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Biomedical subjects

D E Clarke

Publications and source records attributed to D E Clarke.

At least 91 records · Page 5Linked to original sources
PubMed1984

Kynuramine: high affinity for [3H]tryptamine binding sites.

Kynuramine, an endogenously occurring metabolite of L-tryptophan, was found to displace [3H]tryptamine from its high affinity binding sites in rat brain cortex with an inhibition constant (Ki) of 28 nM. Kynuramine exhibited structural specificity and considerable selectivity, compared with its affinity for serotonergic, adrenergic and benzodiazepine recognition sites. This novel finding opens-up the possibility that kynuramine may exert physiological actions via the putative tryptamine receptor.

Animals↗
PubMed1984

Vasoconstrictor and norepinephrine potentiating action of 5-hydroxykynuramine in the isolated perfused rat kidney: involvement of serotonin receptors and alpha 1-adrenoceptors.

Kynuramines are endogenously occurring diamines derived from tryptophan. In the present study, we have compared the pharmacological actions of 5-hydroxykynuramine (5-OH-K) with kynuramine and 5-hydroxytryptamine (5-HT) on vascular resistance changes and responsiveness to adrenergic stimuli in the isolated perfused rat kidney. 5-OH-K was found to mimic the actions of 5-HT in that it produced vasoconstriction, potentiation of alpha 1-adrenoceptor-mediated responses to norepinephrine (NE) and periarterial nerve stimulation, and displaced specific [3H]spiroperidol binding from rat cortical membranes. With regard to all parameters measured, 5-OH-K was about 15-times less active than 5-HT. Vascular responses to 5-OH-K and 5-HT were inhibited noncompetitively by ketanserin and cyproheptadine. Unlike 5-OH-K, kynuramine, failed to evoke vasoconstriction and inhibited vascular responses to NE via alpha 1-adrenoceptors. Thus, kynuramine lacks serotonin receptor agonist activity but possesses alpha 1-adrenoceptor blocking properties. In contrast, 5-OH-K potentiates NE and acts as a serotonin agonist. The present results raise the possibility that kynuramine and 5-OH-K might act as endogenous modulators of serotonergic and adrenergic mechanisms in the renal vascular bed.

Animals↗
PubMed1983

Blood pressure and heart rate effects of kynuramine in pithed rats.

Kynuramine increased heart rate and blood pressure in pithed rats. Heart rate responses were blocked by beta-adrenoceptor antagonists and reserpine pretreatment. Both of these treatments reduced the pressor responses to kynuramine. Remaining pressor activity was inhibited by phentolamine. The pressor responses to kynuramine were reversed to depressor responses during infusion of norepinephrine but not vasopressin. It is concluded that kynuramine releases cardiac catecholamines and acts as a partial agonist on vascular alpha-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1983

Amine oxidase activity in commercial preparations of bovine serum albumin.

Amine oxidase activity has been identified in commercial samples of bovine serum albumin (BSA). Benzylamine, phenylethylamines and to a lesser extent, indoleamines, were found to be substrates. The amine oxidase activity was inhibited by semicarbazide and was virtually absent in electrophoretically purified samples. Kinetic analysis of benzylamine deamination and experiments utilizing mixed substrates indicate that more than one catalytic activity may be involved. The results show that amine deamination should be considered as a potential source of error in experiments employing high concentrations of commercially available BSA preparations. This would be of particular importance for in vitro studies with dopamine since this amine was found to be deaminated at a rapid rate.

Amine Oxidase (Copper-Containing)↗
PubMed1983

Cardiovascular actions of kynuramine and 5-hydroxykynuramine in pithed rats.

