. When the P815 target cells rather than the CTL's were exposed to heat their susceptibility to immune lysis was not affected even after treatment times that were lethal to the tumor cells. Despite the dissimilar heat sensitivities of CTL and P815 cells, the dose-response curves for inhibition of protein synthesis by heat, as indicated by [3H]leucine incorporation, were similar for both cell types: neither the depression of protein synthesis in heated CTL's nor the decreased cytolytic ability of these cells was reversed within 3 hr. When irradiated or heated P815 cells were incubated with CTL's, the resulting survival curves were always additive, indicating that neither irradiation nor heat treatment affected the susceptibility of the tumor cells to immune attack. The extreme heat sensitivity of cytotoxic T-lymphocytes raises important questions about the possible effects of hyperthermic treatment on the immune competence of cancer patients. | [
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PMID:6146 | Conditions of cultivation required for the formation of hemicysts in vitro by rat bladder carcinoma R-4909. | Rat urinary bladder carcinoma R-4909 grew readily in vitro. In areas where saturation density occurred in the cultures, occasional hemicysts were observed. A modification of technique producing "packed cultures" resulted in the appearance of greater numbers of hemicysts. Four clonal isolates of R-4909 were also studied in packed culture. Clone B formed hemicysts in abundance. Clone D produced occasional hemicysts similar to the parent stock line. No hemicysts were seen in cultures of clone A or clone C. The number of hemicysts formed by clone B in packed culture was responsive to the ratio between cell number and volume of medium, to serum concentration in the medium, and to pH of the medium. The last was of particular interest since a pH of 7.8 enhanced and a pH of 6.6 inhibited hemicyst formation. The effects were all reversible. On scanning electron microscopy, we found well-developed cell membrane structures between contiguous cells. In media with sufficient serum for hemicyst formation, the articulations between cells were prominent. With low serum concentrations, hemicysts did not form and the intercellular articulations were less distinct. We interpret the formation of hemicysts as an expression of fluid transport by epithelia, a function that requires a constellation of differentiated characteristics within cells and in their level of integrated association. | Conditions of cultivation required for the formation of hemicysts in vitro by rat bladder carcinoma R-4909. Rat urinary bladder carcinoma R-4909 grew readily in vitro. In areas where saturation density occurred in the cultures, occasional hemicysts were observed. A modification of technique producing "packed cultures" resulted in the appearance of greater numbers of hemicysts. Four clonal isolates of R-4909 were also studied in packed culture. Clone B formed hemicysts in abundance. Clone D produced occasional hemicysts similar to the parent stock line. No hemicysts were seen in cultures of clone A or clone C. The number of hemicysts formed by clone B in packed culture was responsive to the ratio between cell number and volume of medium, to serum concentration in the medium, and to pH of the medium. The last was of particular interest since a pH of 7.8 enhanced and a pH of 6.6 inhibited hemicyst formation. The effects were all reversible. On scanning electron microscopy, we found well-developed cell membrane structures between contiguous cells. In media with sufficient serum for hemicyst formation, the articulations between cells were prominent. With low serum concentrations, hemicysts did not form and the intercellular articulations were less distinct. We interpret the formation of hemicysts as an expression of fluid transport by epithelia, a function that requires a constellation of differentiated characteristics within cells and in their level of integrated association. | [
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PMID:6147 | Differential transglutaminase distribution in normal rat liver and rat hepatoma. | Distribution of transglutaminase activity was determined in normal rat liver, a 3'-methyl-4-dimethylaminoazobenzene-induced primary hepatoma, and the Novikoff hepatoma. Over 90% of the total enzyme activity was found in the 105,000 X g supernatant of normal liver, whereas only 30% was found in this fraction of the hepatomas, the remainder being found in the particulate fraction. The is distribution pattern did not correlate with protein distribution nor did it change during cellular proliferation, since regenerating liver and embryonic tissue had the same pattern as normal liver. Cell protein was a suitable acceptor substrate for the enzyme. Kinetic analyses showed that liver and hepatoma enzymes had a similar Km and Vmax for putrescine incorporation into cell protein. Hepatoma particulate enzyme was more stable than either liver or hepatoma supernatant enzyme. The enzyme may also act as the acceptor molecule. | Differential transglutaminase distribution in normal rat liver and rat hepatoma. Distribution of transglutaminase activity was determined in normal rat liver, a 3'-methyl-4-dimethylaminoazobenzene-induced primary hepatoma, and the Novikoff hepatoma. Over 90% of the total enzyme activity was found in the 105,000 X g supernatant of normal liver, whereas only 30% was found in this fraction of the hepatomas, the remainder being found in the particulate fraction. The is distribution pattern did not correlate with protein distribution nor did it change during cellular proliferation, since regenerating liver and embryonic tissue had the same pattern as normal liver. Cell protein was a suitable acceptor substrate for the enzyme. Kinetic analyses showed that liver and hepatoma enzymes had a similar Km and Vmax for putrescine incorporation into cell protein. Hepatoma particulate enzyme was more stable than either liver or hepatoma supernatant enzyme. The enzyme may also act as the acceptor molecule. | [
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PMID:6149 | The form and function of cnidarian spirocysts. 1. Ultrastructure of the capsule exterior and relationship to the tentacle sensory surface. | The commonest intracellular organelle characteristic of the Phylum Cnidaria or Coelenterata (Subclass Zoantharia) is the spirocyst. Based on scanning and transmission electron microscopy of the tentacles of sea anemones and corals, it appears that the tip of the spirocyst is either exposed to the environment or covered by a thin plasma membrane and often has a pebbled or knobby appearance. Surrounding the spirocyst tip is a ring-like structure which seems to be formed by the junction of the enclosing cell (the spirocyte) and the tip of the spirocyst. The spirocyst thread is continuous with the capsule wall and emerges from within the apical ring during discharge. No ciliary structures appear to be associated with spirocysts. Instead, two different types of microvilli have been found: short microvilli on the spirocyte itself and long microvilli furnished by the cell or cells surrounding the spirocyte. The significance of these findings is discussed in relation to the reception of stimuli for spirocyst discharge. | The form and function of cnidarian spirocysts. 1. Ultrastructure of the capsule exterior and relationship to the tentacle sensory surface. The commonest intracellular organelle characteristic of the Phylum Cnidaria or Coelenterata (Subclass Zoantharia) is the spirocyst. Based on scanning and transmission electron microscopy of the tentacles of sea anemones and corals, it appears that the tip of the spirocyst is either exposed to the environment or covered by a thin plasma membrane and often has a pebbled or knobby appearance. Surrounding the spirocyst tip is a ring-like structure which seems to be formed by the junction of the enclosing cell (the spirocyte) and the tip of the spirocyst. The spirocyst thread is continuous with the capsule wall and emerges from within the apical ring during discharge. No ciliary structures appear to be associated with spirocysts. Instead, two different types of microvilli have been found: short microvilli on the spirocyte itself and long microvilli furnished by the cell or cells surrounding the spirocyte. The significance of these findings is discussed in relation to the reception of stimuli for spirocyst discharge. | [
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PMID:6159 | [Effect of pH on bacteria in early log phase]. | The bacteria harvested in the early log phase lyse when they are submitted to a pH above 10. The peptidoglycan is not degraded in these conditions. Thus, the authors used these properties to extract the peptidoglycan from several gram negative and gram positive bacteria. | [Effect of pH on bacteria in early log phase]. The bacteria harvested in the early log phase lyse when they are submitted to a pH above 10. The peptidoglycan is not degraded in these conditions. Thus, the authors used these properties to extract the peptidoglycan from several gram negative and gram positive bacteria. | [
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PMID:6161 | Effect of timolol versus propranolol on hypertension and hemodynamics. | The effect of timolol versus propranolol on hypertension, hemodynamics, and plasms renin activity was evaluated in 20 men. After two weeks of placebo, 11 men received timolol 30 to 60 mg daily, and nine men received propranolol, 240 to 480 mg daily, for five weeks in a double-blind randomized study. The 20 men then received placebo again for two weeks. Right heart catheterization was performed in all 20 patients after two weeks of the first placebo and after five weeks of timolol or propranolol. Equipotent doses of timolol and propranolol were equally effective in significantly lowering supine and upright systolic and diastolic blood pressure and heart rate recorded on an outpatient basis. Equipotent doses of timolol and propranolol caused similar hemodynamic effects including similar significant depression of cardiac index. Equipotent doses of timolol and propranolol caused similar marked depression of plasma renin activity. The hypotensive action of timolol and of propranolol was unrelated to their effect on plasma renin activity. | Effect of timolol versus propranolol on hypertension and hemodynamics. The effect of timolol versus propranolol on hypertension, hemodynamics, and plasms renin activity was evaluated in 20 men. After two weeks of placebo, 11 men received timolol 30 to 60 mg daily, and nine men received propranolol, 240 to 480 mg daily, for five weeks in a double-blind randomized study. The 20 men then received placebo again for two weeks. Right heart catheterization was performed in all 20 patients after two weeks of the first placebo and after five weeks of timolol or propranolol. Equipotent doses of timolol and propranolol were equally effective in significantly lowering supine and upright systolic and diastolic blood pressure and heart rate recorded on an outpatient basis. Equipotent doses of timolol and propranolol caused similar hemodynamic effects including similar significant depression of cardiac index. Equipotent doses of timolol and propranolol caused similar marked depression of plasma renin activity. The hypotensive action of timolol and of propranolol was unrelated to their effect on plasma renin activity. | [
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PMID:6163 | Determination of clomipramine and desmethyl-clomipramine in plasma or urine by the double-radioisotope derivative technique. | A double radioisotope derivative method was developed for the determination of clomipramine and desmethyl-clomipramine in plasma or urine. After addition of 14C-labeled clomipramine and desmethyl-clomipramine as internal standards and extractive isolation of both compounds, desmethyl-clomipramine is acetylated with [3H]acetic anhydride. The [3H]acetamide is separated from clomipramine by thin-layer chromatography and its radioactivity is measured. Clomipramine, extracted from the cilica gel, is reacted with trichloroethyl chloroformate. The urethane is saponified and decarboxylated. The resulting desmethyl-clomipramine is acetylated with [3H]acetic anhydride. The [3H]acetamide is purified by thin-layer chromatography and its radioactivity is measured. The sensitivity of the method is 15 mug/liter for clomipramine and 2 mug/liter for desmethyl-clomipramine. Its specificity was made sure by a cross-check with a gas chromatography-mass spectrometry technique. | Determination of clomipramine and desmethyl-clomipramine in plasma or urine by the double-radioisotope derivative technique. A double radioisotope derivative method was developed for the determination of clomipramine and desmethyl-clomipramine in plasma or urine. After addition of 14C-labeled clomipramine and desmethyl-clomipramine as internal standards and extractive isolation of both compounds, desmethyl-clomipramine is acetylated with [3H]acetic anhydride. The [3H]acetamide is separated from clomipramine by thin-layer chromatography and its radioactivity is measured. Clomipramine, extracted from the cilica gel, is reacted with trichloroethyl chloroformate. The urethane is saponified and decarboxylated. The resulting desmethyl-clomipramine is acetylated with [3H]acetic anhydride. The [3H]acetamide is purified by thin-layer chromatography and its radioactivity is measured. The sensitivity of the method is 15 mug/liter for clomipramine and 2 mug/liter for desmethyl-clomipramine. Its specificity was made sure by a cross-check with a gas chromatography-mass spectrometry technique. | [
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PMID:6164 | Diazepam abuse: incidence, rapid screening, and confirming methods. | We studied 2500 patients suspected to be drug-overdose victims. Blood samples were quantitatively screened for the most commonly abused drugs, including diazepam. Of these, 61% had positive findings, including diazepam in about one of every four. A new rapid, simple, and quantitative gas-chromatographic method for simultaneous analysis of diazepam and sedatives (in two instruments) is described. A single extraction at low pH is used, preserving the balance of the sample to be used for confirming methods via ultraviolet spectrophotometry and thin-layer chromatography. Prevalance of other positive findings is also listed, and findings for diazepam are categorized by age. | Diazepam abuse: incidence, rapid screening, and confirming methods. We studied 2500 patients suspected to be drug-overdose victims. Blood samples were quantitatively screened for the most commonly abused drugs, including diazepam. Of these, 61% had positive findings, including diazepam in about one of every four. A new rapid, simple, and quantitative gas-chromatographic method for simultaneous analysis of diazepam and sedatives (in two instruments) is described. A single extraction at low pH is used, preserving the balance of the sample to be used for confirming methods via ultraviolet spectrophotometry and thin-layer chromatography. Prevalance of other positive findings is also listed, and findings for diazepam are categorized by age. | [
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PMID:6166 | Determination of ionized calcium in serum that has been exposed to air. | We examined changes in ionized calcium concentration in serum after its exposure to air. Samples with total protein concentrations ranging from 50 to 90 g/liter were equilibrated with CO2 in nitrogen (5/95, by vol) or CO2 alone, to produce pH values of 7.0 to 8.0. Ionized calcium was then measured with an Orion flow-through electrode system. Curves relating pH and ionized calcium concentration had statistically identical slopes regardless of protein concentration. A factor was derived, based on pH change, for correcting values for ionized calcium in serum exposed to air, and its validity was confirmed by comparing corrected values for samples allowed to stand at ambient temperature (23 degrees C) without anaerobic precautions with values initially obtained on anaerobic aliquots of the same samples. | Determination of ionized calcium in serum that has been exposed to air. We examined changes in ionized calcium concentration in serum after its exposure to air. Samples with total protein concentrations ranging from 50 to 90 g/liter were equilibrated with CO2 in nitrogen (5/95, by vol) or CO2 alone, to produce pH values of 7.0 to 8.0. Ionized calcium was then measured with an Orion flow-through electrode system. Curves relating pH and ionized calcium concentration had statistically identical slopes regardless of protein concentration. A factor was derived, based on pH change, for correcting values for ionized calcium in serum exposed to air, and its validity was confirmed by comparing corrected values for samples allowed to stand at ambient temperature (23 degrees C) without anaerobic precautions with values initially obtained on anaerobic aliquots of the same samples. | [
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PMID:6167 | In vitro changes in blood P50 and erythrocyte 2,3-diphosphoglycerate concentration. | We studied in vitro changes in P50 and erythrocyte 2,3-diphosphoglycerate concentration occurring in blood 2 to 8 h after venipuncture. When blood was incubated at 37 degrees C, significant decreases in P50 were observed at 2, 4, and 8 hr. Such a change was significantly less when blood was kept at 4 degrees C. The rate of decrease in P50 was not changed when pH was altered by adding either lactic acid or sodium bicarbonate to the blood before incubation at 37 degrees C for 2 h. The erythrocyte 2,3-diphosphoglycerate concentration of blood incubated at 37 degrees C did not change by 2 h, but had significantly decreased by 4 h. To avoid in vitro changes, we recommend that P50 be determined as soon as possible for blood sampling. | In vitro changes in blood P50 and erythrocyte 2,3-diphosphoglycerate concentration. We studied in vitro changes in P50 and erythrocyte 2,3-diphosphoglycerate concentration occurring in blood 2 to 8 h after venipuncture. When blood was incubated at 37 degrees C, significant decreases in P50 were observed at 2, 4, and 8 hr. Such a change was significantly less when blood was kept at 4 degrees C. The rate of decrease in P50 was not changed when pH was altered by adding either lactic acid or sodium bicarbonate to the blood before incubation at 37 degrees C for 2 h. The erythrocyte 2,3-diphosphoglycerate concentration of blood incubated at 37 degrees C did not change by 2 h, but had significantly decreased by 4 h. To avoid in vitro changes, we recommend that P50 be determined as soon as possible for blood sampling. | [
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PMID:6169 | Alkaline phosphatase. I. Kinetics and inhibition by levamisole of purified isoenzymes from humans. | I studied the kinetics and sensitivity toward inhibition by levamisole and R 8231 of the most important human alkaline phosphatase isoenzymes. N-Ethylaminoethanol proved superior to the now widely used diethanolamine buffer, especially for the enzymes from the intestine and placenta, behaving as an uncompetitive activator. The optimum pH largely depends on the substrate concentration. The addition of Mg2+ has no effect on the activities. The meaning of Km-values for alkaline phosphatases is questioned. Isoenzymes from human liver, bone, kidney, and spleen are strongly inhibited by levamisole or R 8231 at concentrations that barely affect the enzymes from intestine or placenta. The inhibition is stereospecific, uncompetitive, and not changed by Mg2+. Inhibition is counteracted by increasing concentrations of N-ethylaminoethanol. The mechanism of inhibition is suggested to be formation of a complex with the phosphoenzyme. | Alkaline phosphatase. I. Kinetics and inhibition by levamisole of purified isoenzymes from humans. I studied the kinetics and sensitivity toward inhibition by levamisole and R 8231 of the most important human alkaline phosphatase isoenzymes. N-Ethylaminoethanol proved superior to the now widely used diethanolamine buffer, especially for the enzymes from the intestine and placenta, behaving as an uncompetitive activator. The optimum pH largely depends on the substrate concentration. The addition of Mg2+ has no effect on the activities. The meaning of Km-values for alkaline phosphatases is questioned. Isoenzymes from human liver, bone, kidney, and spleen are strongly inhibited by levamisole or R 8231 at concentrations that barely affect the enzymes from intestine or placenta. The inhibition is stereospecific, uncompetitive, and not changed by Mg2+. Inhibition is counteracted by increasing concentrations of N-ethylaminoethanol. The mechanism of inhibition is suggested to be formation of a complex with the phosphoenzyme. | [
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PMID:6170 | Determination of erythrocyte folate by competitive protein binding assay preceded by extraction. | Determination of the concentration of erythrocyte folate by means of competitive protein binding assay critically depends on the extraction procedure applied. Results will be influenced by variable factors such as the in vitro age of the blood samples, the degree of hemolysis, the presence of ascorbic acid, and the pH during extraction and elimination of proteins. The radioassay is strongly influenced by the pH of the final reaction mixture, the method used to separate free and protein-bound molecules, and the molecular configuration of the folates present. Based on experimental results presented, I describe a method for the determination of erythrocyte folate. | Determination of erythrocyte folate by competitive protein binding assay preceded by extraction. Determination of the concentration of erythrocyte folate by means of competitive protein binding assay critically depends on the extraction procedure applied. Results will be influenced by variable factors such as the in vitro age of the blood samples, the degree of hemolysis, the presence of ascorbic acid, and the pH during extraction and elimination of proteins. The radioassay is strongly influenced by the pH of the final reaction mixture, the method used to separate free and protein-bound molecules, and the molecular configuration of the folates present. Based on experimental results presented, I describe a method for the determination of erythrocyte folate. | [
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PMID:6171 | [Compared efficiency of mean corpuscular volume (MCV) and serum gamma-glutamyltransferase (gamma-GT) as screening tests for excess-ethanol drinkers (author's transl)]. | 53 percent of ethanol drinkers had, before detoxication, a gamma-GT higher than the upper limit of the reference interval at the 2.5 percent risk level (36 mU/ml). 44 percent had a mean corpuscular volume (MCV) higher than the limit (99.2 mum3). In alcoholics not previously "weaned" during a rest cure or in a hospital the proportion becomes 67 percent for gamma-GT but remains at 44 percent for MCV. gamma-GT thus seems a better test for the screening of an excessive ethanol intake than MCV, especially when the subject has not been previously weaned. | [Compared efficiency of mean corpuscular volume (MCV) and serum gamma-glutamyltransferase (gamma-GT) as screening tests for excess-ethanol drinkers (author's transl)]. 53 percent of ethanol drinkers had, before detoxication, a gamma-GT higher than the upper limit of the reference interval at the 2.5 percent risk level (36 mU/ml). 44 percent had a mean corpuscular volume (MCV) higher than the limit (99.2 mum3). In alcoholics not previously "weaned" during a rest cure or in a hospital the proportion becomes 67 percent for gamma-GT but remains at 44 percent for MCV. gamma-GT thus seems a better test for the screening of an excessive ethanol intake than MCV, especially when the subject has not been previously weaned. | [
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PMID:6173 | [Separation of metanephrine and normetanephrine from urine for automated fluorimetric routine determination (author's transl)]. | It is possible to separate metanephrine and normetanephrine from urine for the automated fluorimetric routine determination by means of a combination of liquid-liquid partition with ethylacetate and clean-up of the extract through Amberlite XAD-4. The differentiated fluorimetric determination is based on the oxidation with potassium hexacyanoferrate (III) in the presence of zinc ions and different pH values in an autoanalyzer. No quenching effects were observed. The recovery yields were in the range of 60%, the relative standard deviation being less than 10%. | [Separation of metanephrine and normetanephrine from urine for automated fluorimetric routine determination (author's transl)]. It is possible to separate metanephrine and normetanephrine from urine for the automated fluorimetric routine determination by means of a combination of liquid-liquid partition with ethylacetate and clean-up of the extract through Amberlite XAD-4. The differentiated fluorimetric determination is based on the oxidation with potassium hexacyanoferrate (III) in the presence of zinc ions and different pH values in an autoanalyzer. No quenching effects were observed. The recovery yields were in the range of 60%, the relative standard deviation being less than 10%. | [
