Inhibitors of prostaglandin synthesis augment beta-adrenergic responsiveness in canine coronary arteries.
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The effects of inhibition of endogenous prostaglandin synthesis on the release of norepinephrine from sympathetic nerves and on postjunctional adrenergic responsiveness were studied in isolated canine left circumflex coronary arteries. In rings, suspended for isometric tension recording and contracted with prostaglandin F2 alpha, transmural electrical stimulation caused frequency-dependent relaxations, which were blocked by propranolol and augmented by indomethacin. In superfused strips, previously incubated with [3H]norepinephrine, electrical stimulation (2 Hz) increased the overflow of tritiated neurotransmitter; indomethacin did not influence basal or evoked [3H]norepinephrine overflow. Exogenous norepinephrine caused relaxations in rings contracted with prostaglandin F2 alpha, but increases in tension in potassium-depolarized tissues which could be abolished by phentolamine; isoproterenol induced relaxations in both cases. Indomethacin significantly augmented the relaxation in response to exogenous norepinephrine (during contractions with prostaglandin F2 alpha) and reversed norepinephrine-induced contractions (during potassium-depolarization) into relaxation. Other cyclooxygenase inhibitors had comparable effects. In the presence of propranolol, indomethacin did not diminish contractions evoked by norepinephrine in depolarized rings. Relaxations induced by sodium nitroprusside or acetylcholine during contractions caused by prostaglandin F2 alpha or potassium chloride were not affected by indomethacin. The augmentation of beta-adrenergic responsiveness by indomethacin was abolished by exogenous prostacyclin. The prostacyclin synthetase inhibitor tranylcypromine and exogenous prostaglandin E2 depressed beta-adrenergic responsiveness. Indomethacin did not affect the facilitatory action of phosphodiesterase inhibition on beta-adrenergic relaxation. The data suggest that endogenous prostaglandins (most probably prostacyclin and prostaglandin E2) exert a "braking" effect on beta-adrenergic responsiveness in coronary arterial smooth muscle. (+info)
Reduced peripheral presynaptic adrenoceptor sensitivity following chronic antidepressant treatment in rats.
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Responses of the isolated vas deferens of the rat to clonidine (inhibition of contractions to field stimulation at 0.1 Hz) and noradrenaline (contraction of longitudinal muscle) were determined after one or 21 daily injections of the animals with desmethylimipramine, clorgyline, selegiline or tranylcypromine. Desmethylimipramine (10 mg kg-1) and clorgyline (2 mg kg-1) increased the clonidine EC50 in the isolated vas deferens after 21 but not after one daily injection(s). Tranylcypromine (5 mg kg-1) increased clonidine EC50 after both one and 21 injections and selegiline (1 mg kg-1) did not affect clonidine EC50 after either one or 21 injections. Only desmethylimipramine had a significant effect on noradrenaline responsiveness, producing an inconsistent decrease in EC50 with a consistent increase in maximum contractile response after 21 but not after one daily injection(s). Clorgyline (10(-5) M) increased the contractile response of the isolated vas deferens to field stimulation and antagonized the inhibitory effect of clonidine when added directly to the isolated tissue preparation. Neither clorgyline (5 mg kg-1), selegiline (1 mg kg-1) nor tranylcypromine (2.5 mg kg-1) affected significantly the inhibitory response to clonidine (1 microgram kg-1) on contractions of in situ sympathetically stimulated vas deferens in pithed rats. These results show that down-regulation of alpha 2-presynaptic adrenoceptors by chronic treatment with desmethylimipramine and clorgyline occurs in peripheral organs as well as in the central nervous system. (+info)
beta-Adrenoceptor antagonists inhibit the behavioural responses of rats to increased brain 5-hydroxytryptamine.