Kynuramines occur endogenously in brain and peripheral tissues as metabolites of indoleamino acids and indolamines but little is known regarding their possible physiological and/or pharmacological activity. The present study has investigated the effects of kynuramine and 5-hydroxykynuramine on the cardiovascular system of pithed rats and attempted to correlate effects seen on adrenergic and serotonergic receptors with ligand binding experiments done in vitro using rat brain membranes. Kynuramine was found to release cardiac catecholamines and to act as a weak partial agonist on vascular alpha-adrenoceptors. Hydroxylation in the 5-position (5-hydroxykynuramine) did not alter cardiac potency but increased pressor activity 100-fold. Vasopressor responses to 5-hydroxykynuramine were mediated via a dual agonistic action on both postsynaptic alpha 2-adrenoceptors and vascular serotonin2 receptors. These findings were supported by ligand binding studies, in which both kynuramine and 5-hydroxykynuramine showed affinity for cortical [3H]spiroperidol and [3H]clonidine binding sites. Overall, the results show that kynuramines can exert peripheral (and possibly central) actions which may prove to be of physiological and/or pharmacological significance.

Adrenergic alpha-Agonists↗
PubMed1983

Benzylamine oxidase in normal and atherosclerotic human aortae.

Assays of serum benzylamine oxidase (BzAO) have led some workers to postulate a relationship between elevated BzAO activity and diseases characterized by proliferating connective tissue. The present study was designed to determine whether BzAO activity of a cellular tissue is also affected. BzAO was assayed in homogenates of normal and atherosclerotic human aortae. Characterization done in normal aortae showed that BzAO is not a classical monoamine, diamine, polyamine, or lysyl oxidase, nor is it a ceruloplasmin. The enzyme is heat stable at 60 degrees C and is associated primarily with the microsomal fraction on density centrifugation. Compared with phenylethylamines and indoleamines, benzylamine is the best substrate. BzAO is sensitive to inhibition by hydrazines and chymotrypsin but not trypsin, and is insensitive to Triton X-100 and sulfhydryl-group blockade. BzAO activity of atherosclerotic plaque (expressed per gram wet weight or per milligram protein) was decreased markedly compared to that in adjacent, nonplaque regions and in normal aortae. However, on a per milligram DNA basis, the BzAO activity of plaque did not differ from that of nonplaque tissue. We conclude that there is a decreased cell population density in plaque, a contention supported by kinetic analysis. Plaque BzAO showed a decreased Vmax with no change in the Km of benzylamine compared with nonplaque tissue. Thus, if a relationship exists between BzAO activity and proliferating connective tissue, it is not apparent at the level of the cellular enzyme in atherosclerotic aortae of man.

Adolescent↗
PubMed1983

Pharmacological characterization of alpha-adrenoreceptor subtypes in rat isolated thoracic aorta.

The subtype of alpha-adrenoreceptor mediating contraction in rat isolated thoracic aorta was classified pharmacologically using preferential agonists and antagonists, and by utilizing mixed agonist and antagonist interactions. Noradrenaline was 8 to 10-times more potent at contracting the aorta than phenylephrine and both agonists were about 1000 and 10,000-fold respectively more potent than azepexole (a preferential alpha 2-agonist). Prazosin (a preferential alpha 1-antagonist) inhibited the dose-response curves to noradrenaline and phenylephrine 100 and 1000-times respectively more effectively than either phentolamine or rauwolscine (a preferential alpha 2-antagonist). Furthermore, prazosin (5 x 10(-9) M) completely abolished contractions elicited by a single concentration of azepexole (3 x 10(-4) M). In mixed antagonist studies, rauwolscine (5 x 10(-7) M) failed to shift the dose-response curves to noradrenaline and phenylephrine obtained in the presence of prazosin (5 x 10(-9) M). In mixed agonist experiments, azepexole (3 x 10(-4) M) acted as a partial antagonist toward phenylephrine-induced contractions. The results suggest that the alpha-adrenoreceptor of the rat thoracic aorta is predominantly, if not exclusively, of the alpha 1-subtype.

Animals↗
PubMed1983

Effect of ovariectomy and estrogen treatment on uterine benzylamine oxidase and monoamine oxidase type A.