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PMID:6174 | Improved radioiodination of glucagon with the lactoperoxidase method. Influence of pH on iodine substitution. | To produce a 125I-labelled glucagon suitable for radioligand assays, we studied the influence of variations in the lactoperoxidase iodination method. Both the degree of iodine substitution and the formation of monoiodo- or diiodo-tyrosines were pH dependent. The substitution increased and the diiodo-/monoiodotyrosine ratio decreased when pH increased. These two factors affected the immunoreactivity of the iodoglucagon relatively independently of each other. It was found that iodination at pH 10.0 with an average of 0.3 gatom I/mol glucagon resulted in 125I-labelled glucagon with higher immunoreactivity and stability than that produced at the conventional pH 7.5 and 8.5. | Improved radioiodination of glucagon with the lactoperoxidase method. Influence of pH on iodine substitution. To produce a 125I-labelled glucagon suitable for radioligand assays, we studied the influence of variations in the lactoperoxidase iodination method. Both the degree of iodine substitution and the formation of monoiodo- or diiodo-tyrosines were pH dependent. The substitution increased and the diiodo-/monoiodotyrosine ratio decreased when pH increased. These two factors affected the immunoreactivity of the iodoglucagon relatively independently of each other. It was found that iodination at pH 10.0 with an average of 0.3 gatom I/mol glucagon resulted in 125I-labelled glucagon with higher immunoreactivity and stability than that produced at the conventional pH 7.5 and 8.5. | [
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PMID:6175 | Arylamidases in normal and diseased human muscle. | Human skeletal muscle homogenates were found to contain enzymes that catalyze the hydrolysis of beta-naphthylamides of leucine, arginine and lysine, known substrates for neutral and basic arylamidases. They also contained a trace of activity towards alpha-aspartyl-beta-naphthylamide. The muscle arylamidases were found to be inhibited by p-chloromercuribenzoate, Hg2+ and puromycin. Leucyl, arginyl and lysysl arylamidases were slightly activated by cobalt ions. When compared to controls, no significant differences in muscle arylamidase activities were observed in patients with muscular dystrophies and certain denervating diseases. | Arylamidases in normal and diseased human muscle. Human skeletal muscle homogenates were found to contain enzymes that catalyze the hydrolysis of beta-naphthylamides of leucine, arginine and lysine, known substrates for neutral and basic arylamidases. They also contained a trace of activity towards alpha-aspartyl-beta-naphthylamide. The muscle arylamidases were found to be inhibited by p-chloromercuribenzoate, Hg2+ and puromycin. Leucyl, arginyl and lysysl arylamidases were slightly activated by cobalt ions. When compared to controls, no significant differences in muscle arylamidase activities were observed in patients with muscular dystrophies and certain denervating diseases. | [
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PMID:6178 | Surgical aspects of infertility. | These surgical procedures that have been used in the management of male infertility have recently been subjected to critical review. In a recent study (Getzoff, 1973) designed to summarise the experience of 150 urologists in the surgical treatment of male infertility, several valuable viewpoints were revealed. 1. There is a need for establishing criteria for labelling an operation as a 'success'. In this group, 42 per cent defined a successful operation as the postoperative appearance of a normal semen analysis in the azoospermic or oligospermic man regardless of whether his wife fails to conceive. Thirty per cent were more stringent and required that the wife become pregnant and carry to term a normal viable infant. 2. The prerequisites for selecting suitable candidates for surgery were apparent. 3. The significance of establishing basic effective operative techniques is self-evident. 4. The importance of emphasising the limitations of the surgical management of impaired fertility is stressed. | Surgical aspects of infertility. These surgical procedures that have been used in the management of male infertility have recently been subjected to critical review. In a recent study (Getzoff, 1973) designed to summarise the experience of 150 urologists in the surgical treatment of male infertility, several valuable viewpoints were revealed. 1. There is a need for establishing criteria for labelling an operation as a 'success'. In this group, 42 per cent defined a successful operation as the postoperative appearance of a normal semen analysis in the azoospermic or oligospermic man regardless of whether his wife fails to conceive. Thirty per cent were more stringent and required that the wife become pregnant and carry to term a normal viable infant. 2. The prerequisites for selecting suitable candidates for surgery were apparent. 3. The significance of establishing basic effective operative techniques is self-evident. 4. The importance of emphasising the limitations of the surgical management of impaired fertility is stressed. | [
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PMID:6179 | Effects of cardioselective beta adrenoceptor blockade on specific airways resistance in normal subjects and in patients with bronchial asthma. | The effects of single oral doses of the cardioselective beta adrenoceptor blocking drugs, metoprolol and tolamolol, on specific airways resistance (SRaw) were compared with those of propranolol and practolol in 6 healthy volunteers and in 12 patients with bronchial asthma. Whole-body plethysmography was used to measure SRaw and the blocking potency of different antagonists assessed by the degree of inhibition of tachycardia due to exercise on a treadmill. The changes correlated with plasma drug levels. Propranolol and practolol were measured fluorometrically and metoprolol by electron-capture gas-liquid chromatography. In normal subjects, about 30% reduction in exercise-induced tachycardia resulted from single doses of 80 mg propranolol (plasma levels, 50.3, SD, 29.5 to 60.8, SD, 26 ng/ml), 250 mg practolol (plasma levels, 1.05, SD, 0.32 to 1.10, SD, 0.55 mug/ml), 100 mg metoprolol (plasma levels, 137, SD, 111 to 152, SD, 100 ng/ml), and 100 mg tolamolol. In patients, these doses of the drugs produced significant increases in SRaw. These increases were greater than those after placebo but significantly so only during the peak effect 1 hr after propranolol. Compared with changes after placebo, significant effects on SRaw were also found in 3 patients given 200 mg of tolamolol. None of the drugs had a significant effect on SRaw in normal subjects. It is concluded that metoprolol, practolol, and tolamolol may impair ventilatory function in asthmatics less than propranolol and that at high doses this difference may not be demonstrable. | Effects of cardioselective beta adrenoceptor blockade on specific airways resistance in normal subjects and in patients with bronchial asthma. The effects of single oral doses of the cardioselective beta adrenoceptor blocking drugs, metoprolol and tolamolol, on specific airways resistance (SRaw) were compared with those of propranolol and practolol in 6 healthy volunteers and in 12 patients with bronchial asthma. Whole-body plethysmography was used to measure SRaw and the blocking potency of different antagonists assessed by the degree of inhibition of tachycardia due to exercise on a treadmill. The changes correlated with plasma drug levels. Propranolol and practolol were measured fluorometrically and metoprolol by electron-capture gas-liquid chromatography. In normal subjects, about 30% reduction in exercise-induced tachycardia resulted from single doses of 80 mg propranolol (plasma levels, 50.3, SD, 29.5 to 60.8, SD, 26 ng/ml), 250 mg practolol (plasma levels, 1.05, SD, 0.32 to 1.10, SD, 0.55 mug/ml), 100 mg metoprolol (plasma levels, 137, SD, 111 to 152, SD, 100 ng/ml), and 100 mg tolamolol. In patients, these doses of the drugs produced significant increases in SRaw. These increases were greater than those after placebo but significantly so only during the peak effect 1 hr after propranolol. Compared with changes after placebo, significant effects on SRaw were also found in 3 patients given 200 mg of tolamolol. None of the drugs had a significant effect on SRaw in normal subjects. It is concluded that metoprolol, practolol, and tolamolol may impair ventilatory function in asthmatics less than propranolol and that at high doses this difference may not be demonstrable. | [
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PMID:6180 | Sleep laboratory studies of flurazepam: a model for evaluating hypnotic drugs. | The results from six separate evaluations of flurazepam 30 mg in the sleep laboratory were combined to determine the effectiveness of the drug in inducing and maintaining sleep and its effects on sleep stages in a large sample of insomniac subjects. The combined studies provide a model from which a detailed profile of the effects of a hypnotic drug over short-, intermediate-, and long-term conditions can be thoroughly evaluated. Although sleep was significantly improved on the first night of flurazepam administration, peak effectiveness of the drug did not result until the second and third consecutive drug nights. Flurazepam continued to be effective in inducing and maintaining sleep with intermediate-and long-term drug use with only a slight loss of effectiveness with long-term use. Sleep was also significantly improved on the first and second nights of drug withdrawal. Carryover effectiveness of active metabolites of flurazepam from one drug night to the next drug night and to withdrawl nights is discussed. The clinical implications are discussed with regard to the time of peak effectiveness of the drug, dosage recommendations and schedule, minimizing possible effects of the drug on daytime performance, and the rationale and method for using drug holidays in the treatment regimen. With this comprehensive profile of the drug's actions, the physician is able to more rationally and effectively utilize the drug in treating the insomniac patient. With short-term administration, flurazepam produced a slight decrease in rapid eye movement (REM) sleep and an increase in REM latency. These effects were much more pronounced with intermediate-term drug administration, again possibly due to the accumulation of active metabolites. After withdrawal there was no rebound in REM sleep. Stages 3 and 4 sleep decreased progressively through short and intermediate drug administration. With initial withdrawal, there was a slight recovery in both sleep stages. | Sleep laboratory studies of flurazepam: a model for evaluating hypnotic drugs. The results from six separate evaluations of flurazepam 30 mg in the sleep laboratory were combined to determine the effectiveness of the drug in inducing and maintaining sleep and its effects on sleep stages in a large sample of insomniac subjects. The combined studies provide a model from which a detailed profile of the effects of a hypnotic drug over short-, intermediate-, and long-term conditions can be thoroughly evaluated. Although sleep was significantly improved on the first night of flurazepam administration, peak effectiveness of the drug did not result until the second and third consecutive drug nights. Flurazepam continued to be effective in inducing and maintaining sleep with intermediate-and long-term drug use with only a slight loss of effectiveness with long-term use. Sleep was also significantly improved on the first and second nights of drug withdrawal. Carryover effectiveness of active metabolites of flurazepam from one drug night to the next drug night and to withdrawl nights is discussed. The clinical implications are discussed with regard to the time of peak effectiveness of the drug, dosage recommendations and schedule, minimizing possible effects of the drug on daytime performance, and the rationale and method for using drug holidays in the treatment regimen. With this comprehensive profile of the drug's actions, the physician is able to more rationally and effectively utilize the drug in treating the insomniac patient. With short-term administration, flurazepam produced a slight decrease in rapid eye movement (REM) sleep and an increase in REM latency. These effects were much more pronounced with intermediate-term drug administration, again possibly due to the accumulation of active metabolites. After withdrawal there was no rebound in REM sleep. Stages 3 and 4 sleep decreased progressively through short and intermediate drug administration. With initial withdrawal, there was a slight recovery in both sleep stages. | [
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PMID:6181 | Antibacterial activity and pharmacokinetics of bacampicillin and ampicillin. | Single equimolar oral doses of bacampicillin and ampicillin were given to 9 healthy subjects on a crossover randomized basis. Data were interpreted in terms of a 3-compartment pharmacokinetic open model. Intestinal absorption of bacampicillin was found to be faster and more complete than that of ampicillin, yielding an increase in bioavailability of 30% to 40% as measured by the area under serum levels curve, the urinary excretion and absorption rate constants. After the administration of bacampicillin, much higher and sharper peaks were achieved in the serum and in the "tissue" water than after the administration of ampicillin. The maximum bactericidal dilution (MBD) of the serum samples taken 1 hr after the administration of the antibiotics against 10 strains of Diplococcus pneumoniae was higher following bacampicillin (p less than 0.01), as was the MBD of the 0 to 2 hr urine specimens against 10 strains of Escherichia coli. Further clinical trials are required to accurately assess the possible greater therapeutic effectiveness of bacampicillin than of ampicillin. | Antibacterial activity and pharmacokinetics of bacampicillin and ampicillin. Single equimolar oral doses of bacampicillin and ampicillin were given to 9 healthy subjects on a crossover randomized basis. Data were interpreted in terms of a 3-compartment pharmacokinetic open model. Intestinal absorption of bacampicillin was found to be faster and more complete than that of ampicillin, yielding an increase in bioavailability of 30% to 40% as measured by the area under serum levels curve, the urinary excretion and absorption rate constants. After the administration of bacampicillin, much higher and sharper peaks were achieved in the serum and in the "tissue" water than after the administration of ampicillin. The maximum bactericidal dilution (MBD) of the serum samples taken 1 hr after the administration of the antibiotics against 10 strains of Diplococcus pneumoniae was higher following bacampicillin (p less than 0.01), as was the MBD of the 0 to 2 hr urine specimens against 10 strains of Escherichia coli. Further clinical trials are required to accurately assess the possible greater therapeutic effectiveness of bacampicillin than of ampicillin. | [
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PMID:6182 | Effect of phenobarbitone on plasma lipids in normal subjects. | 1. Phenobarbitone in a dose of 180 mg daily was administered to ten normal subjects for 3 weeks. There was a significant increase in total plasma cholesterol, plasma low-density-lipoprotein cholesterol, plasma low-density-lipoprotein (LDL) triglycerides and plasma LDL protein. The increase in plasma LDL cholesterol accounted for the increase in total plasma cholesterol. There was a significant reduction in the ratio of LDL cholesterol to LDL protein. 2. No significant changes were observed in total plasma triglycerides, plasma very-low-density-lipoprotein (VLDL) triglycerides, plasma VLDL cholesterol or plasma VLDL protein. 3. Evidence that drug-metabolizing enzymes were induced by phenobarbitone was provided by an increase in antipyrine clearance. No relationship was observed between changes in plasma cholesterol and changes in antipyrine clearance. Serum gamma-glutamyl transpeptidase was also increased after phenobarbitone administration, the increase being unrelated to changes in antipyrine clearance or plasma cholesterol. | Effect of phenobarbitone on plasma lipids in normal subjects. 1. Phenobarbitone in a dose of 180 mg daily was administered to ten normal subjects for 3 weeks. There was a significant increase in total plasma cholesterol, plasma low-density-lipoprotein cholesterol, plasma low-density-lipoprotein (LDL) triglycerides and plasma LDL protein. The increase in plasma LDL cholesterol accounted for the increase in total plasma cholesterol. There was a significant reduction in the ratio of LDL cholesterol to LDL protein. 2. No significant changes were observed in total plasma triglycerides, plasma very-low-density-lipoprotein (VLDL) triglycerides, plasma VLDL cholesterol or plasma VLDL protein. 3. Evidence that drug-metabolizing enzymes were induced by phenobarbitone was provided by an increase in antipyrine clearance. No relationship was observed between changes in plasma cholesterol and changes in antipyrine clearance. Serum gamma-glutamyl transpeptidase was also increased after phenobarbitone administration, the increase being unrelated to changes in antipyrine clearance or plasma cholesterol. | [
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PMID:6183 | Analytical subcellular fractionation studies on rat liver and on isolated jejunal enterocytes with special reference to the separation of lysosomes, peroxisomes and mitochondria. | 1. Enterocytes were isolated from rat jejunum and characterized morphologically. 2. Attempts to separate the enterocyte subcellular organelles, characterized by their marker enzymes, with isopycnic centrifugation were unsuccessful but good separation of peroxisomes, lysosomes and mitochondria was achieved by sedimentation through a shallow sucrose density gradient with a super-imposed inverse gradient of low-molecular-weight dextran. 3. The properties and enzyme activities of the principal subcellular organelles in rat liver cells and enterocytes were compared. | Analytical subcellular fractionation studies on rat liver and on isolated jejunal enterocytes with special reference to the separation of lysosomes, peroxisomes and mitochondria. 1. Enterocytes were isolated from rat jejunum and characterized morphologically. 2. Attempts to separate the enterocyte subcellular organelles, characterized by their marker enzymes, with isopycnic centrifugation were unsuccessful but good separation of peroxisomes, lysosomes and mitochondria was achieved by sedimentation through a shallow sucrose density gradient with a super-imposed inverse gradient of low-molecular-weight dextran. 3. The properties and enzyme activities of the principal subcellular organelles in rat liver cells and enterocytes were compared. | [
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PMID:6184 | The ventilatory response in severe metabolic acidosis. | 1. The ventilatory response to severe metabolic acidosis was studied by measuring arterial blood carbon dioxide tension and pH in sixty-seven patients with blood pH less than 7-10, none of whom had hypercapnia, pulmonary oedema, or chronic pulmonary insufficiency. The results were compared with those previously found in patients with uncomplicated diabetic ketoacidosis. 2. By that comparison, fifty-two of the sixty-seven patients with blood pH less than 7-10 were judged to have "appropriate hypocapnia", and fifteen had "submaximal hypocapnia". Thirteen of the latter fifteen had circulatory failture and/or acute hypoxia, and seven of nine in whom it was measured had plasma lactate greater than 9 mmol/1. 3. Hyperventilation was therefore usually well sustained in these patients with severe metabolic acidosis, except in most of those with acute tissue hypoxia. The latter may have had insufficient time to achieve maximum hyperventilation in response to their acidosis, or perhaps their submaximal hypercapnia presaged imminent failure of the hyperventilatory response. | The ventilatory response in severe metabolic acidosis. 1. The ventilatory response to severe metabolic acidosis was studied by measuring arterial blood carbon dioxide tension and pH in sixty-seven patients with blood pH less than 7-10, none of whom had hypercapnia, pulmonary oedema, or chronic pulmonary insufficiency. The results were compared with those previously found in patients with uncomplicated diabetic ketoacidosis. 2. By that comparison, fifty-two of the sixty-seven patients with blood pH less than 7-10 were judged to have "appropriate hypocapnia", and fifteen had "submaximal hypocapnia". Thirteen of the latter fifteen had circulatory failture and/or acute hypoxia, and seven of nine in whom it was measured had plasma lactate greater than 9 mmol/1. 3. Hyperventilation was therefore usually well sustained in these patients with severe metabolic acidosis, except in most of those with acute tissue hypoxia. The latter may have had insufficient time to achieve maximum hyperventilation in response to their acidosis, or perhaps their submaximal hypercapnia presaged imminent failure of the hyperventilatory response. | [
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PMID:6185 | Some properties of human platelet monoamine oxidase in iron-deficiency anaemia. | 1. Monoamine oxidase activity in platelets prepared from the blood of patients with iron-deficiency anaemia was significantly lowered when compared with that in platelets from normal subjects. 2. The Km values of the platelet enzyme for the substrates dopamine, 5-hydroxytryptamine, phenylethylamine and kynuramine were similar for the platelet enzyme from iron-deficient and normal groups. 3. Heat-in-activation studies showed that the platelet monoamine oxidase from iron-deficient subjects was more labile to this treatment, when compared with the platelet enzyme from normal subjects. 4. The sensitivity of platelet monoamine oxidase to the inhibitors, clorgyline and deprenil, was increased in iron-deficiency anaemia. 5. Binding studies with the 14C-binding irreversible monoamine oxidase inhibitor, deprenil, showed that the amount of enzyme capable of binding this inhibitor was lowered by 48% in platelets from iron-deficient patients when compared with platelets from normal subjects. 6. The results show that there is a lowered amount of active enzyme in platelets from iron-deficient subjects. It is suggested that iron is necessary either for the synthesis of monoamine oxidase apoenzyme or is a cofactor for an enzyme which attaches flavin-adenine dinucleotide covalently to the monoamine oxidase apoenzyme. | Some properties of human platelet monoamine oxidase in iron-deficiency anaemia. 1. Monoamine oxidase activity in platelets prepared from the blood of patients with iron-deficiency anaemia was significantly lowered when compared with that in platelets from normal subjects. 2. The Km values of the platelet enzyme for the substrates dopamine, 5-hydroxytryptamine, phenylethylamine and kynuramine were similar for the platelet enzyme from iron-deficient and normal groups. 3. Heat-in-activation studies showed that the platelet monoamine oxidase from iron-deficient subjects was more labile to this treatment, when compared with the platelet enzyme from normal subjects. 4. The sensitivity of platelet monoamine oxidase to the inhibitors, clorgyline and deprenil, was increased in iron-deficiency anaemia. 5. Binding studies with the 14C-binding irreversible monoamine oxidase inhibitor, deprenil, showed that the amount of enzyme capable of binding this inhibitor was lowered by 48% in platelets from iron-deficient patients when compared with platelets from normal subjects. 6. The results show that there is a lowered amount of active enzyme in platelets from iron-deficient subjects. It is suggested that iron is necessary either for the synthesis of monoamine oxidase apoenzyme or is a cofactor for an enzyme which attaches flavin-adenine dinucleotide covalently to the monoamine oxidase apoenzyme. | [
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PMID:6188 | Central nervous system salicylate. | The poor correlation between clinical salicylate toxicity and serum blood levels is reapproached in light of recent evidence linking clinical severity with initial volume of distribution (Vd). It is recognized that two variables alter salicylate Vd in such manner that serum salicylate levels are misleading (thus, the change in Vd is not detected by present methods). These variables are serum protein binding and the pH-dependent ionized/un-ionized ratio in the unbound salicylate fraction. Measurements of salicylate concentration in the cerebro spinal fluid (CSF) would circumvent these variables, but would be clinically impractical. Thus, an alternative is sought to the inexact total serum salicylate levels and the impractical CSF salicylate levels for assessment of the severity of salicylate poisoning. This study indicates that, in dogs, serum unbound salicylate levels closely reflect CSF salicylate levels, even as a decrease in serum protein binding is in progress. However, serum unbound salicylate concentration does not reflect CSF salicylate concentration as a decrease in serum pH is elicited (CSF salicylate actually increased as serum unbound salicylate decreased). On the other hand, serum unbound salicylate measurement would seem preferable to total serum salicylate measurements now used in that the total value decreased markedly as either protein binding change or acidosis produced a change in distribution and the resultant increase in CSF salicylate. | Central nervous system salicylate. The poor correlation between clinical salicylate toxicity and serum blood levels is reapproached in light of recent evidence linking clinical severity with initial volume of distribution (Vd). It is recognized that two variables alter salicylate Vd in such manner that serum salicylate levels are misleading (thus, the change in Vd is not detected by present methods). These variables are serum protein binding and the pH-dependent ionized/un-ionized ratio in the unbound salicylate fraction. Measurements of salicylate concentration in the cerebro spinal fluid (CSF) would circumvent these variables, but would be clinically impractical. Thus, an alternative is sought to the inexact total serum salicylate levels and the impractical CSF salicylate levels for assessment of the severity of salicylate poisoning. This study indicates that, in dogs, serum unbound salicylate levels closely reflect CSF salicylate levels, even as a decrease in serum protein binding is in progress. However, serum unbound salicylate concentration does not reflect CSF salicylate concentration as a decrease in serum pH is elicited (CSF salicylate actually increased as serum unbound salicylate decreased). On the other hand, serum unbound salicylate measurement would seem preferable to total serum salicylate measurements now used in that the total value decreased markedly as either protein binding change or acidosis produced a change in distribution and the resultant increase in CSF salicylate. | [
