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J H Hurst

Publications and source records attributed to J H Hurst.

14 recordsLinked to original sources
PubMed1986

Inhibition of rat brainstem monoamine oxidase activity by CGP 6085 A.

CGP 6085 A [4-(5,6-dimethyl-2-benzofuranyl)piperidine] HCl, a known serotonin inhibitor, also inhibits rat brainstem monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) in both in vivo and in vitro experiments. Serotonin (5-HT) deamination by MAO-A is inhibited 35% at a dose of 100 mg/kg i.p. in vivo. Similar experiments show a maximal 20% decrease in phenylethylamine (PEA) deamination by MAO-B at a dosage of 30 mg/kg i.p. Over the range of 0.1 to 10 mg/kg i.p., CGP 6085 A decreases 5-HIAA levels in the brainstem. This in vivo inhibition of MAO activity is confirmed by in vitro experiments. In vitro studies in rat brainstem mitochondrial preparations show a dose-dependent, reversible, inhibition of MAO using tyramine as the substrate for the enzyme reaction. With an in vitro IC50 of 2-3 microM, the potency of CGP 6085 A is comparable to pargyline.

Animals↗
PubMed1985

CSF dopamine-beta-hydroxylase activity in Parkinson's disease.

Although the most prominent neurochemical change in parkinsonism is nigrostriatal dopamine deficiency, norepinephrine content is also diminished in the CNS. In this study, dopamine-beta-hydroxylase (DBH) activity, a marker of central noradrenergic activity, was measured in the CSF of previously unmedicated parkinsonian patients and normal controls. The parkinsonian patients showed a reduction in CSF DBH levels to 41% of control values (p less than 0.01). Possible explanations for the decrease included a decreased noradrenergic nerve pool or a diminished rate of synthesis of catecholamines.

Adult↗
PubMed1985

The hypotensive action of 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A) in spontaneously hypertensive rats.

CGP 6085 A, [4-(5,6-dimethyl-2-benzofuranyl)piperidine HCl], has been found to be a mild to moderately potent hypotensive agent. One hour following CGP 6085 A administration (10 mg/kg, i.p.), a maximal reduction in blood pressure of approximately 20-30 mm Hg is observed in spontaneously hypertensive rats. The maximal reduction in blood pressure was observed at a dose of 3 mg/kg. CGP 6085 A blocks 5-HT uptake in the brainstem when assessed in vivo by use of the serotonin depletor, H 75/12 (3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine). The maximal inhibitory effect on 5-HT uptake occurred at 10 mg/kg CGP 6085 A. The reduction in blood pressure correlates well with the ability of the drug to inhibit 5-HT uptake as assayed by H 75/12, with a correlation coefficient of 0.71 for SH rats. However, since the drug has not been widely characterized, alternate explanations for the cardiovascular pharmacological properties of CGP 6085 A are also proposed.

Amphetamines↗
PubMed1984

The hypothermic effect of 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A) in Wistar Kyoto rats.

CGP 6085 A [4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl], a reported serotonin uptake and MAO (16) inhibitor, is a potent hypothermic agent. The hypothermic action of CGP 6085 A is dose dependent with a maximal reduction in rectal core temperature of greater than 1 degree C within one hour after drug administration. Fluoxetine and citalopram elicit a similar response at equal doses. These results suggest that inhibition of serotonin uptake may produce the hypothermic effect. To assess the in vivo action of CGP 6085 A in inhibiting hypothalamic serotonin uptake, CGP 6085 A (10 mg/kg) was injected one hour prior to injection of 3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine (H75/12), a serotonin depletor. The ability of CGP 6085 A to block the uptake of H75/12 by the 5HT uptake system was indicative of its ability to block serotonin uptake. Pretreatment with p-chlorophenylalanine (pCPA), an inhibitor of serotonin synthesis, resulted in the loss of the hypothermic response to CGP 6085 A. Thus, these data are consistent with the idea that CGP 6085 A may produce its hypothermic response by inhibiting serotonin uptake.