The activity of monoamine oxidase type A (MAO-A) of rat uteri is known to be modulated by sex steroids but no information is available with regard to benzylamine oxidase (BzAO). Thus, uterine MAO-A and BzAO activities were assayed in ovariectomized (3 weeks) and ovariectomized plus estrogen treated rats (17 beta-estradiol, 10 micrograms/kg/day, i.p. for three days). Compared with sham operated controls, MAO-A activity (total and specific) was decreased by ovariectomy and restored partially by estrogen treatment. In contrast, BzAO activity was not influenced selectively. Total BzAO activity followed changes in uterine weight such that the specific activity of BzAO, per mg tissue, was not statistically different between the three experimental groups. Although changes in the specific activity of BzAO were found on a protein and DNA basis, these changes reflect primarily alterations in protein and DNA contents and not BzAO activity. Since BzAO appears to be insensitive to direct modulation by sex steroids and may be located predominantly in uterine blood vessels, it is speculated that the enzyme may serve as a marker for hormonal influences on the vascularity and structure of the uterine vascular bed.

Animals↗
PubMed1982

Characteristics and specificity of phenelzine and benserazide as inhibitors of benzylamine oxidase and monoamine oxidase.

The selectivity of benserazide and phenelzine toward inhibition of benzylamine oxidase (BzAO) and monoamine oxidases (MAO-A and MAO-B) was studied in homogenates of rat skull and lung. In addition, the kinetic interaction and reversibility of BzAO inhibition were assessed. Both drugs inhibited BzAO but only phenelzine inhibited MAO, whether tested in vitro or in vivo. Neither compound acted as an irreversible inhibitor of BzAO. Benserazide was found to be a noncompetitive inhibitor. Phenelzine acted as a substrate for BzAO followed by product-induced noncompetitive inhibition which was labile at 37 degrees but not at 4 degrees. A reversible component in phenelzine-induced inhibition of MAO-A and -B is also suggested from in vivo studies.

Animals↗
PubMed1981

An alpha-adrenoceptor inhibitory action of kynuramine.

Kynuramine, an endogenously occurring amine, inhibited the vasoconstrictor responses to norepinephrine in the isolated perfused mesenteric arteries of rats and blocked the relaxation of rabbit intestinal smooth muscle by phenylephrine. Similarly, kynuramine reversed clonidine-induced inhibition of the cholinergic twitch response in the guinea pig ileum. These effects, seen with concentration ranging from 4 to 60 microgram/ml, are consistent with an alpha-adrenoceptor inhibitory action of kynuramine at both presynaptic and postsynaptic sites. Kynuramine itself, lacked intrinsic activity on alpha-adrenoceptors and showed a complete lack of affinity for beta-adrenoceptors in the rabbit intestine and guinea pig tracheal chain preparation. None of the effects of kynuramine could be attributed to the formation of 4-hydroxyquinoline, the deaminated metabolite of kynuramine. Additionally, no evidence was obtained for an action on muscarinic receptors or non-specific effects on vascular smooth muscle. However, a slight, transient stimulant action was evident on intestinal smooth muscle. It is concluded that kynuramine inhibits both presynaptic and postsynaptic alpha-adrenoceptors in vitro and it is conceivable that the compound might function as an endogenous inhibitor of alpha-adrenoceptors in vivo.

Adrenergic alpha-Antagonists↗
PubMed1981

Studies on the mechanism of captopril induced hypotension in rats.

The mechanism of the hypotensive response to captopril was investigated in pithed and urethane anesthetized rats. Cumulative intravenous doses of captopril produced dose-dependent hypotensive responses which were correlated with blockade of the pressor response to angiotensin I. Angiotensin II responses were unaffected. Infusions of saralasin, an angiotensin receptor antagonist, inhibited the hypotensive action of captopril, the degree of antagonism being correlated with inhibition of angiotensin II pressor responses. Bilateral nephrectomy lowered blood pressure to approximately the same level as captopril and completely abolished the hypotensive effect of captopril. No evidence was obtained for the involvement of endogenous bradykinin or prostaglandins in the hypotensive action of captopril. It is concluded that in pithed and urethane anesthetized rats, captopril mediates its hypotensive response by removing the renal renin-angiotensin system, most probably via inhibition of angiotensin I - converting enzyme. The results contrast with similar studies conducted in anesthetized dogs. In this species, the mechanism of action of captopril remains for further resolution.

Angiotensin I↗