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PMID:6221 | Polypharmacy in the psychiatric treatment of elderly hospitalized patients: a survey of 12 Veterans Administration Hospitals. | Polypharmacy with psychoactive drugs was surveyed in 1276 elderly psychiatric patients from 12 Veterans Administration hospitals. One out of every six patients received two or more psychoactive agents. No specific combination of drugs was overly popular. The most frequently administered combinations, thioridazine plus phenobarbital and chlorpromazine plus phenobarbital, were administered to only 13 patients each (1% of the sample). The large majority of the combinations involved antipsychotic agents. One antipsychotic drug, thioridazine, was a component of nearly one-third of the combinations. The most frequent pairings were an antipsychotic drug plus and antidepressant, two antipsychotic drugs, and an antipsychotic drug plus an antianxiety agent or sedative-hypnotic. The use of polypharmacy was significantly related to patient age. One out of every four patients 60 to 65 years of age received two or more psychoactive drugs compared to only one out of eight over 75 years of age. The implications of these findings for treatment and research are discussed. | Polypharmacy in the psychiatric treatment of elderly hospitalized patients: a survey of 12 Veterans Administration Hospitals. Polypharmacy with psychoactive drugs was surveyed in 1276 elderly psychiatric patients from 12 Veterans Administration hospitals. One out of every six patients received two or more psychoactive agents. No specific combination of drugs was overly popular. The most frequently administered combinations, thioridazine plus phenobarbital and chlorpromazine plus phenobarbital, were administered to only 13 patients each (1% of the sample). The large majority of the combinations involved antipsychotic agents. One antipsychotic drug, thioridazine, was a component of nearly one-third of the combinations. The most frequent pairings were an antipsychotic drug plus and antidepressant, two antipsychotic drugs, and an antipsychotic drug plus an antianxiety agent or sedative-hypnotic. The use of polypharmacy was significantly related to patient age. One out of every four patients 60 to 65 years of age received two or more psychoactive drugs compared to only one out of eight over 75 years of age. The implications of these findings for treatment and research are discussed. | [
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PMID:6222 | Mixed function oxidase activity in a marsupial. The quokka (Seton;x brachyurus). | Components of the cytochrome P-450 pathway and rates of oxidative hepatic metabolism of the substrates, ethylmorphine, 3,4-benzpyrene, and aniline, have been investigated in a marsupial (the quokka, Setonix brachyurus) and compared with those of the rat. In general the quokka had lower rates of drug metabolism and higher KM values than those found in the rat. Sex differences in Vmax and KM were also found for the quokka. These species and sex differences in oxidative drug metabolism did not correlate with measured concentrations of cytochromes P-450 or b5 or with NADPH-cytochrome c reductase activities, and have been attributed to differences in both KM and Vmax values. | Mixed function oxidase activity in a marsupial. The quokka (Seton;x brachyurus). Components of the cytochrome P-450 pathway and rates of oxidative hepatic metabolism of the substrates, ethylmorphine, 3,4-benzpyrene, and aniline, have been investigated in a marsupial (the quokka, Setonix brachyurus) and compared with those of the rat. In general the quokka had lower rates of drug metabolism and higher KM values than those found in the rat. Sex differences in Vmax and KM were also found for the quokka. These species and sex differences in oxidative drug metabolism did not correlate with measured concentrations of cytochromes P-450 or b5 or with NADPH-cytochrome c reductase activities, and have been attributed to differences in both KM and Vmax values. | [
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PMID:6223 | A comprehensive study of in vitro drug metabolism in several laboratory species. | A shortage of rhesus monkeys for use in drug toxicity studies has made it necessary to search for a potential replacement species in the event that one should be needed in the near future. To this end, 14 parameters of drug metabolism in hepatic microsomal and soluble fractions were examined in preparations from adult male and female rhesus monkeys, squirrel monkeys, Hanford miniature pigs, common tree shrews, and Sprague-Dawley rats. Model substrates were utilized and comparisons were made on a quantitative basis. All species tested demonstrated activity in all but one test assay and all showed some similarity to the rhesus. None of the species, however, was totally comparable to the rhesus in drug-metabolizing ability. The squirrel monkey showed the least similarity to the rhesus and the miniature pig was the most similar. With the exception of the expected differences in the rat, the tree shrew demonstrated the only sex difference in drug metabolism, the enzyme activities of females being higher than the male in several pathways. The data suggest that any of the four species tested could be a suitable replacement for the rhesus in studies of drug metabolism in vitro. | A comprehensive study of in vitro drug metabolism in several laboratory species. A shortage of rhesus monkeys for use in drug toxicity studies has made it necessary to search for a potential replacement species in the event that one should be needed in the near future. To this end, 14 parameters of drug metabolism in hepatic microsomal and soluble fractions were examined in preparations from adult male and female rhesus monkeys, squirrel monkeys, Hanford miniature pigs, common tree shrews, and Sprague-Dawley rats. Model substrates were utilized and comparisons were made on a quantitative basis. All species tested demonstrated activity in all but one test assay and all showed some similarity to the rhesus. None of the species, however, was totally comparable to the rhesus in drug-metabolizing ability. The squirrel monkey showed the least similarity to the rhesus and the miniature pig was the most similar. With the exception of the expected differences in the rat, the tree shrew demonstrated the only sex difference in drug metabolism, the enzyme activities of females being higher than the male in several pathways. The data suggest that any of the four species tested could be a suitable replacement for the rhesus in studies of drug metabolism in vitro. | [
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PMID:6224 | Biochemical properties of some microsomal xenobiotic-metabolizing enzymes in rabbit small intestine. | Comparison of xenobiotic-metabolizing enzymes in rabbit small intestinal and hepatic microsomal fractions showed mainly quantitative differences; most of the activities were two to seven times higher in liver than in intestine. However, UDP-glucuronyltransferase activity was higher in intestine than in liver. The apparent absence of benzene hydroxylase in small intestine was the only qualitative difference noticed. Aniline hydroxylase, aminopyrine N-demethylase, and aryl hydrocarbon dydroxylase were characterized in intestinal microsomes and compared to those of liver. Distribution of these enzymes along the entire length of small intestine showed that maximum activities of the enzymes were present in the proximal 60 cm of the intestine. All the enzymes in both tissues required NADPH and O2 for maximum activity and were inhibited by cytochrome c, SKF 525-A, and CO. The in vitro addition of drug substrates to microsomal fractions of both tissues produced typical type I and type II binding spectra. Comparison of the relationships between activities and pH, duration of incubation, and substrate and protein concentration suggested that the rabbit intestinal and hepatic xenobiotic-metabolizing enzymes studied have similar characteristics. | Biochemical properties of some microsomal xenobiotic-metabolizing enzymes in rabbit small intestine. Comparison of xenobiotic-metabolizing enzymes in rabbit small intestinal and hepatic microsomal fractions showed mainly quantitative differences; most of the activities were two to seven times higher in liver than in intestine. However, UDP-glucuronyltransferase activity was higher in intestine than in liver. The apparent absence of benzene hydroxylase in small intestine was the only qualitative difference noticed. Aniline hydroxylase, aminopyrine N-demethylase, and aryl hydrocarbon dydroxylase were characterized in intestinal microsomes and compared to those of liver. Distribution of these enzymes along the entire length of small intestine showed that maximum activities of the enzymes were present in the proximal 60 cm of the intestine. All the enzymes in both tissues required NADPH and O2 for maximum activity and were inhibited by cytochrome c, SKF 525-A, and CO. The in vitro addition of drug substrates to microsomal fractions of both tissues produced typical type I and type II binding spectra. Comparison of the relationships between activities and pH, duration of incubation, and substrate and protein concentration suggested that the rabbit intestinal and hepatic xenobiotic-metabolizing enzymes studied have similar characteristics. | [
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PMID:6225 | Comparison of hepatic microsomal drug-metabolizing systems from rats fed crude and purified diets. | Hepatic microsomes from rats fed a crude or a purified diet were compared by measureing their contents of protein, cytochrome P-450, and cytochrome b5, their rates of activity of NADPH- and NADH-cytochrome c reductases, NADPH-cytochrome P-450 reductase, NADPH oxidase, lipid peroxidase, ethylmorphine N-demethylase, aniline hydroxylase, benzpyrene hydroxylase, and their substrate-binding spectra (ethylmorphine, hexobarbital, aniline, and ethyl isoyanide). With the exception of lipid peroxidase activity, which was much higher in microsomes from animals fed the crude diet, little or no consistent diet-related differences in these measurements were observed over a 4-week experimental period, nor were results significantly less variable with one or the other diet. No consistent significant differences were observed with two strains of rats. The lower lipid peroxidase activity seen with the purified diet appeared to be due to the high vitamin E intake when that diet was employed; rats fed the crude diet and an oral supplement of alpha-tocopherol yielded microsomes with low lipid peroxidase activities similar to those seen in microsomes from rats fed the purified diet. A gradual temporal increase in benzpyrene hydroxylase activity was observed with both diets. This was interpreted to be due to environment inducing agents other than those present in the diet. | Comparison of hepatic microsomal drug-metabolizing systems from rats fed crude and purified diets. Hepatic microsomes from rats fed a crude or a purified diet were compared by measureing their contents of protein, cytochrome P-450, and cytochrome b5, their rates of activity of NADPH- and NADH-cytochrome c reductases, NADPH-cytochrome P-450 reductase, NADPH oxidase, lipid peroxidase, ethylmorphine N-demethylase, aniline hydroxylase, benzpyrene hydroxylase, and their substrate-binding spectra (ethylmorphine, hexobarbital, aniline, and ethyl isoyanide). With the exception of lipid peroxidase activity, which was much higher in microsomes from animals fed the crude diet, little or no consistent diet-related differences in these measurements were observed over a 4-week experimental period, nor were results significantly less variable with one or the other diet. No consistent significant differences were observed with two strains of rats. The lower lipid peroxidase activity seen with the purified diet appeared to be due to the high vitamin E intake when that diet was employed; rats fed the crude diet and an oral supplement of alpha-tocopherol yielded microsomes with low lipid peroxidase activities similar to those seen in microsomes from rats fed the purified diet. A gradual temporal increase in benzpyrene hydroxylase activity was observed with both diets. This was interpreted to be due to environment inducing agents other than those present in the diet. | [
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PMID:6226 | Depression of the hepatic cytochrome P-450 mono-oxygenase system by administered tilorone (2,7-bis(2-(diethylamino)ethoxy)fluoren-9-one dihydrochloride). | The oral administration of the antiviral agent, tilorone-HCl (50 mg/day for 4 days) to rats caused losses of hepatic microsomal ethylmorphine N-demethylase, benzo(a)pyrene hydroxylase and aniline hydroxylase activities of 50, 44 and 22%, respectively. Microsomal levels of cytochrome P-450 and NADPH-cytochrome c reductase were lowered by 40 and 20% respectively, but levels of cytochrome b5 and NADH-cytochrome c reductase remained unchanged. After a single oral dose of tilorone-HCl (50 mg/kg) a loss of 38% of the microsomal cytochrome P-450 and 25% of the ethylmorphine N-demethylase activity was observed within 24 hr; recovery was complete within 8 to 10 days. Hexobarbital sleeping times and blood levels were elevated after tilorone administration (20 or 50 mg/kg/day for 4 days). In vitro, tilorone-HCl showed no inhibitory effect on microsomal drug metabolism nod did it affect the cytochrome P-450 content of the microsomes. The rate of incorporation of delta-amino(3H)levulinic acid into cytochrome P-450 was not affected by tilorone-HCl. | Depression of the hepatic cytochrome P-450 mono-oxygenase system by administered tilorone (2,7-bis(2-(diethylamino)ethoxy)fluoren-9-one dihydrochloride). The oral administration of the antiviral agent, tilorone-HCl (50 mg/day for 4 days) to rats caused losses of hepatic microsomal ethylmorphine N-demethylase, benzo(a)pyrene hydroxylase and aniline hydroxylase activities of 50, 44 and 22%, respectively. Microsomal levels of cytochrome P-450 and NADPH-cytochrome c reductase were lowered by 40 and 20% respectively, but levels of cytochrome b5 and NADH-cytochrome c reductase remained unchanged. After a single oral dose of tilorone-HCl (50 mg/kg) a loss of 38% of the microsomal cytochrome P-450 and 25% of the ethylmorphine N-demethylase activity was observed within 24 hr; recovery was complete within 8 to 10 days. Hexobarbital sleeping times and blood levels were elevated after tilorone administration (20 or 50 mg/kg/day for 4 days). In vitro, tilorone-HCl showed no inhibitory effect on microsomal drug metabolism nod did it affect the cytochrome P-450 content of the microsomes. The rate of incorporation of delta-amino(3H)levulinic acid into cytochrome P-450 was not affected by tilorone-HCl. | [
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PMID:6228 | Oxisuran reduction by rabbit tissue preparations. | Oxisuran, 2-((methylsulfinyl)acetyl)pyridine is reduced to alpha-((methylsulfinyl)methyl-2-pyridinemethanol, oxisuranol, by cytoplasmic enzymes from rabbit liver, kidney, brain, intestine, and lung. The cytoplasmic enzyme from liver is dependent on NADPH as cofactor and has an optimal pH of 6.0. Enzymatic activity is also present in liver mitochondria but at a lower specific activity. The cytoplasmic extracts catalyze the formation of two oxisuranol products, presumably the diastereoisomers described by Di Carlo and associates from in vivo studies. Verification of the product as oxisuranol was accomplished by thin-layer chromatography and mass spectrometry. | Oxisuran reduction by rabbit tissue preparations. Oxisuran, 2-((methylsulfinyl)acetyl)pyridine is reduced to alpha-((methylsulfinyl)methyl-2-pyridinemethanol, oxisuranol, by cytoplasmic enzymes from rabbit liver, kidney, brain, intestine, and lung. The cytoplasmic enzyme from liver is dependent on NADPH as cofactor and has an optimal pH of 6.0. Enzymatic activity is also present in liver mitochondria but at a lower specific activity. The cytoplasmic extracts catalyze the formation of two oxisuranol products, presumably the diastereoisomers described by Di Carlo and associates from in vivo studies. Verification of the product as oxisuranol was accomplished by thin-layer chromatography and mass spectrometry. | [
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PMID:6229 | SKF 525-A inhibition, induction, and 452-nm complex formation. | After administration of SKF 525-A to rats a portion of the cytochrome P-450 in hepatic microsomes was found in the reduced form as a stable complex absorbing at 452 nm. As much as 40% of the total cytochrome P-450 was bound in the complexed form after a single administration of SKF 525-A. The addition of potassium ferricyanide (50 muM) to hepatic microsomes from SKF 525-A-treated rats destroyed the complex and made the total cytochrome P-450 available for carbon monoxide binding. At early times after administration of SKF 525-A, when the amount of complexed cytochrome P-450 was maximum, mixed-function oxidase activities (p-nitroanisole O-demethylase and norbenzphetamine 455-nm complex formation) were greatly inhibited. Later, as the amount of complexed cytochrome P-450 slowly decreased, these mixed-function oxidase activities gradually returned and reached control values in about 48 hr. Induction with daily doses of SKF 525-A for several days increased total cytochrome P-450 content up to 5-fold, which was more than induction with phenobarbital, but this was evident only after destruction of the complex with ferricyanide. The maximum increase in uncomplexed cytochrome P-450 was only 2-fold. Treatment of these microsomal suspensions with ferricyanide enhanced ethylmorphine N-demethylase, p-nitroanisole O-demethylase and norbenzphetamine 455-nm complex formation. | SKF 525-A inhibition, induction, and 452-nm complex formation. After administration of SKF 525-A to rats a portion of the cytochrome P-450 in hepatic microsomes was found in the reduced form as a stable complex absorbing at 452 nm. As much as 40% of the total cytochrome P-450 was bound in the complexed form after a single administration of SKF 525-A. The addition of potassium ferricyanide (50 muM) to hepatic microsomes from SKF 525-A-treated rats destroyed the complex and made the total cytochrome P-450 available for carbon monoxide binding. At early times after administration of SKF 525-A, when the amount of complexed cytochrome P-450 was maximum, mixed-function oxidase activities (p-nitroanisole O-demethylase and norbenzphetamine 455-nm complex formation) were greatly inhibited. Later, as the amount of complexed cytochrome P-450 slowly decreased, these mixed-function oxidase activities gradually returned and reached control values in about 48 hr. Induction with daily doses of SKF 525-A for several days increased total cytochrome P-450 content up to 5-fold, which was more than induction with phenobarbital, but this was evident only after destruction of the complex with ferricyanide. The maximum increase in uncomplexed cytochrome P-450 was only 2-fold. Treatment of these microsomal suspensions with ferricyanide enhanced ethylmorphine N-demethylase, p-nitroanisole O-demethylase and norbenzphetamine 455-nm complex formation. | [
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PMID:6230 | In vivo phenolic metabolites of N-alkylamphetamines in the rat. Evidence in favor of catechol formation. | The major in vivo metabolites of 1-phenyl-2-(n-propylamino)propane (N-n-propylamphetamine) in the rat were phenolic compounds, identified as 1-(4-hydroxyphenyl)-2-(n-propylamino)-propane (metabolite A) and 1-(4-hydroxy-3-methoxyphenyl)-2-(n-propylamino)propane (metabolite B) by gas chromatography-mass spectrometry, and by comparison with authentic synthetic samples of A and B. Metabolites A and B were formed from the substrate in 18.3% and 3.3% yields, respectively, and are excreted in the urine mainly in conjugated form. In vivo metabolism in the rat of the homolog, 1-phenyl-2-(n-butylamino)propane (N-n-butylamphetamine) resulted in the formation of two homologous metabolites in similar yields, which were tentatively identified, from their gas chromatographic and mass spectrometric behav-propane (metabolite A) and 1-(4-hydroxy-3-methoxyphenyl)-2-(n-propylamino)propane (metaboior and by comparison with metabolites A and B, as 2-(n-butylamino)-1-(4-hydroxyphenyl)propane (metabolite C) and 2-(n-butylamino)-1-(4-hydroxy-3-methoxyphenyl)propane (metabolite D). It is suggested that the methylated metabolites B and D were formed from metabolites A and C, respectively, via catecholamine intermediates. | In vivo phenolic metabolites of N-alkylamphetamines in the rat. Evidence in favor of catechol formation. The major in vivo metabolites of 1-phenyl-2-(n-propylamino)propane (N-n-propylamphetamine) in the rat were phenolic compounds, identified as 1-(4-hydroxyphenyl)-2-(n-propylamino)-propane (metabolite A) and 1-(4-hydroxy-3-methoxyphenyl)-2-(n-propylamino)propane (metabolite B) by gas chromatography-mass spectrometry, and by comparison with authentic synthetic samples of A and B. Metabolites A and B were formed from the substrate in 18.3% and 3.3% yields, respectively, and are excreted in the urine mainly in conjugated form. In vivo metabolism in the rat of the homolog, 1-phenyl-2-(n-butylamino)propane (N-n-butylamphetamine) resulted in the formation of two homologous metabolites in similar yields, which were tentatively identified, from their gas chromatographic and mass spectrometric behav-propane (metabolite A) and 1-(4-hydroxy-3-methoxyphenyl)-2-(n-propylamino)propane (metaboior and by comparison with metabolites A and B, as 2-(n-butylamino)-1-(4-hydroxyphenyl)propane (metabolite C) and 2-(n-butylamino)-1-(4-hydroxy-3-methoxyphenyl)propane (metabolite D). It is suggested that the methylated metabolites B and D were formed from metabolites A and C, respectively, via catecholamine intermediates. | [
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PMID:6227 | Decrease in the activity of the drug-metabolizing enzymes of rat liver following the administration of tilorone hydrochloride. | Tilorone hydrochloride, 2,7-bias(2-(diethylamino)ethoxy(fluoren-9-one dihydrochloride, has been studied to determine its effect on the drug-metabolizing enzymes of the liver of male Charles River CD strain rats. Single and multiple doses of tilorone-HCl, 100 mg/kg/day po, were used. Most experiments were performed 24 hr after the last dose, except for a study 5 hr after dosing, and those in which the duration of effects of tilorone hydrochloride were determined. The hexobarbital sleeping time was prolonged after both single doses and four doses of tilorone hydrochloride. The 4-dose regimen prolonged the zoxazolamine paralysis time but the single dose did not. A decrease in microsomal protein was observed after the single- and 4-dose regimens but not after 21 daily doses of tilorone-HCl. Cytochrome P-450 content of microsomes was decreased by the single doses, 100 and 250 mg/kg po, and by 4 and 21 doses of 100 mg/kg/day po. Activities of aminopyrine demethylase and hexobarbital oxidase also were decreased by the above regimens, but the activity of hexobarbital oxidase was affected more markedly. Electron micrographs of rat liver, after treatment with tilorone-HCl, 100 mg/kg/day for 21 days, revealed many membranous structures in the form of whorls. | Decrease in the activity of the drug-metabolizing enzymes of rat liver following the administration of tilorone hydrochloride. Tilorone hydrochloride, 2,7-bias(2-(diethylamino)ethoxy(fluoren-9-one dihydrochloride, has been studied to determine its effect on the drug-metabolizing enzymes of the liver of male Charles River CD strain rats. Single and multiple doses of tilorone-HCl, 100 mg/kg/day po, were used. Most experiments were performed 24 hr after the last dose, except for a study 5 hr after dosing, and those in which the duration of effects of tilorone hydrochloride were determined. The hexobarbital sleeping time was prolonged after both single doses and four doses of tilorone hydrochloride. The 4-dose regimen prolonged the zoxazolamine paralysis time but the single dose did not. A decrease in microsomal protein was observed after the single- and 4-dose regimens but not after 21 daily doses of tilorone-HCl. Cytochrome P-450 content of microsomes was decreased by the single doses, 100 and 250 mg/kg po, and by 4 and 21 doses of 100 mg/kg/day po. Activities of aminopyrine demethylase and hexobarbital oxidase also were decreased by the above regimens, but the activity of hexobarbital oxidase was affected more markedly. Electron micrographs of rat liver, after treatment with tilorone-HCl, 100 mg/kg/day for 21 days, revealed many membranous structures in the form of whorls. | [