Amphetamines↗
PubMed1984

Photoaffinity labelling of methyltransferase enzymes with S-adenosylmethionine: effects of methyl acceptor substrates.

Radioactivity from 3H-[methyl]-S-adenosyl-L-methionine (AdoMet) was covalently bound to protein-O-carboxylmethyltransferase and phenylethanolamine N-methyltransferase following 10-15 min irradiation by short-wave ultraviolet light. This photoaffinity binding of 3H-[methyl]-AdoMet was blocked by S-adenosylhomocysteine and sinefungin, but was not affected by 5 mM dithiothreitol. The binding was also inhibited by including methyl acceptors such as calmodulin (protein-O-carboxylmethyltransferase) or phenylethanolamine (phenylethanolamine N-methyltransferase) in the photoaffinity incubation. Staphlococcus V8 protease digests of 3H-[methyl]-AdoMet/enzyme complexes revealed that the primary structure around the AdoMet binding site is different in these two enzymes. Thus, protein-O-carboxylmethyltransferase, a large molecule methyltransferase, can covalently bind 3H-[methyl]-AdoMet in a manner similar to that of phenylethanolamine-N-methyltransferase.

Affinity Labels↗
PubMed1984

Inheritance of adrenal phenylethanolamine N-methyltransferase activity in the rat.

Phenylethanolamine N-methyltransferase (PNMT) is the enzyme that catalyzes the S-adenosyl-L-methionine-dependent methylation of (-)norepinephrine to (-)epinephrine in the adrenal medulla. Adrenal PNMT activity is markedly different in two highly inbred rat strains; enzyme activity in the F344 strain is more than fivefold greater than that in the Buf strain. Initial characterization of the enzyme in the two inbred strains reveals evidence for catalytic and structural differences, as reflected in dissimilar Km values for the cosubstrate (S-adenosyl-L-methionine) and prominent differences in thermal inactivation curves. To assess adrenal PNMT activity in an F344 X Buf pedigree, we employed a statistical procedure to test for one- and two-locus hypotheses in the presence of within-class correlations due to cage or litter effects. The PNMT data in the pedigree are best accounted for by segregation at a simple major locus superimposed upon a polygenic background; data obtained from the biochemical studies suggest that the major locus is a structural gene locus.

Adrenal Medulla↗
PubMed1983

Phenylethanolamine N-methyltransferase: notes on its purification from bovine adrenal medulla and separation from protein carboxymethyltransferase.

Standard procedures for the purification of phenylethanolamine N-methyltransferase were modified by the addition of an affinity chromatography step utilizing immobilized S-adenosyl-L-homocysteine and by use of preparative isoelectric focusing. Enzyme derived from bovine adrenal medullae was bound to S-adenosyl-L-homocysteine agarose, and could be eluted with 0.1 M NaCl. Concentrations of S-adenosyl-L-methionine as high as 10 mM were ineffective in eluting the enzyme. Preparative isoelectric focusing of bovine phenylethanolamine N-methyltransferase showed a single peak with the pI = 4.95. The potential use of immobilized S-adenosyl-L-homocysteine in the differential separation of phenylethanolamine N-methyltransferase from other methyltransferase enzymes is discussed.

Adrenal Medulla↗
PubMed1983

Metabolic clearance rate of dopamine beta-hydroxylase in the rat.

The metabolic clearance rate (MCR) of both bovine and rat dopamine beta-hydroxylase (DBH) preparations was measured using two complementary procedures, pulse-dose injection and constant infusion of enzyme into the rat circulation. Rats that received injections of DBH activity had plasma DBH activity levels similar to those of controls by 24 hr after a pulse dose of rat DBH. The DBH MCR computed by stochastic analysis of the disappearance curve of injected DBH activity was about 1.0 ml/hr/100 g body weight; the mean transit time of DBH was about 8 hr. The disappearance curve of heterologous enzyme (bovine DBH) was more rapid than that of the rat, yielding an MCR of about 8 ml/hr/100 g body weight. MCR values obtained with the constant-infusion technique were similar to those obtained with the pulse-dose technique. These kinetic parameters are consistent with the time frame for altered plasma DBH activity observed with pharmacological and endocrinological factors. These data support the conclusion that plasma DBH turnover time is measured in hours, not days.