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PMID:6231 | Biotransformation of mazindol. I. Isolation and identification of some metabolites from rat urine. | Three metabolites of tritium-labeled mazindol were isolated from rat urine by the inverse isotope-dilution technique in which the labeled metabolites were synthesized by a second, smaller group of rats. These metabolites were isolated by Amberlite XAD-2 chromatography and silica gel column and preparative thin-layer chromatography. The major metabolite (II) was shown by mass spectrometry of its trimethylsilyl derivative. NMR spectroscopy, and degradation studies to be 5-(p-chlorophenyl)-2,5-dihydro-5-hydroxy-3H-imidazol(2,1-a)isoindol-3-one. A comparison of its mass spectrum with that of an authentic sample prepared from 1-(p-chlorophenyl)-3-ethoxy-1-methoxy-1H-isoindole and glycine ethyl ester confirmed the assignment. Metabolite III was shown by its mass spectrum, NMR spectrum, degradation, and analogy with metabolite II to be 5-(p-chlorophenyl)-2,5-dihydro-2,5-dihydroxy-3H-imidazo (2,1-a)isoindol-3-one. Only a small amount of metabolite IV was isolated as an artifact, 3-(p-chlorophenyl)-2-glycyl-3-methoxy-1-isoindolinone, as shown by its mass spectrum and degradation to 2-(p-chlorobenzoy)benzoic acid. The metabolite IV is believed to be the corresponding 3-hydroxy compound. Synthesis of IV by base-catalyzed hydrolysis of metabolite II supports the structural assignment. In addition, the facile conversion of synthetic IV into the corresponding 3-methoxy derivative by acidic methanol was also observed. | Biotransformation of mazindol. I. Isolation and identification of some metabolites from rat urine. Three metabolites of tritium-labeled mazindol were isolated from rat urine by the inverse isotope-dilution technique in which the labeled metabolites were synthesized by a second, smaller group of rats. These metabolites were isolated by Amberlite XAD-2 chromatography and silica gel column and preparative thin-layer chromatography. The major metabolite (II) was shown by mass spectrometry of its trimethylsilyl derivative. NMR spectroscopy, and degradation studies to be 5-(p-chlorophenyl)-2,5-dihydro-5-hydroxy-3H-imidazol(2,1-a)isoindol-3-one. A comparison of its mass spectrum with that of an authentic sample prepared from 1-(p-chlorophenyl)-3-ethoxy-1-methoxy-1H-isoindole and glycine ethyl ester confirmed the assignment. Metabolite III was shown by its mass spectrum, NMR spectrum, degradation, and analogy with metabolite II to be 5-(p-chlorophenyl)-2,5-dihydro-2,5-dihydroxy-3H-imidazo (2,1-a)isoindol-3-one. Only a small amount of metabolite IV was isolated as an artifact, 3-(p-chlorophenyl)-2-glycyl-3-methoxy-1-isoindolinone, as shown by its mass spectrum and degradation to 2-(p-chlorobenzoy)benzoic acid. The metabolite IV is believed to be the corresponding 3-hydroxy compound. Synthesis of IV by base-catalyzed hydrolysis of metabolite II supports the structural assignment. In addition, the facile conversion of synthetic IV into the corresponding 3-methoxy derivative by acidic methanol was also observed. | [
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PMID:6232 | Disposition of bethanidine, N-benzyl-N',N''-dimethylguanidine, in the rat, dog and man. | Bethanidine is metabolized in the rat and dog to a significant degree to N-benzyl-N'-methylguanidine, N-benzylguanidine, N-hydroxybenzyl-N'-methylguanidine, N-methylguanidine, N-hydroxybenzyl-N',N''-di-methylguanidine, and benzoic acid, whereas in man the drug is not metabolized. It is readily absorbed in all three species. The elimination kinetics in man show a difference between the urinary excretion rate and the rate of decline in the blood. Whole body autoradiograms showed a high concentration of drug in rat tissues rich in adrenergic nerve terminals, but insignificant penetration, if any, of the blood-brain barrier. | Disposition of bethanidine, N-benzyl-N',N''-dimethylguanidine, in the rat, dog and man. Bethanidine is metabolized in the rat and dog to a significant degree to N-benzyl-N'-methylguanidine, N-benzylguanidine, N-hydroxybenzyl-N'-methylguanidine, N-methylguanidine, N-hydroxybenzyl-N',N''-di-methylguanidine, and benzoic acid, whereas in man the drug is not metabolized. It is readily absorbed in all three species. The elimination kinetics in man show a difference between the urinary excretion rate and the rate of decline in the blood. Whole body autoradiograms showed a high concentration of drug in rat tissues rich in adrenergic nerve terminals, but insignificant penetration, if any, of the blood-brain barrier. | [
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PMID:6233 | Disposition of (15,16-3H)naltrexone in the central nervous system of the rat. | After injection of (15,16-3H)naltrexone (10 mg/kg s.c.) in male Wistar rats, peak concentrations of drug occurred in brain and plasma within 0.5 hr. Levels of naltrexone were sustained in brain between 2 and 24 hr and were barely detectable at 48 hr. Significant amounts of metabolities were present in brain and plasma at longer time periods. The t1/2 of naltrexone in brain and plasma were approximately 8.0 and 11.4 hr. respectively. The brain/plasma ratios of naltrexone at earlier times (0.5-1 hr) were higher than those at later times. The binding of naltrexone in vitro with rat plasma proteins in concentrations of 1-10 mug/ml ranged between 41 and 59% 6beta-Naltrexol was present in very small amounts in brain but not in plasma. In addition to 7,8-dihydro-14-hydroxynormophinone and 7,8-dihydro-14-hydroxynormophine, tentative evidence was obtained for three other metabolites of naltrexone in brain. These metabolites were also present in plasma in addition to free and conjugated naltrexone and its N-dealkylated metabolites. | Disposition of (15,16-3H)naltrexone in the central nervous system of the rat. After injection of (15,16-3H)naltrexone (10 mg/kg s.c.) in male Wistar rats, peak concentrations of drug occurred in brain and plasma within 0.5 hr. Levels of naltrexone were sustained in brain between 2 and 24 hr and were barely detectable at 48 hr. Significant amounts of metabolities were present in brain and plasma at longer time periods. The t1/2 of naltrexone in brain and plasma were approximately 8.0 and 11.4 hr. respectively. The brain/plasma ratios of naltrexone at earlier times (0.5-1 hr) were higher than those at later times. The binding of naltrexone in vitro with rat plasma proteins in concentrations of 1-10 mug/ml ranged between 41 and 59% 6beta-Naltrexol was present in very small amounts in brain but not in plasma. In addition to 7,8-dihydro-14-hydroxynormophinone and 7,8-dihydro-14-hydroxynormophine, tentative evidence was obtained for three other metabolites of naltrexone in brain. These metabolites were also present in plasma in addition to free and conjugated naltrexone and its N-dealkylated metabolites. | [
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PMID:6234 | Mirex kinetics in the rhesus monkey. I. Disposition and excretion. | Three female rhesus monkeys were given 14C-Mirex (5.23 mCi/mmol) iv (two animals) or po (one animal) in a dose of about 1 mg/kg for the purpose of determining the distribution and excretion of this polycyclic perchlorinated insecticide. Blood, plasma, urine, feces, and tissue samples were analyzed for 14C content. Monkeys were autopsied 23, 106, and 388 days after receiving 14C-Mirex. Following iv administration, plasma 14C showed a rapid decrease over the first few hours from the initial high levels. In the monkey given the compound orally, 14C first appeared in the plasma at 2 hr and reached a maximum at 5 hr. Thereafter, the decline in plasma radioactivity paralleled that found in the animals dosed i.v. After 2 weeks, the rate of decline in all animals was very slow. Excretion and tissue distribution of Mirex were essentially the same whether the compound was given po or iv. Less than 0.6% of the dose was found in the urine. 14C was excreted in the feces for the duration of the experiment with a maximum cumulative excretion of 7% after 388 days. At autopsy all tissues analyzed contained 14C. The highest concentration of 14C was found in the fat (estimated to contain at least 80% of the dose), followed by adrenal, peripheral nerve, thyroid, and skin. Chemical analysis of the nature of the radioactivity in fat and feces showed that at least 95% and was present as unchanged Mirex. There was a small amount of a compound more polar than Mirex in the feces, containing less than 3% of the fecal radioactivity. | Mirex kinetics in the rhesus monkey. I. Disposition and excretion. Three female rhesus monkeys were given 14C-Mirex (5.23 mCi/mmol) iv (two animals) or po (one animal) in a dose of about 1 mg/kg for the purpose of determining the distribution and excretion of this polycyclic perchlorinated insecticide. Blood, plasma, urine, feces, and tissue samples were analyzed for 14C content. Monkeys were autopsied 23, 106, and 388 days after receiving 14C-Mirex. Following iv administration, plasma 14C showed a rapid decrease over the first few hours from the initial high levels. In the monkey given the compound orally, 14C first appeared in the plasma at 2 hr and reached a maximum at 5 hr. Thereafter, the decline in plasma radioactivity paralleled that found in the animals dosed i.v. After 2 weeks, the rate of decline in all animals was very slow. Excretion and tissue distribution of Mirex were essentially the same whether the compound was given po or iv. Less than 0.6% of the dose was found in the urine. 14C was excreted in the feces for the duration of the experiment with a maximum cumulative excretion of 7% after 388 days. At autopsy all tissues analyzed contained 14C. The highest concentration of 14C was found in the fat (estimated to contain at least 80% of the dose), followed by adrenal, peripheral nerve, thyroid, and skin. Chemical analysis of the nature of the radioactivity in fat and feces showed that at least 95% and was present as unchanged Mirex. There was a small amount of a compound more polar than Mirex in the feces, containing less than 3% of the fecal radioactivity. | [
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PMID:6235 | Mirex kinetics in the rhesus monkey. II. Pharmacokinetic model. | 14C-Mirex was given iv and po to female rhesus monkeys (Macaca mulatta) and radioactivity was measured in plasma, urine, and feces at intervals after dosing and in tissues when animals were killed. Graphical analysis of plots of the logarithm of plasma concentration vs. time was used to provide estimates of the values of the first-order rate constants required by the proposed pharmacokinetic models. A BASIC-language program, FITKIN, was used to obtain numerical solutions to the differential equations for each model and to adjust the estimates to obtain a normalized, least squares fit. Of several models postulated, a mammillary, four-compartment, open-system model, providing for the urinary excretion of Mirex from a "central" compartment and for the fecal excretion of Mirex from a "fast" tissue compartment, yielded theoretical data in agreement with observed values. This model predicted that the accumulation of Mirex into fat would be retarded by the presence of a "slow" tissue compartment so that distribution equilibrium would take about half a year. From that time to the end of a 5-year projection, little decline in the quantities of Mirex was predicted for any compartment. Sequestration in fat and a lack of metabolism were responsible for the long biological half-life of Mirex in the rhesus monkey. | Mirex kinetics in the rhesus monkey. II. Pharmacokinetic model. 14C-Mirex was given iv and po to female rhesus monkeys (Macaca mulatta) and radioactivity was measured in plasma, urine, and feces at intervals after dosing and in tissues when animals were killed. Graphical analysis of plots of the logarithm of plasma concentration vs. time was used to provide estimates of the values of the first-order rate constants required by the proposed pharmacokinetic models. A BASIC-language program, FITKIN, was used to obtain numerical solutions to the differential equations for each model and to adjust the estimates to obtain a normalized, least squares fit. Of several models postulated, a mammillary, four-compartment, open-system model, providing for the urinary excretion of Mirex from a "central" compartment and for the fecal excretion of Mirex from a "fast" tissue compartment, yielded theoretical data in agreement with observed values. This model predicted that the accumulation of Mirex into fat would be retarded by the presence of a "slow" tissue compartment so that distribution equilibrium would take about half a year. From that time to the end of a 5-year projection, little decline in the quantities of Mirex was predicted for any compartment. Sequestration in fat and a lack of metabolism were responsible for the long biological half-life of Mirex in the rhesus monkey. | [
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PMID:6240 | Medication for hyperkinetic children. | The hyperkinetic syndrome is a symptom complex of hyperactivity, short attention span, distractibility, impulsivity, learning difficulties, other behaviour problems and 'equivocal' neurological signs. However, none of these terms has ever been objectively defined and at present diagnosis is largely a matter of clinical judgement. In the management of the disorder, drugs do have a place but the decision to use medication is a complex procedure diagnostically and therapeutically calling for the highest in clinical skill and medical supervision. The most useful medication at present is the stimulant group of drugs, particularly dextroamphetamine and methylphenidate. Antipsychotic drugs are sometimes useful but carry the risk of depressing higher CNS functions such as attention and cognition. Other drugs which have been shown to be of value include tricyclic antidepressants (although their effect is less predictable and less striking than that of the stimulants) and pemoline. | Medication for hyperkinetic children. The hyperkinetic syndrome is a symptom complex of hyperactivity, short attention span, distractibility, impulsivity, learning difficulties, other behaviour problems and 'equivocal' neurological signs. However, none of these terms has ever been objectively defined and at present diagnosis is largely a matter of clinical judgement. In the management of the disorder, drugs do have a place but the decision to use medication is a complex procedure diagnostically and therapeutically calling for the highest in clinical skill and medical supervision. The most useful medication at present is the stimulant group of drugs, particularly dextroamphetamine and methylphenidate. Antipsychotic drugs are sometimes useful but carry the risk of depressing higher CNS functions such as attention and cognition. Other drugs which have been shown to be of value include tricyclic antidepressants (although their effect is less predictable and less striking than that of the stimulants) and pemoline. | [
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PMID:6242 | Some aspects of the pharmacology of beta-adrenorecptor blockers. | The pharmacodynamic properties of a beta-blocker are mainly determined by its affinity to beta1 and beta2-receptors respectively and by its intrinsic activity. It is suggested that there is no absolute organ separation of the two receptor sub-types. Instead both beta1 and beta2-receptors are involved in the mediation of the same effect. The frequency distribution ratio of beta1/beta2-receptors varied markedly among various effector responses. A non-selective and a beta1-selective blocker may have different haemodynamic effects when the levels of circulating adrenaline are high, because of their markedly different potency in inhibiting the beta2-mediated vasodilator effect of adrenaline. Data are presented which suggest the existence of a presynaptic beta1-receptor mediating a positive feedback mechanism on neuronal release of noradrenaline. | Some aspects of the pharmacology of beta-adrenorecptor blockers. The pharmacodynamic properties of a beta-blocker are mainly determined by its affinity to beta1 and beta2-receptors respectively and by its intrinsic activity. It is suggested that there is no absolute organ separation of the two receptor sub-types. Instead both beta1 and beta2-receptors are involved in the mediation of the same effect. The frequency distribution ratio of beta1/beta2-receptors varied markedly among various effector responses. A non-selective and a beta1-selective blocker may have different haemodynamic effects when the levels of circulating adrenaline are high, because of their markedly different potency in inhibiting the beta2-mediated vasodilator effect of adrenaline. Data are presented which suggest the existence of a presynaptic beta1-receptor mediating a positive feedback mechanism on neuronal release of noradrenaline. | [
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PMID:6236 | Correlation of mouse tissue distribution of arabinosylcytosine in vivo with enzymatic activities in vitro. | The distribution of arabinosylcytosine (ara-C) and its metabolites has been measured in the liver, small intestine, spleen, and kidney of mice inoculated ip 5-6 days earlier with L1210 leukemia cells. Two major metabolites were found in the tissues--the nucleotides and the deaminated inactive product, arabinosyluracil (ara-U). The decay curve of ara-C in most of these tissues was curvilinear; the ara-C half-lives estimated from the terminal phases were 8. 11, 12, and 12 hr for spleen, kidney, intestine, and liver tissues, respectively. The ara-C half-life was not correlated with the deoxycytidine deaminase activity in the tissues. However, the deaminase activity in vitro correlated well with the amount of ara-U present in vivo. Similar analyses were made for L1210 leukemic cells and ascites fluid. A high nucleotide level was found in the cells and a significant amount of nucleotides was also identifiable in the ascites fluid. The activities of deoxycytidine kinase, but not of deoxycytidine deaminase, in host tissues of mice inoculated with L1210 leukemic cells sensitive to ara-C were greater than in those of normal mice. The phosphorylating activities in vitro correlated with the amount of nucleotide present in vivo in mice bearing L1210 leukemic cells. However, the infiltration of leukemic cells containing high kinase activities into the host tissues accounted for most, if not all, of the nucleotide level in these tissues. This is further evidenced by the fact that inoculating mice with L1210 leukemic cells resistant to ara-C did not alter the kinase activity or nucleotide levels of the host tissues; these resistant cells contain negligible amounts of ara-C phosphorylating activities. | Correlation of mouse tissue distribution of arabinosylcytosine in vivo with enzymatic activities in vitro. The distribution of arabinosylcytosine (ara-C) and its metabolites has been measured in the liver, small intestine, spleen, and kidney of mice inoculated ip 5-6 days earlier with L1210 leukemia cells. Two major metabolites were found in the tissues--the nucleotides and the deaminated inactive product, arabinosyluracil (ara-U). The decay curve of ara-C in most of these tissues was curvilinear; the ara-C half-lives estimated from the terminal phases were 8. 11, 12, and 12 hr for spleen, kidney, intestine, and liver tissues, respectively. The ara-C half-life was not correlated with the deoxycytidine deaminase activity in the tissues. However, the deaminase activity in vitro correlated well with the amount of ara-U present in vivo. Similar analyses were made for L1210 leukemic cells and ascites fluid. A high nucleotide level was found in the cells and a significant amount of nucleotides was also identifiable in the ascites fluid. The activities of deoxycytidine kinase, but not of deoxycytidine deaminase, in host tissues of mice inoculated with L1210 leukemic cells sensitive to ara-C were greater than in those of normal mice. The phosphorylating activities in vitro correlated with the amount of nucleotide present in vivo in mice bearing L1210 leukemic cells. However, the infiltration of leukemic cells containing high kinase activities into the host tissues accounted for most, if not all, of the nucleotide level in these tissues. This is further evidenced by the fact that inoculating mice with L1210 leukemic cells resistant to ara-C did not alter the kinase activity or nucleotide levels of the host tissues; these resistant cells contain negligible amounts of ara-C phosphorylating activities. | [
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PMID:6243 | Clinical pharmacokinetics of beta-adrenoreceptors blockers. | beta-blockers are completely and rapidly absorbed from the gastro-intestinal tract. In their first passage through the liver they are metabolised to a varying extent - the so-called first-pass effect. For propranolol and alprenolol this degradation is partly compensated for by the formation of active metabolites, the 4-OH derivatives. The beta-blocking effect is linearly correlated with the log plasma concentration of the drugs. Although there is also a relationship between the antihypertensive effect of the drugs and their log plasma concentration, it seems to be of limited value to determine the plasma levels of the drugs in order to adjust the therapeutic dose. This is due to the great inter-individual differences of the plasma concentration-antihypertensive effect relationship. It is essential to investigate whether pharmacologically active metabolites are formed. These may not only influence the relationship between plasma concentration and therapeutic effect but may also modify the pharmacological profile of the drug. The plasma levels, and thereby the effects of the drugs, can be modified by other drugs and diseases. Thus practolol, which is mainly eliminated via the kidneys, has a longer plasma half-life in patients with renal failure. The plasma of propranolol, which is eliminated from the body by bio-transformation in the liver, is not prolonged in patients with renal failure, but its metabolites are excreted at a lower rate in such patients. Although most beta-blockers have a relatively short plasma half-life (2 to 5 hours), the drugs can be administered twice daily in clinical practice. This due to the fact that the effect declines according to zero-order kinetics while the elimination of the drug follows first-order kinetics. It is desirable that all these factors are clarified before a drug is used in clinical practice as they all will have an influence on its dose regimen. The responsibility for this must be on the drug company, which must be able to inform physicians not only about the standard dosage of the drug but also how other drugs and diseases can change the individual responses to the drug. | Clinical pharmacokinetics of beta-adrenoreceptors blockers. beta-blockers are completely and rapidly absorbed from the gastro-intestinal tract. In their first passage through the liver they are metabolised to a varying extent - the so-called first-pass effect. For propranolol and alprenolol this degradation is partly compensated for by the formation of active metabolites, the 4-OH derivatives. The beta-blocking effect is linearly correlated with the log plasma concentration of the drugs. Although there is also a relationship between the antihypertensive effect of the drugs and their log plasma concentration, it seems to be of limited value to determine the plasma levels of the drugs in order to adjust the therapeutic dose. This is due to the great inter-individual differences of the plasma concentration-antihypertensive effect relationship. It is essential to investigate whether pharmacologically active metabolites are formed. These may not only influence the relationship between plasma concentration and therapeutic effect but may also modify the pharmacological profile of the drug. The plasma levels, and thereby the effects of the drugs, can be modified by other drugs and diseases. Thus practolol, which is mainly eliminated via the kidneys, has a longer plasma half-life in patients with renal failure. The plasma of propranolol, which is eliminated from the body by bio-transformation in the liver, is not prolonged in patients with renal failure, but its metabolites are excreted at a lower rate in such patients. Although most beta-blockers have a relatively short plasma half-life (2 to 5 hours), the drugs can be administered twice daily in clinical practice. This due to the fact that the effect declines according to zero-order kinetics while the elimination of the drug follows first-order kinetics. It is desirable that all these factors are clarified before a drug is used in clinical practice as they all will have an influence on its dose regimen. The responsibility for this must be on the drug company, which must be able to inform physicians not only about the standard dosage of the drug but also how other drugs and diseases can change the individual responses to the drug. | [
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PMID:6244 | Metabolic effects of beta-adrenoreceptor blockers. | The effects of beta-blockade on glucose metabolism are complex. Some patients with impaired glucose tolerance while taking a non-selective beta-blocker, showed some improvement in glucose tolerance when therapy was changed to a beta1-blocker (metoprolol). Serum K+ values tend to rise slightly on beta-blocking therapy; small increases in serum urea and creatinine also occur. A rise in plasma triglycerides was noted in patients starting beta-blocking therapy; this effect seemed to be more marked on metoprolol than on non-selective beta-blockers. | Metabolic effects of beta-adrenoreceptor blockers. The effects of beta-blockade on glucose metabolism are complex. Some patients with impaired glucose tolerance while taking a non-selective beta-blocker, showed some improvement in glucose tolerance when therapy was changed to a beta1-blocker (metoprolol). Serum K+ values tend to rise slightly on beta-blocking therapy; small increases in serum urea and creatinine also occur. A rise in plasma triglycerides was noted in patients starting beta-blocking therapy; this effect seemed to be more marked on metoprolol than on non-selective beta-blockers. | [
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PMID:6245 | Haemodynamic effects of beta-adrenorecptor blockers in hypertension. | The haemodynamic effect pattern of beta-blockers in hypertension is discussed. The time curve of the antihypertensive effect differs from that of cardiac beta-blockade. The antihypertensive effect is characterized by a slower onset at the start of treatment and a more gradual disappearance when therapy is withdrawn. It appears that the crucial effect of beta-blockers in hypertension is a gradually developing reduction in total peripheral vascular resistance. The mechanism of this apparent vasodilator action is unknown. Various possible factors involved are mentioned. One is a reduced efficiency of transmitter release from the peripheral adrenergic neuron. Such an action may contribute to the antihypertensive effect, as judged by results of animal experiments described. | Haemodynamic effects of beta-adrenorecptor blockers in hypertension. The haemodynamic effect pattern of beta-blockers in hypertension is discussed. The time curve of the antihypertensive effect differs from that of cardiac beta-blockade. The antihypertensive effect is characterized by a slower onset at the start of treatment and a more gradual disappearance when therapy is withdrawn. It appears that the crucial effect of beta-blockers in hypertension is a gradually developing reduction in total peripheral vascular resistance. The mechanism of this apparent vasodilator action is unknown. Various possible factors involved are mentioned. One is a reduced efficiency of transmitter release from the peripheral adrenergic neuron. Such an action may contribute to the antihypertensive effect, as judged by results of animal experiments described. | [
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PMID:6246 | Effects of beta-adrenoreceptor blocking drugs on adrenergic transmission. | The peripheral actions of beta-adrenoreceptor antagonists on adrenergic transmitter mechanisms have been reviewed. In addition to receptor blockade, beta-adrenoreceptor antagonists may in high concentrations inhibit neuronal uptake of noradrenaline; inhibit monoamine oxidase; inhibit the uptake of noradrenaline into transmitter storage vesicles and inhibit the extraneuronal uptake of noradrenaline. High concentrations of beta-adrenoreceptor antagonists (threshold about 30 muM) also release noradrenaline from intraneuronal stores; however, their intrinsic sympathomimetic activity is generally attributed to their partial agonist property. Beta-adrenoreceptor antagonists possess adrenergic neurone blocking activity and quinidine-like or local anaesthetic activity. The existance of a positive feedback mechanism involving prejunctional beta-adrenoreceptors is discussed. It is suggested that bradycardia produced by beta-adrenoreceptor antagonists is due to blockade of the action of circulating catecholamines or of transmitter noradrenaline at cardiac extrajunctional beta-adrenoreceptor sites. | Effects of beta-adrenoreceptor blocking drugs on adrenergic transmission. The peripheral actions of beta-adrenoreceptor antagonists on adrenergic transmitter mechanisms have been reviewed. In addition to receptor blockade, beta-adrenoreceptor antagonists may in high concentrations inhibit neuronal uptake of noradrenaline; inhibit monoamine oxidase; inhibit the uptake of noradrenaline into transmitter storage vesicles and inhibit the extraneuronal uptake of noradrenaline. High concentrations of beta-adrenoreceptor antagonists (threshold about 30 muM) also release noradrenaline from intraneuronal stores; however, their intrinsic sympathomimetic activity is generally attributed to their partial agonist property. Beta-adrenoreceptor antagonists possess adrenergic neurone blocking activity and quinidine-like or local anaesthetic activity. The existance of a positive feedback mechanism involving prejunctional beta-adrenoreceptors is discussed. It is suggested that bradycardia produced by beta-adrenoreceptor antagonists is due to blockade of the action of circulating catecholamines or of transmitter noradrenaline at cardiac extrajunctional beta-adrenoreceptor sites. | [
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PMID:6247 | The role of renin in the antihypertensive action of beta-adrenoreceptor blocking agents. | Since the original reports suggesting that the antihypertensive action of beta-adrenoreceptor blocking drugs is related to their inhibitory action on renin release, much evidence has been put forward both to refute and support this hypothesis. Our studies of the acute and chronic effects of treatment with propranolol in hypertensive patients showed that the antihypertensive action of the drug was of later onset than the initial cardio-depressant and renin-suppressive effects and had little relationship to the pre-treatment levels of treatment-induced changes in plasma renin activity (PRA). When pindolol was substituted for propranolol in these studies PRA rose, but blood pressure control was undisturbed. Again, in animal experiments, although a range of different beta-adrenoreceptor blocking agents induced decreases in both blood pressure and PRA, the hypotensive effects of pindolol was associated with a rise in PRA. Further, PRA proved to be a poor guide to therapeutic effectiveness in the treatment of an unselected population of hypertensive patients with propranolol. It is concluded that the antihypertensive action of beta-adrenoreceptor blocking agents, as a class, is not dependent upon suppression of PRA. | The role of renin in the antihypertensive action of beta-adrenoreceptor blocking agents. Since the original reports suggesting that the antihypertensive action of beta-adrenoreceptor blocking drugs is related to their inhibitory action on renin release, much evidence has been put forward both to refute and support this hypothesis. Our studies of the acute and chronic effects of treatment with propranolol in hypertensive patients showed that the antihypertensive action of the drug was of later onset than the initial cardio-depressant and renin-suppressive effects and had little relationship to the pre-treatment levels of treatment-induced changes in plasma renin activity (PRA). When pindolol was substituted for propranolol in these studies PRA rose, but blood pressure control was undisturbed. Again, in animal experiments, although a range of different beta-adrenoreceptor blocking agents induced decreases in both blood pressure and PRA, the hypotensive effects of pindolol was associated with a rise in PRA. Further, PRA proved to be a poor guide to therapeutic effectiveness in the treatment of an unselected population of hypertensive patients with propranolol. It is concluded that the antihypertensive action of beta-adrenoreceptor blocking agents, as a class, is not dependent upon suppression of PRA. | [
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PMID:6248 | Effects of beta-adrenoreceptor blocking drugs on plasma volume. Renin and aldosterone as components of their antihypertensive action. | In young males with essential hypertension, propranolol and pindolol in small doses caused significant expansion of plasma volume (PV) after one month which did not prevent a reduction in BP. With higher doses, changes in PV were inconsistent and reductions in plasma renin activity (PRA) and 24-hour aldosterone excretion (AE) not closely related to BP changes. The effects of beta-adrenoreceptor blocking drugs on PV, PRA, and AE do not appear to be important components of their anti-hypertensive action. | Effects of beta-adrenoreceptor blocking drugs on plasma volume. Renin and aldosterone as components of their antihypertensive action. In young males with essential hypertension, propranolol and pindolol in small doses caused significant expansion of plasma volume (PV) after one month which did not prevent a reduction in BP. With higher doses, changes in PV were inconsistent and reductions in plasma renin activity (PRA) and 24-hour aldosterone excretion (AE) not closely related to BP changes. The effects of beta-adrenoreceptor blocking drugs on PV, PRA, and AE do not appear to be important components of their anti-hypertensive action. | [
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PMID:6249 | Experience with beta-adrenoreceptor blockers in hypertension. | At the Dunedin Hypertension Clinic beta-blockers are the drugs of choice for most hypertensive patients, usually in combination with diuretics (especially in older subjects) and often with other drugs in the more severe cases. All beta-blockers have an antihypertensive effect, regardless of other characteristics (e.g. cardio-selectivity, instrinsic sympathomimetic effect, or membrane activity). d-Propranolol has no significant effect on blood pressure. Beta-blockers do not prevent stress-induced (mental arithmetic) rises in blood pressure in hypertensive subjects through the level of blood pressure reached during stress tends to be lower because the base line is lower. Twice-daily dosage of beta-blockers is usually satisfactory. | Experience with beta-adrenoreceptor blockers in hypertension. At the Dunedin Hypertension Clinic beta-blockers are the drugs of choice for most hypertensive patients, usually in combination with diuretics (especially in older subjects) and often with other drugs in the more severe cases. All beta-blockers have an antihypertensive effect, regardless of other characteristics (e.g. cardio-selectivity, instrinsic sympathomimetic effect, or membrane activity). d-Propranolol has no significant effect on blood pressure. Beta-blockers do not prevent stress-induced (mental arithmetic) rises in blood pressure in hypertensive subjects through the level of blood pressure reached during stress tends to be lower because the base line is lower. Twice-daily dosage of beta-blockers is usually satisfactory. | [
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PMID:6250 | Use of beta-adrenoreceptor blockers in combination with beta-stimulators in patients with obstructive lung disease. | Lung function can be reduced not only by a non-selective beta-blocker but also by a selective beta1-receptor blocker. If both types of drug are without intrinsic sympathomimetic activity, the effect of the non-selective drug is more pronounced than that of a beta1-receptor selective drug under basal conditions. The effect of a beta2-receptor stimulating drug on the bronchi is inhibited by a non-selective drug, but much less by a selective beta1-receptor blocker. A selective beta1-receptor blocker can be used in asthmatics when it is combined with optimal anti-asthmatic therapy, while a non-selective drug is contra-indicated in patients with broncho-obstructive diseases. It is necessary to induce bronchodilatation (e.g. with a beta2-stimulator) in order to test whether or not a beta-blocker can be used in broncho-obstructive disease. | Use of beta-adrenoreceptor blockers in combination with beta-stimulators in patients with obstructive lung disease. Lung function can be reduced not only by a non-selective beta-blocker but also by a selective beta1-receptor blocker. If both types of drug are without intrinsic sympathomimetic activity, the effect of the non-selective drug is more pronounced than that of a beta1-receptor selective drug under basal conditions. The effect of a beta2-receptor stimulating drug on the bronchi is inhibited by a non-selective drug, but much less by a selective beta1-receptor blocker. A selective beta1-receptor blocker can be used in asthmatics when it is combined with optimal anti-asthmatic therapy, while a non-selective drug is contra-indicated in patients with broncho-obstructive diseases. It is necessary to induce bronchodilatation (e.g. with a beta2-stimulator) in order to test whether or not a beta-blocker can be used in broncho-obstructive disease. | [
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PMID:6251 | Effect of beta-adrenoreceptor blockers on heart rate and blood pressure in dynamic and isometric exercise. | Previous studies on the effects on heart rate and blood pressure in normals and hypertensive patients during dynamic exercise (ergometer bicycling or treadmill walking) and isometric exercise (sustained handgrip) are reviewed. In one study utilising sub-maximal bicycle exercise in hypertensives, there was a 43% increase in heart rate for a 33% increase in systolic pressure and 5% fall in diastolic pressure. Beta-adrenoreceptor blockade decreased the heart rate level by 18 to 19% for a decrease of systolic blood pressure level by 4 to 11%, whereas the diastolic pressure level was unaffected. A protocol is described utilising a blind indirect blood pressure recording machine ("Auto-Manometer") with which cuff inflation and deflation are automatic and constant, and blood pressure values stored at suitable Korotkov sound phases. The machine also records heart rate. By this method, isometric exercise at 50% of maximal voluntary contraction (sustained handgrip) has been studied in normals and hypertensives off and on different treatments. Both in normals and established hypertensives, there was about a 25% increase in systolic blood pressure during isometric exercise for about a 22% increase in diastolic blood pressure, and 26% increase in heart rate. Normotensive women had the lowest rise in blood pressure and the highest rise in heart rate. Beta-Adrenoreceptor blocking agents lowered heart rate during isometric exercise by 15 to 20% but did not affect the blood pressure level. Since resting blood pressure levels were decreased, the percentage rise in pressure was enhanced following beta-blockers. A combination of a beta-blocker, clonidine and/or a vasodilator produced a reduction in both systolic (24%) and diastolic (12%) pressure, as well as in heart rate (18%), during isometric exercise. | Effect of beta-adrenoreceptor blockers on heart rate and blood pressure in dynamic and isometric exercise. Previous studies on the effects on heart rate and blood pressure in normals and hypertensive patients during dynamic exercise (ergometer bicycling or treadmill walking) and isometric exercise (sustained handgrip) are reviewed. In one study utilising sub-maximal bicycle exercise in hypertensives, there was a 43% increase in heart rate for a 33% increase in systolic pressure and 5% fall in diastolic pressure. Beta-adrenoreceptor blockade decreased the heart rate level by 18 to 19% for a decrease of systolic blood pressure level by 4 to 11%, whereas the diastolic pressure level was unaffected. A protocol is described utilising a blind indirect blood pressure recording machine ("Auto-Manometer") with which cuff inflation and deflation are automatic and constant, and blood pressure values stored at suitable Korotkov sound phases. The machine also records heart rate. By this method, isometric exercise at 50% of maximal voluntary contraction (sustained handgrip) has been studied in normals and hypertensives off and on different treatments. Both in normals and established hypertensives, there was about a 25% increase in systolic blood pressure during isometric exercise for about a 22% increase in diastolic blood pressure, and 26% increase in heart rate. Normotensive women had the lowest rise in blood pressure and the highest rise in heart rate. Beta-Adrenoreceptor blocking agents lowered heart rate during isometric exercise by 15 to 20% but did not affect the blood pressure level. Since resting blood pressure levels were decreased, the percentage rise in pressure was enhanced following beta-blockers. A combination of a beta-blocker, clonidine and/or a vasodilator produced a reduction in both systolic (24%) and diastolic (12%) pressure, as well as in heart rate (18%), during isometric exercise. | [
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PMID:6253 | The kidney and antihypertensive therapy. | Renal disease and hypertension is a continuing challenge to the nephrologist. At present there are few effective methods of dealing with the common renal diseases such as glomerulonephritis, but fortunately there is now a wide selection of potent antihypertensive agents. Drug resistant hypertension should be a rarity in clinical practice. Malignant hypertension remains a therapeutic emergency. If a patient with hypertension has renal functional impairment it is essential to lower the blood pressure to normal. In the presence of renal failure this should be done with caution so as to avoid a further deterioration in the glomerular filtration rate. However, if the blood pressure is controlled and especially if the renal failure is a result of hypertension alone, renal function may stabilise or even improve, often dramatically. | The kidney and antihypertensive therapy. Renal disease and hypertension is a continuing challenge to the nephrologist. At present there are few effective methods of dealing with the common renal diseases such as glomerulonephritis, but fortunately there is now a wide selection of potent antihypertensive agents. Drug resistant hypertension should be a rarity in clinical practice. Malignant hypertension remains a therapeutic emergency. If a patient with hypertension has renal functional impairment it is essential to lower the blood pressure to normal. In the presence of renal failure this should be done with caution so as to avoid a further deterioration in the glomerular filtration rate. However, if the blood pressure is controlled and especially if the renal failure is a result of hypertension alone, renal function may stabilise or even improve, often dramatically. | [
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PMID:6254 | The treatment of resistant hypertension. | Resistant hypertension can be defined in terms of lack of blood pressure response to hypotensive agents, but there may be a big difference between standing and lying blood pressure levels. In general target organ damage and papilloedema improve if the standing blood pressure is controlled; however, progression can occasionally be documented when only the supine blood pressure remains uncontrolled. Resistant hypertension was a frequent phenomenon when ganglion blocking agents and hydrallazine were the only effective hypotensive agents. With the advent of the thiazides, effective control of the blood pressure became the exception rather than the rule; however, it was not until the advent of adrenergic blocking agents that reduction of supine blood pressures was regularly achieved. The addition of hydrallazine or prazosin to a combination of a thiazide and beta-adrenoreceptor blocking agent produces a further significant fall in the blood pressure lying and standing. This combination will control the blood pressure in most patients, but a few remain refractory to maximum doses and will require treatment with oral diazoxide or minoxidil. Both these powerful vasodilators are very effective in resistant hypertension. Oral diazoxide permits excellent control and allows a 10-fold reduction in the doses of other agents. Minoxidil usually needs to be combined with moderate doses of beta-blocking agents to reduce the marked reflex tachycardia. Only a 50% reduction in other hypotensive agents was achieved in patients treated with minoxidil and two patients proved resistant to minoxidil, but subsequently responded to oral diazoxide. | The treatment of resistant hypertension. Resistant hypertension can be defined in terms of lack of blood pressure response to hypotensive agents, but there may be a big difference between standing and lying blood pressure levels. In general target organ damage and papilloedema improve if the standing blood pressure is controlled; however, progression can occasionally be documented when only the supine blood pressure remains uncontrolled. Resistant hypertension was a frequent phenomenon when ganglion blocking agents and hydrallazine were the only effective hypotensive agents. With the advent of the thiazides, effective control of the blood pressure became the exception rather than the rule; however, it was not until the advent of adrenergic blocking agents that reduction of supine blood pressures was regularly achieved. The addition of hydrallazine or prazosin to a combination of a thiazide and beta-adrenoreceptor blocking agent produces a further significant fall in the blood pressure lying and standing. This combination will control the blood pressure in most patients, but a few remain refractory to maximum doses and will require treatment with oral diazoxide or minoxidil. Both these powerful vasodilators are very effective in resistant hypertension. Oral diazoxide permits excellent control and allows a 10-fold reduction in the doses of other agents. Minoxidil usually needs to be combined with moderate doses of beta-blocking agents to reduce the marked reflex tachycardia. Only a 50% reduction in other hypotensive agents was achieved in patients treated with minoxidil and two patients proved resistant to minoxidil, but subsequently responded to oral diazoxide. | [
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PMID:6255 | Adverse drug reactions during treatment of hypertension. | Adverse drug reactions (ADRs) can be broadly classified as either "a nuisance" or "life-threatening". Voluntary reporting systems gradually accumulate a quite impressive list of suspected ADRs with antihypertensive drugs as their use becomes widespread. Such data gives no clue to true or relative incidence. The absolute and comparative incidence of ADRs can only be determined fairly by a system of unbiased general data collection of ADRs from which the data for antihypertensive drugs is then selected. The Boston Collaborative Drug Surveillance Program provides such a source of information. Data from the Boston Program reveals that most of the listed ADRs with antihypertensive drugs occur very infrequently, that "nuisance" ADRs occur in 10 to 29% of patients in whom they are used, and that "life-threatening" ADRs occur in less than 1%. ADRs tend to discourage patient compliance with medication aims. In selecting specific antihypertensive therapy the clinician should be mindful not only of the severity of the hypertension to be treated, but also of the nature, type, and severity of potential ADRs, the personality and likely complicance of the patient, and the need for patient education regarding drug effects, possible unwanted effects, and what measures should be taken when ADRs occur. | Adverse drug reactions during treatment of hypertension. Adverse drug reactions (ADRs) can be broadly classified as either "a nuisance" or "life-threatening". Voluntary reporting systems gradually accumulate a quite impressive list of suspected ADRs with antihypertensive drugs as their use becomes widespread. Such data gives no clue to true or relative incidence. The absolute and comparative incidence of ADRs can only be determined fairly by a system of unbiased general data collection of ADRs from which the data for antihypertensive drugs is then selected. The Boston Collaborative Drug Surveillance Program provides such a source of information. Data from the Boston Program reveals that most of the listed ADRs with antihypertensive drugs occur very infrequently, that "nuisance" ADRs occur in 10 to 29% of patients in whom they are used, and that "life-threatening" ADRs occur in less than 1%. ADRs tend to discourage patient compliance with medication aims. In selecting specific antihypertensive therapy the clinician should be mindful not only of the severity of the hypertension to be treated, but also of the nature, type, and severity of potential ADRs, the personality and likely complicance of the patient, and the need for patient education regarding drug effects, possible unwanted effects, and what measures should be taken when ADRs occur. | [
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PMID:6257 | [Substituted benzamides]. | The comparison of the therapeutic effects of three molecules belonging to the substituted benzamide family allows the following observations: --the three products are generally well tolerated by the organism; --at sufficient doses they act as a major tranquilizers: -sulpiride is chiefly a disinhibitor but also has antipsychotic properties; -sultopride is at first somewhat sedative, especially when given parenterally, then antipsychotic, and little by little desinhibiting; -GRI 16-65 is "soothing", "euphoriant", "sociabilizing", as well as antipsychotic. Effect of reintegration in reality seems to constitute a common characteristic of these three products. | [Substituted benzamides]. The comparison of the therapeutic effects of three molecules belonging to the substituted benzamide family allows the following observations: --the three products are generally well tolerated by the organism; --at sufficient doses they act as a major tranquilizers: -sulpiride is chiefly a disinhibitor but also has antipsychotic properties; -sultopride is at first somewhat sedative, especially when given parenterally, then antipsychotic, and little by little desinhibiting; -GRI 16-65 is "soothing", "euphoriant", "sociabilizing", as well as antipsychotic. Effect of reintegration in reality seems to constitute a common characteristic of these three products. | [
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PMID:6258 | [Study of free and total tryptophan in the plasma. It value in psychiatry]. | The dosage of the whole tryptophan and of the free tryptophan was conducted in 16 normal subjects to establish reference values and in 12 schizophrenic subjects among whom 7 were under treatment and 5 were not. The method of dosage is made by spectrofluorimetry by increasing the native fluorescence of tryptophan. The results give mean values for the free tryptophan and for the ratio of the free tryptophan to the whole tryptophan values that are higher in the schizophrenics than in the normal subjects used as reference, while the whole tryptophan seems to be little modified ; this increase is more noticeable in the schizophrenics under treatment. The limited number of the cases studied does not enable us yet to establish correlations between the increase of the free tryptophan found in some cases and the nature of the schizophrenia, its age and its evolutivity or even the clinical response to the treatment. However, some figures for the free tryptophan being very much higher than the mean value in some schizophrenics, suggest ways of research for understanding the pathogenisis of schizophrenia and the mechanisms of the therapeutic action of the psychotropic drugs. | [Study of free and total tryptophan in the plasma. It value in psychiatry]. The dosage of the whole tryptophan and of the free tryptophan was conducted in 16 normal subjects to establish reference values and in 12 schizophrenic subjects among whom 7 were under treatment and 5 were not. The method of dosage is made by spectrofluorimetry by increasing the native fluorescence of tryptophan. The results give mean values for the free tryptophan and for the ratio of the free tryptophan to the whole tryptophan values that are higher in the schizophrenics than in the normal subjects used as reference, while the whole tryptophan seems to be little modified ; this increase is more noticeable in the schizophrenics under treatment. The limited number of the cases studied does not enable us yet to establish correlations between the increase of the free tryptophan found in some cases and the nature of the schizophrenia, its age and its evolutivity or even the clinical response to the treatment. However, some figures for the free tryptophan being very much higher than the mean value in some schizophrenics, suggest ways of research for understanding the pathogenisis of schizophrenia and the mechanisms of the therapeutic action of the psychotropic drugs. | [