Animals↗
PubMed1982

Regulation and inheritance of dopamine-beta-hydroxylase.

Dopamine-beta-hydroxylase (DBH) is unique among the catecholamine biosynthetic enzymes in that release from sympathoadrenal cells during neurotransmission is an integral part of the enzyme's physiology. Because of this unique attribute, the metabolic pathways regulating DBH cannot depend solely upon intraneuronal processes. This manuscript summarizes evidence relating to the regulation of DBH metabolism in the rat. Levels of DBH in the circulation, which derive from release of sympathoadrenal cellular enzyme stores, are genetically determined; even though inherited, circulating DBH levels bear no apparent consistent relationship to cellular enzyme levels or to sympathoadrenal function. These findings suggest that processes regulating neuronal release of DBH are separate from other processes regulating disposal of the circulating enzyme. We have evaluated the circulating DBH disposal pathways by standard metabolic techniques. Our data strongly suggest that clearance of DBH from the circulatory compartment is a main, and perhaps the primary, disposal mechanism for cellular enzyme stores.

Animals↗
PubMed1982

Circulating dopamine-beta-hydroxylase in the rat: importance of altered disposal pathways in experimental diabetes.

Circulatory dopamine-beta-hydroxylase (DBH) activity was increased as much as 6-fold in rats with streptozotocin-induced diabetes mellitus. The increased enzymatic activity correlated with increased DBH protein as assessed by neutralization with homologous antiserum. The high levels of circulating DBH activity induced by streptozotocin was associated with a markedly slowed disappearance of enzyme activity after the i.v. injection of exogenous bovine DBH or exogenous rat DBH. Treatment of streptozotocin-treated rats with insulin prevented the increase in circulating DBH activity and reduced the initial half-time of disappearance of bovine DBH in a dose-related manner; the correlation between the initial half-time of disappearance of the bovine enzyme and the circulating DBH activity level was strongly positive. These results indicate that a reduction in the metabolic clearance rate of circulating DBH is a major factor accounting for the increase in serum DBH activity in the streptozotocin-diabetic rat.

Animals↗
PubMed1980

The inverse relationship between serum dopamine-beta-hydroxylase activity and thyroid function.

Serum dopamine-beta-hydroxylase (DBH) activity is inversely related to thyroid status in both humans and rats. The low level of serum DBH activity in hyperthyroid rats is accompanied by a rapid rate of disappearance of enzyme activity after the injection of exogenous bovine DBH. Conversely, the high level of serum DBH activity in hypothyroid rats is accompanied by a slow rate of exogenous DBH disappearance. These results suggest that the extraneuronal disposal pathway for DBH is an important factor in the regulation of the level of DBH activity in altered thyroid function in both humans and rats.

Adrenal Medulla↗
PubMed1977

Arterial hydrogen ion versus CO2 on depth and rate of breathing in decerebrate cats.

Arterial blood hydrogen ion concentration (Ha+) was altered over the range of 25 to 110 nM (pH 7.60 to 6.96) by slow intravenous infusion of 1.0 N NaHCO3 or 0.5 N HC1 at controlled levels of Paco2in unanesthetized decerebrate cats. Respiratory f varied as a single function of Vt irrespective of a lterations in Paco2 and Ha+ even after interruption of the carotid sinus nerves. The dependence of f upon Vt was abolished by vagotomy. However, Vt continued to respond to changes in Ha+ over its entire range after combined section of the vagus and carotid sinus nerves. In all statxceeded by 5 to 10 times the delta Vt/delta Ha+ response to acid or bicarbonate infused under isocapnic control. Increases and decreases of ha+ caused downward and upward shifts, respectively, in the operating setpoint of the CO2 regulation system.

Acidosis, Respiratory↗