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PMID:6259 | Effect of ergoline derivative VUFB-6638 on the adenohypophysial prolactin concentration in rats. | The compound VUFB-6638 (N-/D-6-methyl-8-isoergolin-I-yl/N'-N'-diethylurea hydrogen maleinate) was administered for four consecutive days to lactating rats in daily oral doses of 0.1, 1.0 and 2.0 mg/kg. The adenohypophysial prolactin concentration decreased by 34% to 68%, respectively. Moreover, this compound reduced or even completely suppressed the lactation. In view of the assumed relations between prolactin and breast carcinoma, a potential use of the drug is noted. | Effect of ergoline derivative VUFB-6638 on the adenohypophysial prolactin concentration in rats. The compound VUFB-6638 (N-/D-6-methyl-8-isoergolin-I-yl/N'-N'-diethylurea hydrogen maleinate) was administered for four consecutive days to lactating rats in daily oral doses of 0.1, 1.0 and 2.0 mg/kg. The adenohypophysial prolactin concentration decreased by 34% to 68%, respectively. Moreover, this compound reduced or even completely suppressed the lactation. In view of the assumed relations between prolactin and breast carcinoma, a potential use of the drug is noted. | [
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PMID:6260 | Changes in (3H)leucine incorporation into pineal proteins following estradiol or testosterone administration: involvement of the sympathetic superior cervical ganglion. | Pineal denervation by superior cervical ganglionectomy (Gx) decreased high affinity binding of estradiol (E2) to the pineal cytosol of female rats and of testosterone to the cytosol of male rats by 40 and 26% and by 75 and 80%, 5 and 14 days after sugery; hormone binding remained unchanged up to 24 h after surgery. Binding to the nuclear fraction decreased sigificantly by 2 weeks after incorporation of (3H) leucine into pineal proteins in Gx. A single injection of E2 (mug) to testosterone propionate (TP) (500 mug) failed to increase the Gx rats when injected 1 or 5 days after surgery. Significant increases were observed in sham-operated controls or in rats subjected to bilateral decentralization of ganglia; however on the 5th day an impairment was observed in hormone ability to enhance [3H]leucine incorporation in decentralized rats. The administration of isoproterenol 19 and 3 h before sacrifice replenished pineal-binding sites for E2 and testosterone in Gx rats, but failed to restore the responsiveness of denervated pineals to hormone administration. Moreover, E2 or TP treatment blocked the increase in labeled amino acid incorporation into proteins brought about by isoproterenol per se. The administration of propranolol 2 and 7 h after hormone injection decreased the ability of E2 and TP to enhance [3H]leucine incorporation by 55 and 41%, respectively. Tyrosine hydroxylase activity of the superior cervical ganglia decreased by 36 and 41% 6 h after E2 or TP administration, and by 43 and 47% after 3 daily injections of the hormones, whereas pineal tyrosine hydroxylase remained unchanged. Hormone treatment for 3 days increased the in vitro uptake of norepinephrine by the ganglia but did not affect uptake in the pineal gland. These data indicate that the integrity of neurons of the superior cervical ganglia is an absolute requirement for E2 and testosterone to enhance [3H]leucine incorporation into pineal proteins in rats. | Changes in (3H)leucine incorporation into pineal proteins following estradiol or testosterone administration: involvement of the sympathetic superior cervical ganglion. Pineal denervation by superior cervical ganglionectomy (Gx) decreased high affinity binding of estradiol (E2) to the pineal cytosol of female rats and of testosterone to the cytosol of male rats by 40 and 26% and by 75 and 80%, 5 and 14 days after sugery; hormone binding remained unchanged up to 24 h after surgery. Binding to the nuclear fraction decreased sigificantly by 2 weeks after incorporation of (3H) leucine into pineal proteins in Gx. A single injection of E2 (mug) to testosterone propionate (TP) (500 mug) failed to increase the Gx rats when injected 1 or 5 days after surgery. Significant increases were observed in sham-operated controls or in rats subjected to bilateral decentralization of ganglia; however on the 5th day an impairment was observed in hormone ability to enhance [3H]leucine incorporation in decentralized rats. The administration of isoproterenol 19 and 3 h before sacrifice replenished pineal-binding sites for E2 and testosterone in Gx rats, but failed to restore the responsiveness of denervated pineals to hormone administration. Moreover, E2 or TP treatment blocked the increase in labeled amino acid incorporation into proteins brought about by isoproterenol per se. The administration of propranolol 2 and 7 h after hormone injection decreased the ability of E2 and TP to enhance [3H]leucine incorporation by 55 and 41%, respectively. Tyrosine hydroxylase activity of the superior cervical ganglia decreased by 36 and 41% 6 h after E2 or TP administration, and by 43 and 47% after 3 daily injections of the hormones, whereas pineal tyrosine hydroxylase remained unchanged. Hormone treatment for 3 days increased the in vitro uptake of norepinephrine by the ganglia but did not affect uptake in the pineal gland. These data indicate that the integrity of neurons of the superior cervical ganglia is an absolute requirement for E2 and testosterone to enhance [3H]leucine incorporation into pineal proteins in rats. | [
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PMID:6261 | The effect of bilateral lesions of the ventral noradrenergic bundle on endocrine-induced changes of tyrosine hydroxylase in the rat median eminence. | With the microdissection method of Palkovits, individual hypothalamic nuclei were removed from the brains of adult male rats, and the tyrosine hydroxylase (TH) activity of each nucleus was determined 7 days after gonadectomy or thyroidectomy. Following gonadectomy, TH activity increased significantly in the median eminence with no change in the periventricular (NPV), arcuate (NARC), and dorsomedial nuclei (NDM), or medial forebrain bundle (MF). Following thyroidectomy, TH activity increased significantly in all 5 hypothalamic nuclei examined. Placement of bilateral lesions in the ventral norepinephrine bundles resulted in a greater than an 85% fall in the dopamine-beta-hydroxylase activity of the median eminence, arcuate nucleus, and ventromedial nucleus, but had no effect on tyrosine hydroxylase activity measured in those same areas. Furthermore, placement of such lesions had no effect on the endocrine-induced increases of TH activity found in the median eminence following gonadectomy and thyroidectomy, but did prevent the increase of TH activity found in the NPV, NDM, and MFB following thyroidectomy. Three conclusions appear to be justified: (a) noradrenergic axons which innervate the median eminence, arcuate, and ventromedial nuclei course in the ventral norepinephrine bundles; (b) the TH content of noradrenergic neurons in the median eminence, arcuate nucleus, and ventromedial nuclei is quite small; and (c) the majority, if not all, of the endocrine-responsive catecholaminergic neurons in the median eminence are dopaminergic. | The effect of bilateral lesions of the ventral noradrenergic bundle on endocrine-induced changes of tyrosine hydroxylase in the rat median eminence. With the microdissection method of Palkovits, individual hypothalamic nuclei were removed from the brains of adult male rats, and the tyrosine hydroxylase (TH) activity of each nucleus was determined 7 days after gonadectomy or thyroidectomy. Following gonadectomy, TH activity increased significantly in the median eminence with no change in the periventricular (NPV), arcuate (NARC), and dorsomedial nuclei (NDM), or medial forebrain bundle (MF). Following thyroidectomy, TH activity increased significantly in all 5 hypothalamic nuclei examined. Placement of bilateral lesions in the ventral norepinephrine bundles resulted in a greater than an 85% fall in the dopamine-beta-hydroxylase activity of the median eminence, arcuate nucleus, and ventromedial nucleus, but had no effect on tyrosine hydroxylase activity measured in those same areas. Furthermore, placement of such lesions had no effect on the endocrine-induced increases of TH activity found in the median eminence following gonadectomy and thyroidectomy, but did prevent the increase of TH activity found in the NPV, NDM, and MFB following thyroidectomy. Three conclusions appear to be justified: (a) noradrenergic axons which innervate the median eminence, arcuate, and ventromedial nuclei course in the ventral norepinephrine bundles; (b) the TH content of noradrenergic neurons in the median eminence, arcuate nucleus, and ventromedial nuclei is quite small; and (c) the majority, if not all, of the endocrine-responsive catecholaminergic neurons in the median eminence are dopaminergic. | [
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PMID:6262 | Steroid metabolism in the gonads of a patient with testicular feminization. I. Metabolism of cholesterol, pregnenolone, progesterone and dehydroepiandrosterone in vitro. | The metabolism of cholesterol-4-14C, pregnenolone-4-14C, progesterone-4-14C and dehydroepiandrosterone-4-14C in a right abdominal and a left inguinal testis of a patient with testicular feminization was studied by a double isotope method in vitro. One of the main metabolites found in all incubations was testosterone. In incubations with cholesterol the delta4-pathway seems to be preferred. The rate of conversion of cholesterol to testosterone in the right testis was 1,27% and in the left testis 4,90%. Pregnenolone was converted to testosterone in the right testis at a rate of 6,61% and in the left testis at a rate of 3,23%. The conversion for testosterone using progesterone as precursor was 13,19% and 3,88% respectively and 11,97% of dehydroepiandrosterone was converted to testosterone in the right testis and 12,32% in the left testis. These findings are compared with data from the literature and conclusions are drawn. | Steroid metabolism in the gonads of a patient with testicular feminization. I. Metabolism of cholesterol, pregnenolone, progesterone and dehydroepiandrosterone in vitro. The metabolism of cholesterol-4-14C, pregnenolone-4-14C, progesterone-4-14C and dehydroepiandrosterone-4-14C in a right abdominal and a left inguinal testis of a patient with testicular feminization was studied by a double isotope method in vitro. One of the main metabolites found in all incubations was testosterone. In incubations with cholesterol the delta4-pathway seems to be preferred. The rate of conversion of cholesterol to testosterone in the right testis was 1,27% and in the left testis 4,90%. Pregnenolone was converted to testosterone in the right testis at a rate of 6,61% and in the left testis at a rate of 3,23%. The conversion for testosterone using progesterone as precursor was 13,19% and 3,88% respectively and 11,97% of dehydroepiandrosterone was converted to testosterone in the right testis and 12,32% in the left testis. These findings are compared with data from the literature and conclusions are drawn. | [
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PMID:6265 | Photochemical and biological degradation of water-soluble FWAs. | A study was made of the photochemical and biological degradation of two water-soluble fluorescent whitening agents (FWAs): the disodium 4,4'-bis(2-sulfostyryl)-biphenyl (1) and the disodium 4,4-bis ([4-anilino-6-(N-methyl-N-2-hydroxyethyl)amino 1,3,5-triazin-2-yl]amino)stilbene-2,2'-disulfonate (2). Each represents an important class of detergent fluorescent whitening agents. The photochemical degradation of (1) was studied by irradiating diluted aqueous solutions of this compound with a low intensity high pressure mercury vapor lamp. From the intermediate, as well as the ultimate photodegradation products isolated, it can be infered that photodegradation of (1) followed the proposed scheme. The biologica degradation of (1) and (2) by activated sludge under aerobic conditions was studied using equipment similar to that proposed by the OECD for determining the biodegradation of anionic synthetic surface active agents. Under the conditons applied, both FWAs were slowly biodegraded, within 30 days, whereas the photodegradation products of (1) were completely biodegraded within 14 days. | Photochemical and biological degradation of water-soluble FWAs. A study was made of the photochemical and biological degradation of two water-soluble fluorescent whitening agents (FWAs): the disodium 4,4'-bis(2-sulfostyryl)-biphenyl (1) and the disodium 4,4-bis ([4-anilino-6-(N-methyl-N-2-hydroxyethyl)amino 1,3,5-triazin-2-yl]amino)stilbene-2,2'-disulfonate (2). Each represents an important class of detergent fluorescent whitening agents. The photochemical degradation of (1) was studied by irradiating diluted aqueous solutions of this compound with a low intensity high pressure mercury vapor lamp. From the intermediate, as well as the ultimate photodegradation products isolated, it can be infered that photodegradation of (1) followed the proposed scheme. The biologica degradation of (1) and (2) by activated sludge under aerobic conditions was studied using equipment similar to that proposed by the OECD for determining the biodegradation of anionic synthetic surface active agents. Under the conditons applied, both FWAs were slowly biodegraded, within 30 days, whereas the photodegradation products of (1) were completely biodegraded within 14 days. | [
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PMID:6267 | Characterization of cardiac sarcoplasmic reticulum ATP-ADP phosphate exchange and phosphorylation of the calcium transport adenosine triphosphatase. | 1. The terminal phosphate of (gamma-32P)ATP is rapidly incorporated into cardiac sarcoplasmic reticulum membranes (0.7--1.3 mumol/g protein) in the presence of calcium and magnesium. Cardiac sarcoplasmic reticulum membranes catalize an ATP-ADP phosphate exchange in the presence of calcium and magnesium. 2. Half-maximum activation of the phosphoprotein formation and ATP-ADP phosphate exchange is reached at an ionized calcium concentration of about 0.3 muM. The Hill coefficients are 1.3. 3. Transphosphorylation and ATP-ADP phosphate exchange require magnesium and are maximally activated at magnesium concentrations close to or equal to the ATP concentration. 4. The phosphoprotein level is reduced to about 45% at an ADP/ATP ratio of 0.1. The rate of calcium-dependent ATP splitting declines, whilst the rate of the calcium-dependent ATP-ADP phosphate exchange increases when the ADP/ATP ratio is varied from 0.1 to 1. The sum of both, the rate of ATP splitting and the rate of ADP-ATP phosphate exchange remains constant. 5. Phosphoprotein formation and ATP-ADP phosphate exchange are not affected by azide, dinitrophenol, dicyclohexyl carbodiimide and oubain, whilst both activities are reduced by blockade of -SH groups localized on the outside of the sarcoplasmic reticulum membrane. 6. The isolated phosphoprotein is acid stable. The trichloroacetic acid denatured 32P-labelled membrane complex is dephosphorylated by hydroxylamine, which might indicate that the phosphorylated protein is an acyl-phosphate. 7. Polyacrylamide gel elctrophoresis (performed with phenol/acetic acid/water) of phosphorylated sarcoplasmic reticulum fractions demonstrates that the 32P-incorporation occurs into a protein of about 100000 molecular weight. 8. It is suggested that the phosphoprotein represents a phosphorylated intermediate of the calcium-dependent ATPase which formation occurs as an early step in the reaction sequence of calcium translocation by cardiac sarcoplasmic reticulum similar as in skeletal muscle. | Characterization of cardiac sarcoplasmic reticulum ATP-ADP phosphate exchange and phosphorylation of the calcium transport adenosine triphosphatase. 1. The terminal phosphate of (gamma-32P)ATP is rapidly incorporated into cardiac sarcoplasmic reticulum membranes (0.7--1.3 mumol/g protein) in the presence of calcium and magnesium. Cardiac sarcoplasmic reticulum membranes catalize an ATP-ADP phosphate exchange in the presence of calcium and magnesium. 2. Half-maximum activation of the phosphoprotein formation and ATP-ADP phosphate exchange is reached at an ionized calcium concentration of about 0.3 muM. The Hill coefficients are 1.3. 3. Transphosphorylation and ATP-ADP phosphate exchange require magnesium and are maximally activated at magnesium concentrations close to or equal to the ATP concentration. 4. The phosphoprotein level is reduced to about 45% at an ADP/ATP ratio of 0.1. The rate of calcium-dependent ATP splitting declines, whilst the rate of the calcium-dependent ATP-ADP phosphate exchange increases when the ADP/ATP ratio is varied from 0.1 to 1. The sum of both, the rate of ATP splitting and the rate of ADP-ATP phosphate exchange remains constant. 5. Phosphoprotein formation and ATP-ADP phosphate exchange are not affected by azide, dinitrophenol, dicyclohexyl carbodiimide and oubain, whilst both activities are reduced by blockade of -SH groups localized on the outside of the sarcoplasmic reticulum membrane. 6. The isolated phosphoprotein is acid stable. The trichloroacetic acid denatured 32P-labelled membrane complex is dephosphorylated by hydroxylamine, which might indicate that the phosphorylated protein is an acyl-phosphate. 7. Polyacrylamide gel elctrophoresis (performed with phenol/acetic acid/water) of phosphorylated sarcoplasmic reticulum fractions demonstrates that the 32P-incorporation occurs into a protein of about 100000 molecular weight. 8. It is suggested that the phosphoprotein represents a phosphorylated intermediate of the calcium-dependent ATPase which formation occurs as an early step in the reaction sequence of calcium translocation by cardiac sarcoplasmic reticulum similar as in skeletal muscle. | [
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PMID:6268 | Uptake of bromosulfophthalein by isolated liver cells. | Uptake of the hepatodiagnostic dye bromosulfophthalein into isolated hepatocytes was studied with special regard to the kinetics of transport. The following results were obtained. 1. The uptake of bromosulfophthalein follows Michaelis-Menten kinetics only at low substrate concentrations with an apparent Km=7 +/- 2 muM and V=2.6 +/- 1.7 nmol X mg protein -1 X min -1. At higher bromosulfophthalein concentrations a second mechanism of uptake is observed as indicated by the deviation from linearity in the Lineweaver-Burk plot. 2. The activation energy of uptake was found to be 11 kcal/mol at 10 muM bromosulfophtalein. 3. Uptake is independent of metabolic energy and of the Na+ gradient across the membrane. 4. Taurocholate does not inhibit uptake while indocyanine green inhibits competitively at low bromosulfophthalein concentrations and activates uptake at high bromosulfophthalein concentrations (greater than 20 muM). 5. Amino acid reagents, such as dinitrofluorobenzene, mersalyl, N-ethylmaleimide, and dithionitrobenzene, which modify specific functional groups, did not affect uptake at a concentration of 100 muM. 6. No pH optimum for bromosulfophthalein uptake was observed in the physiological pH range. 7. Adsorption of bromosulfophthalein to the liver cell membrane has two distinguishable sites with affinities K1=5.7 X 10(-6) M and K2=7 X 10(-5) M and binding capacities n1=1.2 nmol/mg protein and n2=7 nmol/mg protein. Adsorption is inhibited by indocyanine green. The results do not indicate the mediation of bromosulfophthalein uptake by a carrier protein and are consistent with the hypothesis that bromosulfophthalein is bound in an energy-consuming process to a translocating site, possibly in the undissociated form or as ion pair. The consecutive transfer across the membrane appears to require little additional energy. | Uptake of bromosulfophthalein by isolated liver cells. Uptake of the hepatodiagnostic dye bromosulfophthalein into isolated hepatocytes was studied with special regard to the kinetics of transport. The following results were obtained. 1. The uptake of bromosulfophthalein follows Michaelis-Menten kinetics only at low substrate concentrations with an apparent Km=7 +/- 2 muM and V=2.6 +/- 1.7 nmol X mg protein -1 X min -1. At higher bromosulfophthalein concentrations a second mechanism of uptake is observed as indicated by the deviation from linearity in the Lineweaver-Burk plot. 2. The activation energy of uptake was found to be 11 kcal/mol at 10 muM bromosulfophtalein. 3. Uptake is independent of metabolic energy and of the Na+ gradient across the membrane. 4. Taurocholate does not inhibit uptake while indocyanine green inhibits competitively at low bromosulfophthalein concentrations and activates uptake at high bromosulfophthalein concentrations (greater than 20 muM). 5. Amino acid reagents, such as dinitrofluorobenzene, mersalyl, N-ethylmaleimide, and dithionitrobenzene, which modify specific functional groups, did not affect uptake at a concentration of 100 muM. 6. No pH optimum for bromosulfophthalein uptake was observed in the physiological pH range. 7. Adsorption of bromosulfophthalein to the liver cell membrane has two distinguishable sites with affinities K1=5.7 X 10(-6) M and K2=7 X 10(-5) M and binding capacities n1=1.2 nmol/mg protein and n2=7 nmol/mg protein. Adsorption is inhibited by indocyanine green. The results do not indicate the mediation of bromosulfophthalein uptake by a carrier protein and are consistent with the hypothesis that bromosulfophthalein is bound in an energy-consuming process to a translocating site, possibly in the undissociated form or as ion pair. The consecutive transfer across the membrane appears to require little additional energy. | [
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PMID:6269 | Conformation of Escherichia coli glutamic acid tRNA II as studied by hydrogen-tritium exchange catalyzed by cysteine methyl ester. | Incubation of CMP in 2H2O with 0.5M cysteine methyl ester at p2H 5 and 37 degrees C for 24 h resulted in 43% exchange of 5-H to 5-2H. No deamination of the cytosine nucleus was noted during this treatment. Native and denatured DNA samples from calf thymus were treated in 3H2O with cysteine methyl ester at pH 5 and 37 degrees C for 24 h and incorporation of tritium into each DNA base was determined by enzymic digestion of the treated DNA. The order of the specific radioactivity found was cytosine greater than guanine greater than adenine greater than thymine for denatured DNA and guanine greater than adenine approximately cytosine greater than thymine for native DNA. The ratio of radioactivity for denatured/native was 11.6 for cytosine, 1.5 for guanine, 1.8 for adenine and 1.1 for thymine. Hence the incorporation in cytosine under the reaction conditions is preferential for single-stranded, nonhelical regions of DNA. Escherichia coli glutamic acid tRNA II was treated in 3H2O with 1.24 M cysteine methyl ester at pH 5 and 37 degrees C. The 24-h-treated tRNA was digested with ribonuclease T1 and the fragments were fractionated. Each fragment was then digested with ribonuclease T2 into mononucleotides and the radioactivity distribution among the bases was determined. The average radioactivity found for each of the bases of the four major nucleotides was cytosine greater than guanine approximately adenine greater than uracil. The radioactivity in cytosine varied greatly among the RNase T1 fragments, the ratio of the highest to the lowest radioactivity being 18.7. The corresponding value for guanine was 11.1, for adenine 4.73 and for uracil 3.64. Based on the data obtained, it was deduced that in this tRNA the anticodon loop, the dihydrouridine loop and the extra loop were "exposed" under the conditions employed for the labeling. The 5'-terminal cytosine of the anticodon loop was in a "non-exposed" state, a situation similar to that previously reported for E. coli tyrosine tRNA [Cashmore, A. R., Brown, D. M. & Smith, J. D. (1971) J. Mol. Biol. 59, 359-373] and for E. coli formylmethionine tRNA [Goddard J. P.+Schulman L. H. (1972) J. Biol. Chem. 247, 3864-3867]. Both cytosine 48, located at the 3'-terminal of the extra loop, and guanine 15 in the dihydrouridine loop were in an "emposed" state. This finding does not agree with a tRNA model in which this pair of cytosine and guanine, commonly found in tRNA sequences, forms hydrogen bondings. Positions 30--32, 61--64 and 71, which are located in the stems, were found to be strongly "buried". | Conformation of Escherichia coli glutamic acid tRNA II as studied by hydrogen-tritium exchange catalyzed by cysteine methyl ester. Incubation of CMP in 2H2O with 0.5M cysteine methyl ester at p2H 5 and 37 degrees C for 24 h resulted in 43% exchange of 5-H to 5-2H. No deamination of the cytosine nucleus was noted during this treatment. Native and denatured DNA samples from calf thymus were treated in 3H2O with cysteine methyl ester at pH 5 and 37 degrees C for 24 h and incorporation of tritium into each DNA base was determined by enzymic digestion of the treated DNA. The order of the specific radioactivity found was cytosine greater than guanine greater than adenine greater than thymine for denatured DNA and guanine greater than adenine approximately cytosine greater than thymine for native DNA. The ratio of radioactivity for denatured/native was 11.6 for cytosine, 1.5 for guanine, 1.8 for adenine and 1.1 for thymine. Hence the incorporation in cytosine under the reaction conditions is preferential for single-stranded, nonhelical regions of DNA. Escherichia coli glutamic acid tRNA II was treated in 3H2O with 1.24 M cysteine methyl ester at pH 5 and 37 degrees C. The 24-h-treated tRNA was digested with ribonuclease T1 and the fragments were fractionated. Each fragment was then digested with ribonuclease T2 into mononucleotides and the radioactivity distribution among the bases was determined. The average radioactivity found for each of the bases of the four major nucleotides was cytosine greater than guanine approximately adenine greater than uracil. The radioactivity in cytosine varied greatly among the RNase T1 fragments, the ratio of the highest to the lowest radioactivity being 18.7. The corresponding value for guanine was 11.1, for adenine 4.73 and for uracil 3.64. Based on the data obtained, it was deduced that in this tRNA the anticodon loop, the dihydrouridine loop and the extra loop were "exposed" under the conditions employed for the labeling. The 5'-terminal cytosine of the anticodon loop was in a "non-exposed" state, a situation similar to that previously reported for E. coli tyrosine tRNA [Cashmore, A. R., Brown, D. M. & Smith, J. D. (1971) J. Mol. Biol. 59, 359-373] and for E. coli formylmethionine tRNA [Goddard J. P.+Schulman L. H. (1972) J. Biol. Chem. 247, 3864-3867]. Both cytosine 48, located at the 3'-terminal of the extra loop, and guanine 15 in the dihydrouridine loop were in an "emposed" state. This finding does not agree with a tRNA model in which this pair of cytosine and guanine, commonly found in tRNA sequences, forms hydrogen bondings. Positions 30--32, 61--64 and 71, which are located in the stems, were found to be strongly "buried". | [
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PMID:6270 | Purification and properties of D-glyceraldehyde-3-phosphate dehydrogenase from an extreme thermophile, Thermus thermophilus strain HB 8. | 1. D-Glyceraldehyde-3-phosphate dehydrogenase from an extreme thermophile, T. thermophilus strain HB8, was purified and crystallized. 2. The enzyme was found to possess remarkable heat stability, being slowly inactivated at 90 degrees C. 3. Basic kinetic constants and pH profile are reported. The enzyme was activated 25-fold by 90 mM NH4Cl, and also by ethanol up to 5-fold at 30 degrees C. 4. The enzyme was found to be far more resistant to urea or sodium dodecylsulfate than the rabbit enzyme. 5. The enzyme was shown to be a tetramer of molecular weight 130000--135000. Amino acid composition analysis revealed no unusual features. Circular dichroic spectra suggested that the contents of the ordered structure of the thermophile enzyme are similar to those of the rabbit enzyme. 6. The other catalytic properties of the thermophile enzyme are discussed in comparison with those of the enzymes from other sources. | Purification and properties of D-glyceraldehyde-3-phosphate dehydrogenase from an extreme thermophile, Thermus thermophilus strain HB 8. 1. D-Glyceraldehyde-3-phosphate dehydrogenase from an extreme thermophile, T. thermophilus strain HB8, was purified and crystallized. 2. The enzyme was found to possess remarkable heat stability, being slowly inactivated at 90 degrees C. 3. Basic kinetic constants and pH profile are reported. The enzyme was activated 25-fold by 90 mM NH4Cl, and also by ethanol up to 5-fold at 30 degrees C. 4. The enzyme was found to be far more resistant to urea or sodium dodecylsulfate than the rabbit enzyme. 5. The enzyme was shown to be a tetramer of molecular weight 130000--135000. Amino acid composition analysis revealed no unusual features. Circular dichroic spectra suggested that the contents of the ordered structure of the thermophile enzyme are similar to those of the rabbit enzyme. 6. The other catalytic properties of the thermophile enzyme are discussed in comparison with those of the enzymes from other sources. | [
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PMID:6272 | Effect of pH on the transient reduction of pig-plasma benzylamine oxidase by benzylamine derivatives. | 1. The transient kinetics of reduction of the 470-nm absorption band in benzylamine oxidase by substrate at different pH values between 6 and 10 have been studied by stopped-flow techniques, and substituent effects on kinetic parameters for the reduction process have been examined using a series of ring-substituted benzylamine derivatives as the substrates. 2. Reduction of the enzyme by substrate takes place in two kinetically distinguishable steps, with the intermediate formation of an enzyme-substrate complex in which the substrate appears to be covalently bound through its amino group to the prosthetic group of the enzyme, possibly in the form of an amine-pyridoxal Schiff-base. 3. The apparent stability of the enzyme-substrate complex shows no obvious dependence on the electronic properties of the amine substrates, but is strongly pH-dependent in a way suggesting that substrate-binding involves the non-protonated amines, exclusively, and requires the presence of the acid form of an ionizing group in the enzyme with apparent pKa of 8.8. 4. Reduction of the enzymatic 470-nm chromophore and release of the aldehyde product of the catalytic process are rate-limited by the same monomolecular reaction step involving the enzyme-substrate complex. Rate constants for the rate-limiting reaction exhibit no significant dependence on pH between 6 and 10, but correlate with Hammett sigma-values for the ring-substituted benzylamine derivatives tested, yielding a phi-value of + 0.3. | Effect of pH on the transient reduction of pig-plasma benzylamine oxidase by benzylamine derivatives. 1. The transient kinetics of reduction of the 470-nm absorption band in benzylamine oxidase by substrate at different pH values between 6 and 10 have been studied by stopped-flow techniques, and substituent effects on kinetic parameters for the reduction process have been examined using a series of ring-substituted benzylamine derivatives as the substrates. 2. Reduction of the enzyme by substrate takes place in two kinetically distinguishable steps, with the intermediate formation of an enzyme-substrate complex in which the substrate appears to be covalently bound through its amino group to the prosthetic group of the enzyme, possibly in the form of an amine-pyridoxal Schiff-base. 3. The apparent stability of the enzyme-substrate complex shows no obvious dependence on the electronic properties of the amine substrates, but is strongly pH-dependent in a way suggesting that substrate-binding involves the non-protonated amines, exclusively, and requires the presence of the acid form of an ionizing group in the enzyme with apparent pKa of 8.8. 4. Reduction of the enzymatic 470-nm chromophore and release of the aldehyde product of the catalytic process are rate-limited by the same monomolecular reaction step involving the enzyme-substrate complex. Rate constants for the rate-limiting reaction exhibit no significant dependence on pH between 6 and 10, but correlate with Hammett sigma-values for the ring-substituted benzylamine derivatives tested, yielding a phi-value of + 0.3. | [
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PMID:6273 | Alcohol oxidases of Kloeckera sp. and Hansenula polymorpha. Catalytic properties and subunit structures. | 1. Alcohol oxidase (alcohol: oxygen oxidoreductase) of a thermophilic methanol-utilizing yeast, Hansenula polymorpha DL-1, was isolated in crystalline form. 2. This alcohol oxidase of H. polymorpha was more stable to heat than was the enzyme of Kloeckera sp. This difference in heat stability is compatible with the difference in growth temperatures for both yeasts. 3. The crystalline alcohol oxidases of both yeast oxidized the lower primary alcohols (C-2 to C-4) as well as methanol. The apparent Km values for the methanol of Kloeckera and H. polymorpha enzymes were 0.44 and 0.23 mM, respectively. The enzymes could also oxidize formaldehyde to formate, and were inactivated by relatively low concentrations of hydrogen peroxide. 4. The molecular weight for both enzymes was calculated to be about 670000. Each enzyme is composed of eight identical subunits (molecular weight 83000) and contains eight moles of FAD as the prosthetic group. The NH2-terminal and COOH-terminal amino acids of H. polymorpha enzyme were identified as alanine and phenylalanine, respectively. The octameric subunits model of each enzyme was confirmed by electron micrographs, which showed an octad aggregate, composed of two tetragons face to face. | Alcohol oxidases of Kloeckera sp. and Hansenula polymorpha. Catalytic properties and subunit structures. 1. Alcohol oxidase (alcohol: oxygen oxidoreductase) of a thermophilic methanol-utilizing yeast, Hansenula polymorpha DL-1, was isolated in crystalline form. 2. This alcohol oxidase of H. polymorpha was more stable to heat than was the enzyme of Kloeckera sp. This difference in heat stability is compatible with the difference in growth temperatures for both yeasts. 3. The crystalline alcohol oxidases of both yeast oxidized the lower primary alcohols (C-2 to C-4) as well as methanol. The apparent Km values for the methanol of Kloeckera and H. polymorpha enzymes were 0.44 and 0.23 mM, respectively. The enzymes could also oxidize formaldehyde to formate, and were inactivated by relatively low concentrations of hydrogen peroxide. 4. The molecular weight for both enzymes was calculated to be about 670000. Each enzyme is composed of eight identical subunits (molecular weight 83000) and contains eight moles of FAD as the prosthetic group. The NH2-terminal and COOH-terminal amino acids of H. polymorpha enzyme were identified as alanine and phenylalanine, respectively. The octameric subunits model of each enzyme was confirmed by electron micrographs, which showed an octad aggregate, composed of two tetragons face to face. | [
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PMID:6274 | Removal of Mn from spinach chloroplasts by sodium cyanide and the binding of Mn2+ to Mn-depleted chloroplasts. | Manganese and copper were released from spinach chloroplasts by NaCN-treatment, though iron was not affected. The Hill reaction activity was also inhibited by this treatment, but was partially recovered by the addition of either Mn2+ or Cu2+, but not of Fe3+. The interaction of Mn2+ with manganese-depleted chloroplasts by NaCN-treatment was studied using 54Mn2+. A Scatchard plot shows the high and low affinity binding sites of Mn2+ on NaCN-treated chloroplast membrane; high affinity binding being specific for NaCN-treated chloroplast with a binding constant, KH, of 1.9 X 10(5) M-1, and a maximum binding number, NH, of 0.0016 g-atom per mole of chlorophyll. The low binding site was also found on untreated chloroplasts; its binding constant, KL, being 1.2 X 10(4) M-1, and its maximum binding number, NL, of 0.0112 g-atom per mole oc chlorophyll at pH 8.2 NH was proportional to the degree of the removal of Mn by NaCN-treatment and was constant at pH 4--9. NL markedly increased at a high pH with a midpoint of pH 7.9 indicating the exposure of a new, similar binding site. Light illumination partially inhibited the binding of Mn2+. Within 1 min in the dark the binding reaction reached equilibrium in the absence of pyrophosphate, however, 20 min were required to transform into pyrophosphate-resistant form. The pH dependence of the binding of Mn2+ with pKa 7.2 and the ineffectiveness of p-chloromercuribenzoate suggest the possible ligand of Mn2+ is the imidazole nitrogen of the histidine residue. | Removal of Mn from spinach chloroplasts by sodium cyanide and the binding of Mn2+ to Mn-depleted chloroplasts. Manganese and copper were released from spinach chloroplasts by NaCN-treatment, though iron was not affected. The Hill reaction activity was also inhibited by this treatment, but was partially recovered by the addition of either Mn2+ or Cu2+, but not of Fe3+. The interaction of Mn2+ with manganese-depleted chloroplasts by NaCN-treatment was studied using 54Mn2+. A Scatchard plot shows the high and low affinity binding sites of Mn2+ on NaCN-treated chloroplast membrane; high affinity binding being specific for NaCN-treated chloroplast with a binding constant, KH, of 1.9 X 10(5) M-1, and a maximum binding number, NH, of 0.0016 g-atom per mole of chlorophyll. The low binding site was also found on untreated chloroplasts; its binding constant, KL, being 1.2 X 10(4) M-1, and its maximum binding number, NL, of 0.0112 g-atom per mole oc chlorophyll at pH 8.2 NH was proportional to the degree of the removal of Mn by NaCN-treatment and was constant at pH 4--9. NL markedly increased at a high pH with a midpoint of pH 7.9 indicating the exposure of a new, similar binding site. Light illumination partially inhibited the binding of Mn2+. Within 1 min in the dark the binding reaction reached equilibrium in the absence of pyrophosphate, however, 20 min were required to transform into pyrophosphate-resistant form. The pH dependence of the binding of Mn2+ with pKa 7.2 and the ineffectiveness of p-chloromercuribenzoate suggest the possible ligand of Mn2+ is the imidazole nitrogen of the histidine residue. | [
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PMID:6275 | Cobalt bovine superoxide dismutase. Reactivity of the cobalt chromophore in the copper-containing and in the copper-free enzyme. | 1. The reactivity of the zinc site of bovine superoxide dismutase has been probed by observing optical and electron paramagnetic resonance changes, under several conditions, of the Co(II)-substituted protein. 2. Only in the absence of copper are the optical and electron paramagnetic resonance spectra of the cobalt chromophore appreciably affected by alkaline pH or by cyanide. With both reagents the reaction with the copper-containing protein appears to involve the water molecule bound to the copper and does not affect the magnetic coupling between copper and cobalt. 3. The reaction of cyanide with the copper-free Co(II) protein leads to a slow detachment of cobalt from the protein as pentacyanocobalt. An oxygen adduct forms in air, analogous to that described in Co(II) carbonic anhydrase (Haffner, P. H. and Coleman, J. E. (1975) J. Biol. Chem. 250, 996--1005.) 4. Acid titration modifies the Co(II) spectra in the same way in the Cu-containing and in the Cu-free protein and brings about uncoupling of the Co(II)--Cu(II) system. Protonation of histidine-61 on the zinc facing nitrogen is suggested. 5. H2O2 modifies the cobalt chromophore only in the presence of copper. Magnetic coupling between Cu(II) and Co(II) seems to be still present after H2O2 inactivation of the enzyme. | Cobalt bovine superoxide dismutase. Reactivity of the cobalt chromophore in the copper-containing and in the copper-free enzyme. 1. The reactivity of the zinc site of bovine superoxide dismutase has been probed by observing optical and electron paramagnetic resonance changes, under several conditions, of the Co(II)-substituted protein. 2. Only in the absence of copper are the optical and electron paramagnetic resonance spectra of the cobalt chromophore appreciably affected by alkaline pH or by cyanide. With both reagents the reaction with the copper-containing protein appears to involve the water molecule bound to the copper and does not affect the magnetic coupling between copper and cobalt. 3. The reaction of cyanide with the copper-free Co(II) protein leads to a slow detachment of cobalt from the protein as pentacyanocobalt. An oxygen adduct forms in air, analogous to that described in Co(II) carbonic anhydrase (Haffner, P. H. and Coleman, J. E. (1975) J. Biol. Chem. 250, 996--1005.) 4. Acid titration modifies the Co(II) spectra in the same way in the Cu-containing and in the Cu-free protein and brings about uncoupling of the Co(II)--Cu(II) system. Protonation of histidine-61 on the zinc facing nitrogen is suggested. 5. H2O2 modifies the cobalt chromophore only in the presence of copper. Magnetic coupling between Cu(II) and Co(II) seems to be still present after H2O2 inactivation of the enzyme. | [
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PMID:6276 | Enzymatic synthesis of two fucose-containing glycolipids with fucosyltransferases of human serum. | Lacto-N-neotetraosylceramide incubated with human serum fucosyltransferase preparations gave rise to two fucoglycolipids. The faster migrating fucoglycolipid I on the basis of its thin-layer chromatographic mobility, susceptibility to alpha(1 leads to 2) fucosidase from Trichomonas foetus, radio-immunoprecipitation with Ulex europeus lectin and studies with Oh (Bombay) sera was identified as H-active glycolipid (H-I). The most probable structure of fucoglycolipid II should be that with fucose linked alpha(1 leads to 3) to N-acetylglucosamine. Lactosylceramide, ceramide trihexoside and globoside were not substrates for human serum fucosyltransferases. Lacto-N-neotetraosyl ceramide served as a fucose acceptor for all serum preparations tested while asialoganglioside was a substrate only when serum preparations containing H-gene dependent alpha-2-L-fucosyltransferase were used. With asialoganglioside only one radioactive reaction product was formed. | Enzymatic synthesis of two fucose-containing glycolipids with fucosyltransferases of human serum. Lacto-N-neotetraosylceramide incubated with human serum fucosyltransferase preparations gave rise to two fucoglycolipids. The faster migrating fucoglycolipid I on the basis of its thin-layer chromatographic mobility, susceptibility to alpha(1 leads to 2) fucosidase from Trichomonas foetus, radio-immunoprecipitation with Ulex europeus lectin and studies with Oh (Bombay) sera was identified as H-active glycolipid (H-I). The most probable structure of fucoglycolipid II should be that with fucose linked alpha(1 leads to 3) to N-acetylglucosamine. Lactosylceramide, ceramide trihexoside and globoside were not substrates for human serum fucosyltransferases. Lacto-N-neotetraosyl ceramide served as a fucose acceptor for all serum preparations tested while asialoganglioside was a substrate only when serum preparations containing H-gene dependent alpha-2-L-fucosyltransferase were used. With asialoganglioside only one radioactive reaction product was formed. | [
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PMID:6277 | Properties of prostaglandin synthetase of rabbit kidney medulla. | The formation in vitro of prostaglandins E2, D2, and F2alpha from arachidonic acid by rabbit kidney medulla homogenate or microsomal fraction is markedly affected by the composition of the incubation medium employed. Optimal biosynthesis is obtained in 0.1 M potassium phosphate buffer, with the optimum pH being 8.0--8.8. Under these conditions prostaglandin formation is linear up to arachidonic acid concentration of 30 muM. The initial rate of formation of prostaglandin E2 + prostaglandin D2 is 3--4 times higher than that of prostaglandin F2alpha. Reduced glutathione (1 mM) did not affect the biosynthesis by medulla homogenate and produced only small stimulation of the biosynthesis by microsomal powder. Hydroquinone produced a small stimulation at a low concentration of 0.005 mM, and a strong inhibition at concentrations of 0.1 mM or higher. Addition of bovine serum albumin (0.1%) reduced the microsomal biosynthesis of prostaglandins by approximately 80%. Addition of boiled homogenate or boiled 140 000 X g supernatant produced small stimulation of microsomal biosynthesis while 140 000 X g supernatant (not boiled) caused small inhibition which was not dose-related. It appears that rabbit kidney prostaglandin-synthetase converts arachidonic acid to prostaglandins E2 and F2alpha in comparable amounts, without apparent need for a cytoplasmic soluble cofactor or specific reducing agents. | Properties of prostaglandin synthetase of rabbit kidney medulla. The formation in vitro of prostaglandins E2, D2, and F2alpha from arachidonic acid by rabbit kidney medulla homogenate or microsomal fraction is markedly affected by the composition of the incubation medium employed. Optimal biosynthesis is obtained in 0.1 M potassium phosphate buffer, with the optimum pH being 8.0--8.8. Under these conditions prostaglandin formation is linear up to arachidonic acid concentration of 30 muM. The initial rate of formation of prostaglandin E2 + prostaglandin D2 is 3--4 times higher than that of prostaglandin F2alpha. Reduced glutathione (1 mM) did not affect the biosynthesis by medulla homogenate and produced only small stimulation of the biosynthesis by microsomal powder. Hydroquinone produced a small stimulation at a low concentration of 0.005 mM, and a strong inhibition at concentrations of 0.1 mM or higher. Addition of bovine serum albumin (0.1%) reduced the microsomal biosynthesis of prostaglandins by approximately 80%. Addition of boiled homogenate or boiled 140 000 X g supernatant produced small stimulation of microsomal biosynthesis while 140 000 X g supernatant (not boiled) caused small inhibition which was not dose-related. It appears that rabbit kidney prostaglandin-synthetase converts arachidonic acid to prostaglandins E2 and F2alpha in comparable amounts, without apparent need for a cytoplasmic soluble cofactor or specific reducing agents. | [
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PMID:6278 | Acetyl-CoA carboxylase during development of plastids in wild-type and mutant barley seedlings. | A soluble acetyl-CoA carboxylase in homogenates of leaves from wild-type barley seedlings was studied. Centrifuging the homogenate at 150,000 X g did not reduce the total activity, but raised the specific activity. During chloroplast development in light-grown seedlings or during light-dependent greening of leaves grown in the dark, both the total activity of the carboxylase per plant and the specific activity per mg of protein in homogenates of the seedlings increased rapidly. The soluble leaf acetyl-CoA carboxylase was studied in a number of barley mutants with lesions in chloroplast development. In a group of three mutants light elicited an increase in acetyl-CoA carboxylase activity as in the wild-type. In two mutants light caused a decrease in activity. Dark-grown leaves of mutant albina-f17 contained levels of soluble acetyl-CoA carboxylase reached only in the light by the wild-type, whereas light-grown albina-f17 seedlings lacked carboxylase activities. The possibility is discussed that leaf cells contain two forms of acetyl-CoA carboxylase, one soluble with unknown location and a dissociable form located in the chloroplast. | Acetyl-CoA carboxylase during development of plastids in wild-type and mutant barley seedlings. A soluble acetyl-CoA carboxylase in homogenates of leaves from wild-type barley seedlings was studied. Centrifuging the homogenate at 150,000 X g did not reduce the total activity, but raised the specific activity. During chloroplast development in light-grown seedlings or during light-dependent greening of leaves grown in the dark, both the total activity of the carboxylase per plant and the specific activity per mg of protein in homogenates of the seedlings increased rapidly. The soluble leaf acetyl-CoA carboxylase was studied in a number of barley mutants with lesions in chloroplast development. In a group of three mutants light elicited an increase in acetyl-CoA carboxylase activity as in the wild-type. In two mutants light caused a decrease in activity. Dark-grown leaves of mutant albina-f17 contained levels of soluble acetyl-CoA carboxylase reached only in the light by the wild-type, whereas light-grown albina-f17 seedlings lacked carboxylase activities. The possibility is discussed that leaf cells contain two forms of acetyl-CoA carboxylase, one soluble with unknown location and a dissociable form located in the chloroplast. | [
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PMID:6279 | Calf-spleen nicotinamide--adenine dinucleotide glycohydrolase. Solubilization purification and properties of the enzyme. | NAD glycohydrolase of calf spleen was solubilized with pancreatic lipase and purified approximatively 800-fold to a specific activity of 7 units/mg of protein by successive DEAE-cellulose and carboxymethyl-cellulose chromatography. The purified enzyme has a molecular weight of 24,000 and is characterized by a double band on disc gel electrophoresis. Some kinetic properties of the NAD-glycohydrolase-catalyzed hydrolsis of NAD have been examined using a titrimetric assay for enzyme activity. The reaction is subject to inhibition be excess of substrate, which disappears at high ionic strength and low pH. At a pH below 5 the kinetic displays an apparent activation by substrate. The effects of pH (4.5-9.0) on the kinetic parameters do not reveal an essential ionizable group in the catalytic process. | Calf-spleen nicotinamide--adenine dinucleotide glycohydrolase. Solubilization purification and properties of the enzyme. NAD glycohydrolase of calf spleen was solubilized with pancreatic lipase and purified approximatively 800-fold to a specific activity of 7 units/mg of protein by successive DEAE-cellulose and carboxymethyl-cellulose chromatography. The purified enzyme has a molecular weight of 24,000 and is characterized by a double band on disc gel electrophoresis. Some kinetic properties of the NAD-glycohydrolase-catalyzed hydrolsis of NAD have been examined using a titrimetric assay for enzyme activity. The reaction is subject to inhibition be excess of substrate, which disappears at high ionic strength and low pH. At a pH below 5 the kinetic displays an apparent activation by substrate. The effects of pH (4.5-9.0) on the kinetic parameters do not reveal an essential ionizable group in the catalytic process. | [
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PMID:6280 | N-Acetylbenzotriazole as a protein reagent. Specific behaviour towards delta-chymotrypsin. | When N-[14C] acetylbenzotriazole, presented here as a new agent for the acetylation of proteins, reacted at pH 8 and 25 degrees C with delta-chymotrypsin, 15 amino groups (the epsilon-amino groups of lysing residues and the alpha-amino terminus of half-cystine-1) and two phenolic groups (those of the two exposed tyrosine residues) were acetylated with respective pseudo first-order constants of 0.056 +/- 0.003 and 0.15 +/- 0.03 min(-1). Surprisingly, in contrast with the acetic anhydride reaction, the alpha-amino group of Ile-16 was found to be not acetylated as shown by N-terminus determination and activity measurements: the modified delta-chymotrypsin (or acetylated delta-chymotrypsin) was fully active after neutral dialysis. Only a transient inactivation due to the incorporation of one [14C] acetyl group per mole of catalytic site was observed. The kinetic constant found for reactivation at pH 8.5 was 0.315 +/- 0.005 min(-1) at 25 degrees C. The enzyme-catalyzed hydrolysis of N-acetylbenzotriazole was described by a k(cat) value of 0.093 +/- 0.005 min(-1) at pH 7 and 25 degrees C. Circular dichroism changes observed at 230 nm during the reaction at pH 8.5, of acetylated delta-chymotrypsin with N-acetylbenzotriazole indicated a total conversion of the amount of enzyme molecules which were in the 'inactive' or 'alkaline' conformation at this pH, into the 'active' or 'neutral' one. Benzotriazole alone was unable to induce such a conformational change. The rate constant of the reverse structural process from the 'neutral' to the 'alkaline' conformation was 0.32 +/- 0.02 min(-1): identical to that of the deacetylation of the catalytic site. Thus, the unusual lack of acetylation of Ile-16 alpha-amino group during delta-chymotrypsin treatment with N-acetylbenzotriazole is interpreted as a stabilization of the enzyme 'neutral' conformation where the Ile-16 alpha-amino group is buried, thus inaccessible to the reagent. The properties of the delta-chymotrypsin modification using N-acetylbenzotriazole led to practical uses: direct spectrophotometric titration of chymotrypsin operational normality at pH 7 and rapid preparation of acetylated delta-chymotrypsin. As a protein reagent, N-acetylbenzotriazole is particularly interesting because of its reactivity towards amino and phenolic groups of amino acid residues, its stability at acid pH, i.e., k(hydrolysis=7.38 X 10(-3) min(-1) at 25 degrees C [Ravaux et al. (1971) Tetrahedron Letters, 4013-4015] and its aromaticity, responsible for optical properties. | N-Acetylbenzotriazole as a protein reagent. Specific behaviour towards delta-chymotrypsin. When N-[14C] acetylbenzotriazole, presented here as a new agent for the acetylation of proteins, reacted at pH 8 and 25 degrees C with delta-chymotrypsin, 15 amino groups (the epsilon-amino groups of lysing residues and the alpha-amino terminus of half-cystine-1) and two phenolic groups (those of the two exposed tyrosine residues) were acetylated with respective pseudo first-order constants of 0.056 +/- 0.003 and 0.15 +/- 0.03 min(-1). Surprisingly, in contrast with the acetic anhydride reaction, the alpha-amino group of Ile-16 was found to be not acetylated as shown by N-terminus determination and activity measurements: the modified delta-chymotrypsin (or acetylated delta-chymotrypsin) was fully active after neutral dialysis. Only a transient inactivation due to the incorporation of one [14C] acetyl group per mole of catalytic site was observed. The kinetic constant found for reactivation at pH 8.5 was 0.315 +/- 0.005 min(-1) at 25 degrees C. The enzyme-catalyzed hydrolysis of N-acetylbenzotriazole was described by a k(cat) value of 0.093 +/- 0.005 min(-1) at pH 7 and 25 degrees C. Circular dichroism changes observed at 230 nm during the reaction at pH 8.5, of acetylated delta-chymotrypsin with N-acetylbenzotriazole indicated a total conversion of the amount of enzyme molecules which were in the 'inactive' or 'alkaline' conformation at this pH, into the 'active' or 'neutral' one. Benzotriazole alone was unable to induce such a conformational change. The rate constant of the reverse structural process from the 'neutral' to the 'alkaline' conformation was 0.32 +/- 0.02 min(-1): identical to that of the deacetylation of the catalytic site. Thus, the unusual lack of acetylation of Ile-16 alpha-amino group during delta-chymotrypsin treatment with N-acetylbenzotriazole is interpreted as a stabilization of the enzyme 'neutral' conformation where the Ile-16 alpha-amino group is buried, thus inaccessible to the reagent. The properties of the delta-chymotrypsin modification using N-acetylbenzotriazole led to practical uses: direct spectrophotometric titration of chymotrypsin operational normality at pH 7 and rapid preparation of acetylated delta-chymotrypsin. As a protein reagent, N-acetylbenzotriazole is particularly interesting because of its reactivity towards amino and phenolic groups of amino acid residues, its stability at acid pH, i.e., k(hydrolysis=7.38 X 10(-3) min(-1) at 25 degrees C [Ravaux et al. (1971) Tetrahedron Letters, 4013-4015] and its aromaticity, responsible for optical properties. | [
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PMID:6281 | Exo-beta-N-acetylmuramidase--a novel hexosaminidase. Production by Bacillus subtilis B, purification and characterization. | Exo-beta-N-acetylmuramidase, or beta-2-acetamido-3-O-(D-1-carboxyethyl)-2-deoxy-D-glucoside acetamidodeoxyglucohydrolase, is produced by Bacillus subtilis B, growing in a succinate/peptone/salts medium, at the end of exponential growth and occurs partly in the medium and partly bound to the cells. A lysozyme digest of Micrococcus lysodeikticus cell walls, O-2-acetamido-2-deoxy-beta-D-glucopyranosyl-(1 leads to 4)-2-acetamido-3-O-(D-1-carboxyethyl)-2-deoxy-D-glucose and O-[2-acetamide-3-O-(D-1-carboxyethyl)-2-deoxy-beta-D-glucopyranosyl]-(1 leads to 4)-2-acetamido-2-deoxy-D-glucose in decreasing order of efficiency, induce the enzyme but O-2-acetamido-2-deoxy-beta-D-glucopyranosyl-(1 leads to 4)-2-acetamido-2-deoxy-D-glucose does not do so. The enzyme was purified from the growth medium, after removal of the cells by continuous centrifugation, by ammonium sulphate precipitation, continuous filtration through XM-300 membranes (to remove the high-molecular-weight material which renders the enzyme sedimentable in low-ionic-strength solutions), diafiltration through PM-30 membranes and ion-exchange chromatography on DEAE-Sephadex and CM-Sephadex. Two peaks of activity were obtained. Peak A was purified 1800-fold and was homogenous on polyacrylamide disc gel electrophoresis. A second heterogeneous fraction (peak B) was also collected. Exo-beta-N-acetylmuramidase is most stable at pH 8.0 and has a molecular weight of about 90000. The results of studies on its ability to attack several synthetic and natural substrates are given. The Km and V values for 4-methylumbelliferyl-2-acetamido-3-O-(D-1-carboxyethyl)-2-deoxy-beta-D-glucose and O-[2-acetamido-3-O-(D-1-carboxyethyl)-2-deoxy-beta-D-glucopyranosyl]-(1 leads to 4)-2-acetamido-2-deoxy-D-glucose are respectively 0.19 and 0.65 mM and 1.50 and 16.29 mumol min(-1) mg(-1). From these results and those of inhibition studies it is concluded that the enzyme is specific for substrates with non-reducing N-acetylmuramic acid end groups. Possible roles for this enzyme are discussed. | Exo-beta-N-acetylmuramidase--a novel hexosaminidase. Production by Bacillus subtilis B, purification and characterization. Exo-beta-N-acetylmuramidase, or beta-2-acetamido-3-O-(D-1-carboxyethyl)-2-deoxy-D-glucoside acetamidodeoxyglucohydrolase, is produced by Bacillus subtilis B, growing in a succinate/peptone/salts medium, at the end of exponential growth and occurs partly in the medium and partly bound to the cells. A lysozyme digest of Micrococcus lysodeikticus cell walls, O-2-acetamido-2-deoxy-beta-D-glucopyranosyl-(1 leads to 4)-2-acetamido-3-O-(D-1-carboxyethyl)-2-deoxy-D-glucose and O-[2-acetamide-3-O-(D-1-carboxyethyl)-2-deoxy-beta-D-glucopyranosyl]-(1 leads to 4)-2-acetamido-2-deoxy-D-glucose in decreasing order of efficiency, induce the enzyme but O-2-acetamido-2-deoxy-beta-D-glucopyranosyl-(1 leads to 4)-2-acetamido-2-deoxy-D-glucose does not do so. The enzyme was purified from the growth medium, after removal of the cells by continuous centrifugation, by ammonium sulphate precipitation, continuous filtration through XM-300 membranes (to remove the high-molecular-weight material which renders the enzyme sedimentable in low-ionic-strength solutions), diafiltration through PM-30 membranes and ion-exchange chromatography on DEAE-Sephadex and CM-Sephadex. Two peaks of activity were obtained. Peak A was purified 1800-fold and was homogenous on polyacrylamide disc gel electrophoresis. A second heterogeneous fraction (peak B) was also collected. Exo-beta-N-acetylmuramidase is most stable at pH 8.0 and has a molecular weight of about 90000. The results of studies on its ability to attack several synthetic and natural substrates are given. The Km and V values for 4-methylumbelliferyl-2-acetamido-3-O-(D-1-carboxyethyl)-2-deoxy-beta-D-glucose and O-[2-acetamido-3-O-(D-1-carboxyethyl)-2-deoxy-beta-D-glucopyranosyl]-(1 leads to 4)-2-acetamido-2-deoxy-D-glucose are respectively 0.19 and 0.65 mM and 1.50 and 16.29 mumol min(-1) mg(-1). From these results and those of inhibition studies it is concluded that the enzyme is specific for substrates with non-reducing N-acetylmuramic acid end groups. Possible roles for this enzyme are discussed. | [
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PMID:6282 | Studies on the active site of yeast hexokinase. Specific phosphorylation of a serine residue induced by D-xylose and ATPMg. | Yeast hexokinase A(ATP:D-hexose 6-phosphotransferase) is inactivated when incubated in the presence of xylose and ATPMg, or in the presence of D-lyxose in a reaction medium in which ATPMg is being continuously regenerated (phosphoenolpyruvate and pyruvate kinase). The inactivation is due to the phorphorylation of the protein. A linear relationship was observed between the inactivation and the incorporation of 32P from [gamma-32P] ATP. All hexokinase and ATPase activity of the enzyme is lost when one phosphoryl group is incorporated per enzyme subunit (molecular weight 51,000). The phosphoryl group is covalently bound by a ester linkage with a serine residue of the protein. | Studies on the active site of yeast hexokinase. Specific phosphorylation of a serine residue induced by D-xylose and ATPMg. Yeast hexokinase A(ATP:D-hexose 6-phosphotransferase) is inactivated when incubated in the presence of xylose and ATPMg, or in the presence of D-lyxose in a reaction medium in which ATPMg is being continuously regenerated (phosphoenolpyruvate and pyruvate kinase). The inactivation is due to the phorphorylation of the protein. A linear relationship was observed between the inactivation and the incorporation of 32P from [gamma-32P] ATP. All hexokinase and ATPase activity of the enzyme is lost when one phosphoryl group is incorporated per enzyme subunit (molecular weight 51,000). The phosphoryl group is covalently bound by a ester linkage with a serine residue of the protein. | [
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PMID:6283 | The transport of S-adenosyl-L-methionine in isolated yeast vacuoles and spheroplasts. | 1. The properties of S-adenosyl-L-methionine accumulating system for both vacuoles and spheroplasts are described. Yeast vacuoles were obtained by a modified metabolic lysis procedure from spheroplasts of Saccharomyces cerevisiae. 2. Isolated vacuoles accumulate S-adenosyl-L-methionine by means of a highly specific transport system as indicated by competition experiments with structural analogs of S-adenosyl-L-methionine. The S-adenosyl-L-methionine transport system shows saturation kinetics with an apparent Km of 68 muM in vacuoles and 11 muM in spheroplasts. 3. S-Adenosyl-L-methionine accumulation into vacuoles does not require glucose, phosphoenolpyruvic acid, ATP, ADP nor any other tri- or di-phosphorylated nucleotides. It is insensitive to azide and 2,4-dinitrophenol which strongly inhibit the glucose-dependent accumulation of S-adenosyl-L-methionine in spheroplasts. 4. The transport of S-adenosyl-L-methionine into vacuoles is optimal at pH 7.4 and is insensitive to nystatin while the uptake of S-adenosyl-L-methionine into spheroplasts is optimal at pH 5.0 and is strongly sensitive to nystatin. On this basis it has thus been possible to measure both the intracytoplasmic and the intravacuolar pool of S-adenosyl-L-methionine. 5. Our results indicate the existence of a highly specific S-adenosyl-L-methionine transport system in the vacuolar membrane which is clearly different from the one present in the plasma membrane of yeast cells. | The transport of S-adenosyl-L-methionine in isolated yeast vacuoles and spheroplasts. 1. The properties of S-adenosyl-L-methionine accumulating system for both vacuoles and spheroplasts are described. Yeast vacuoles were obtained by a modified metabolic lysis procedure from spheroplasts of Saccharomyces cerevisiae. 2. Isolated vacuoles accumulate S-adenosyl-L-methionine by means of a highly specific transport system as indicated by competition experiments with structural analogs of S-adenosyl-L-methionine. The S-adenosyl-L-methionine transport system shows saturation kinetics with an apparent Km of 68 muM in vacuoles and 11 muM in spheroplasts. 3. S-Adenosyl-L-methionine accumulation into vacuoles does not require glucose, phosphoenolpyruvic acid, ATP, ADP nor any other tri- or di-phosphorylated nucleotides. It is insensitive to azide and 2,4-dinitrophenol which strongly inhibit the glucose-dependent accumulation of S-adenosyl-L-methionine in spheroplasts. 4. The transport of S-adenosyl-L-methionine into vacuoles is optimal at pH 7.4 and is insensitive to nystatin while the uptake of S-adenosyl-L-methionine into spheroplasts is optimal at pH 5.0 and is strongly sensitive to nystatin. On this basis it has thus been possible to measure both the intracytoplasmic and the intravacuolar pool of S-adenosyl-L-methionine. 5. Our results indicate the existence of a highly specific S-adenosyl-L-methionine transport system in the vacuolar membrane which is clearly different from the one present in the plasma membrane of yeast cells. | [
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PMID:6284 | Enzymic and molecular properties of base-plate parts of bacteriophage P22. | Using 14C-labeled Salmonella bacterial cells as the substrate, the enzymic and molecular properties of the base-plate parts of phage P22 were studied. The base-plate part consisted of a single protein species which cleaved extensively the O-antigen of Salmonella typhimurium, Salmonelly schottmuellerie and with somewhat slower rate that of Salmonella typhi, releasing oligo-saccharide products with rhamnose at the reducing end. Much less cleavage was observed with a strain of S. typhimurium lysogenic for P22, and no significant reaction with Salmonella anatum, Salmonella newington and Salmonella minneapolis. The base-plate part enzyme was a very heat-stable protein and only 10-20% loss was observed after treatment at 85 degrees C for 5 min. The pH optimum of the enzyme was around 7.5, and the glycosidase activity was not influenced by the ionic strength (25-250 mM( of the medium or the presence of Mg2+. The molecular weight of the base-plate part was 320,000 by sedimentation equilibrium. Dodecylsulphate-acrylamide gel electrophoresis revealed a single band of molecular weight 77,000, indicating that a single base-plate part corresponds to a tetramer of identical subunits. Circular dichroism spectra of P22 base-plate parts showed a major contribution of beta structure. The protein was rich in acidic amino acids, glycine and serine. | Enzymic and molecular properties of base-plate parts of bacteriophage P22. Using 14C-labeled Salmonella bacterial cells as the substrate, the enzymic and molecular properties of the base-plate parts of phage P22 were studied. The base-plate part consisted of a single protein species which cleaved extensively the O-antigen of Salmonella typhimurium, Salmonelly schottmuellerie and with somewhat slower rate that of Salmonella typhi, releasing oligo-saccharide products with rhamnose at the reducing end. Much less cleavage was observed with a strain of S. typhimurium lysogenic for P22, and no significant reaction with Salmonella anatum, Salmonella newington and Salmonella minneapolis. The base-plate part enzyme was a very heat-stable protein and only 10-20% loss was observed after treatment at 85 degrees C for 5 min. The pH optimum of the enzyme was around 7.5, and the glycosidase activity was not influenced by the ionic strength (25-250 mM( of the medium or the presence of Mg2+. The molecular weight of the base-plate part was 320,000 by sedimentation equilibrium. Dodecylsulphate-acrylamide gel electrophoresis revealed a single band of molecular weight 77,000, indicating that a single base-plate part corresponds to a tetramer of identical subunits. Circular dichroism spectra of P22 base-plate parts showed a major contribution of beta structure. The protein was rich in acidic amino acids, glycine and serine. | [
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PMID:6285 | Effects of alpha-adrenoceptor agonists and antagonists on pre- and postsynaptically located alpha-adrenoceptors. | The effects of alpha adrenoceptor agonists and antagonists have been examined at pre- and post-synaptically located alpha-adrenoceptors in the pithed rat. The presynaptic receptors were those located at the cardiac sympathetic nerve terminals and the postsynaptic receptors were those present in vascular smooth muscle. Clonidine was approximately equipotent at pre- and post-synaptic alpha-adrenoceptors, whilst LSD and BAY-1470 were more active at the pre- than at post-synaptic sites. Oxymetazoline, naphazoline, methoxamine and phenylephrine were all much more active at the postsynaptic alpha-adrenoceptors. Phentolamine was the most potent antagonist at both pre- and post-synaptic alpha-adrenoceptors. Piperoxan, yohimbine and tolazoline were about 3-7X less potent than phentolamine at both sites. Thymoxamine was about 10X less potent than phentolamine at postsynaptic alpha-adrenoceptors but about 1000X less active at the presynaptic receptors. The differential actions of both agonsists and antagonists at pre- and post-synaptic alpha-adrenoceptors suggest that the receptors may be of different types. | Effects of alpha-adrenoceptor agonists and antagonists on pre- and postsynaptically located alpha-adrenoceptors. The effects of alpha adrenoceptor agonists and antagonists have been examined at pre- and post-synaptically located alpha-adrenoceptors in the pithed rat. The presynaptic receptors were those located at the cardiac sympathetic nerve terminals and the postsynaptic receptors were those present in vascular smooth muscle. Clonidine was approximately equipotent at pre- and post-synaptic alpha-adrenoceptors, whilst LSD and BAY-1470 were more active at the pre- than at post-synaptic sites. Oxymetazoline, naphazoline, methoxamine and phenylephrine were all much more active at the postsynaptic alpha-adrenoceptors. Phentolamine was the most potent antagonist at both pre- and post-synaptic alpha-adrenoceptors. Piperoxan, yohimbine and tolazoline were about 3-7X less potent than phentolamine at both sites. Thymoxamine was about 10X less potent than phentolamine at postsynaptic alpha-adrenoceptors but about 1000X less active at the presynaptic receptors. The differential actions of both agonsists and antagonists at pre- and post-synaptic alpha-adrenoceptors suggest that the receptors may be of different types. | [
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PMID:6286 | Influence of methamphetamine on nigral and striatal tyrosine hydroxylase activity and on striatal dopamine levels. | In previous reports, methamphetamine was shown to depress tyrosine hydroxylase (TH) activity in the rat corpus striatum. To evaluate further the mechanism of this decrease in TH activity, enzyme activity was measured in the rat corpus striatum and substantia nigra after repetitive and single-dose methamphetamine administration. Following repeated doses of methamphetamine, nigral TH activity decreased and reached 45% of controls at 12 hr and returned to normal at 60 hr. Striatal TH activity decreased to 40% of control at 36 hr and returned toward normal at 60 hr. When methamphetamine was administered every 6 hr for 30 hr and then discontinued, nigral TH activity returned toward control levels 4 days prior to recovery of striatal TH activity. Methamphetamine initially increased striatal dopamine levels at 6 hr (170% of control). Dopamine levels then decreased in parallel with striatal TH activity but failed to increase as the enzyme recovered. Concurrent administration of chlorpromazine with methamphetamine prevented the methamphetamine-induced decrease in nigral and striatal TH activity and striatal dopamine levels. The results indicate that the methamphetamine-induced depression of striatal and nigral TH activity may be related to increased stimulation of dopamine receptors in the striatum. | Influence of methamphetamine on nigral and striatal tyrosine hydroxylase activity and on striatal dopamine levels. In previous reports, methamphetamine was shown to depress tyrosine hydroxylase (TH) activity in the rat corpus striatum. To evaluate further the mechanism of this decrease in TH activity, enzyme activity was measured in the rat corpus striatum and substantia nigra after repetitive and single-dose methamphetamine administration. Following repeated doses of methamphetamine, nigral TH activity decreased and reached 45% of controls at 12 hr and returned to normal at 60 hr. Striatal TH activity decreased to 40% of control at 36 hr and returned toward normal at 60 hr. When methamphetamine was administered every 6 hr for 30 hr and then discontinued, nigral TH activity returned toward control levels 4 days prior to recovery of striatal TH activity. Methamphetamine initially increased striatal dopamine levels at 6 hr (170% of control). Dopamine levels then decreased in parallel with striatal TH activity but failed to increase as the enzyme recovered. Concurrent administration of chlorpromazine with methamphetamine prevented the methamphetamine-induced decrease in nigral and striatal TH activity and striatal dopamine levels. The results indicate that the methamphetamine-induced depression of striatal and nigral TH activity may be related to increased stimulation of dopamine receptors in the striatum. | [
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PMID:6287 | alpha-Adrenoceptors in the ventricular myocardium: clonidine, naphazoline and methoxamine as partial alpha-agonists exerting a competitive dualism in action to phenylephrine. | Tha alpha-sympathomimetic agonists, clonidine, naphazoline, methoxamine, oxymetazoline and phenylephrine were used to further characterize the alpha-adrenoceptors mediating the positive inotropic effect in the isolated papillary muscle of the rabbit heart. The maximal inotropic effects of these amines were compared with the effect of isoprenaline and it was examined whether or not these amines compete for alpha-adrenoceptors. On the papillary muscle stimulated at 0.5 Hz, phenylephrine showed a high affinity (pD2 value=6.13) and produced the most pronounced intrinsic activity of the alpha-sympathomimetic amines. Therefore, the intrinsic activity of phenylephrine, in the presence of prindolol (3 X 10(-8) M), was used for comparison with those of the other alpha-agonists. Clonidine caused a positive inotropic effect: the intrinsic activity amounted to 0.32 of that of phenylephrine; the affinity was the highest among the amines tested (pD2 value=6.46); its effect was inhibited by 10(-6) M phentolamine. The affinity and the intrinsic activity of naphazoline were slightly lower than those of clonidine. Methoxamine showed a relatively high intrinsic activity (0.56) but the lowest affinity (4.68). Oxymetazoline did not cause any positive inotropic effect. Clonidine, naphazoline and oxymetazoline antagonized the positive inotropic effect of phenylephrine, mediated via the alpha-adrenocaptors in the presence of 3 X 10(-8) M prindolol, in a competitive manner. This observation suggests that these alpha-sympathomimetic amines compete with phenylephrine for the same receptor site. Thus the present results provide additional evidence for alpha-adrenoceptors mediating the positive inotropic actions of sympathomimetic amines in the rabbit papillary muscle. | alpha-Adrenoceptors in the ventricular myocardium: clonidine, naphazoline and methoxamine as partial alpha-agonists exerting a competitive dualism in action to phenylephrine. Tha alpha-sympathomimetic agonists, clonidine, naphazoline, methoxamine, oxymetazoline and phenylephrine were used to further characterize the alpha-adrenoceptors mediating the positive inotropic effect in the isolated papillary muscle of the rabbit heart. The maximal inotropic effects of these amines were compared with the effect of isoprenaline and it was examined whether or not these amines compete for alpha-adrenoceptors. On the papillary muscle stimulated at 0.5 Hz, phenylephrine showed a high affinity (pD2 value=6.13) and produced the most pronounced intrinsic activity of the alpha-sympathomimetic amines. Therefore, the intrinsic activity of phenylephrine, in the presence of prindolol (3 X 10(-8) M), was used for comparison with those of the other alpha-agonists. Clonidine caused a positive inotropic effect: the intrinsic activity amounted to 0.32 of that of phenylephrine; the affinity was the highest among the amines tested (pD2 value=6.46); its effect was inhibited by 10(-6) M phentolamine. The affinity and the intrinsic activity of naphazoline were slightly lower than those of clonidine. Methoxamine showed a relatively high intrinsic activity (0.56) but the lowest affinity (4.68). Oxymetazoline did not cause any positive inotropic effect. Clonidine, naphazoline and oxymetazoline antagonized the positive inotropic effect of phenylephrine, mediated via the alpha-adrenocaptors in the presence of 3 X 10(-8) M prindolol, in a competitive manner. This observation suggests that these alpha-sympathomimetic amines compete with phenylephrine for the same receptor site. Thus the present results provide additional evidence for alpha-adrenoceptors mediating the positive inotropic actions of sympathomimetic amines in the rabbit papillary muscle. | [
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