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1 The effect of various beta-adrenoceptor blocking agents on the 5-hydroxytryptamine (5-HT)-induced hyperactivity response produced in rats by administration of tranylcypromine (10 mg/kg i.p.) followed by L-tryptophan (50 mg/kg i.p.) has been investigated. 2 (+/-)-Alprenolol, (+/-)-timolol, (+/-)-sotalol, (+/-)-pindolol (all at 40 mg/kg) all inhibited the hyperactivity response to some degree when given 45 min before the tranylcypromine, as did (+/-)-oxprenolol when given after the L-tryptophan. 3 beta-Adrenoceptor antagonists that are not found in the brain appreciable amount after peripheral injection, (+/-)-atenolol, (+/-)-practolol, (+/-)-labetalol and (+/-)-acebutalol, did not inhibit the 5-HT-mediated behaviour. 4 Neither the beta1-selective drug (+/-)-metoprolol, nor the beta2-selective drug (+/-)-butoxamine inhibited the behavioral response. 5 The drugs that blocked the 5-HT-mediated behaviour did not alter brain 5-HT concentrations, synthesis rate or the accumulation of 5-HT following tranylcypromine/L-tryptophan. However, they did inhibit the hyperactivity produced by the suggested 5-HT agonist, 5-methoxy N,N-dimethyltryptamine, indicating that the beta-adrenoceptor blocking drugs were inhibiting the post-synaptic 5-HT-mediated response. 6 Circling produced by methamphetamine (3 mg/kg) in unilateral nigro-striatal lesioned rats was not altered by alprenolol, sotalol, pindolol or metaprolol, indicating that these drugs do not alter dopamine-mediated behaviour. 7 It is concluded that non-selective (beta1 and beta2) adrenoceptor antagonists which have a high brain/blood ratio following their peripheral injection, block 5-HT-mediated behavioural responses in the rat. (+info)
Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase.
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This is a reversed-phase liquid-chromatographic method, with electrochemical detection, for simultaneously measuring, in plasma, the concentrations of the catecholamine precursor dihydroxyphenylalanine (DOPA); the endogenous catecholamines norepinephrine, epinephrine, and dopamine; and the deaminated catecholamine metabolites dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG). We used this method to assess effects of monoamine oxidase (EC 1.4.3.4) inhibition in humans. Plasma DHPG concentrations as determined by the present method (mean 826, SEM 61 ng/L) were similar to those found by other methods. Inhibition of monoamine oxidase (by administering deprenyl or tranylcypromine) decreased plasma DHPG by greater than 65%, plasma DOPAC by greater than 50%, and plasma DOPA by about 20%, without consistently affecting norepinephrine or epinephrine. Simultaneous measurement of DOPA, catecholamines, and DHPG may be useful for examining the synthesis, release, and intraneuronal metabolism of norepinephrine. The assay method is rapid, reliable, and simple, and it provides a more comprehensive assessment of noradrenergic nervous function than does measurement only of catecholamines. (+info)
Electroconvulsive shock increases the behavioural responses of rats to brain 5-hydroxytryptamine accumulation and central nervous system stimulant drugs.
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1 A single electroconvulsive shock (ECS) of 150 V for 1 s increased the concentration of rat brain 5-hydroxyindoleacetic acid (5-HIAA) but did not alter brain 5-hydroxytryptamine (5-HT) or tryptophan concentrations 3 h later. 2 A single ECS decreased 5-HT synthesis 3 h and 6 h later. Synthesis was back to normal after 24 hours. The ECS-treated rats did not show greater hyperactivity produced by the increased brain 5-HT accumulation following administration of L-tryptophan and tranylcypromine at any time up to 24 h later. This suggests that a single electroshock does not alter 5-HT functional activity. 3 Twenty-four hours after the final ECS of a series of 10 shocks given once daily, the rats were given tranylcypromine and L-tryptophan. They displayed greater hyperactivity than control rats not treated with ECS, suggesting that ECS increases 5-HT functional activity. Brain concentrations of 5-HT, 5-HIAA and tryptophan were then unchanged by ECS. 5-HT synthesis and accumulation of 5-HT following tranylcypromine and L-tryptophan were not altered by ECS. 4 The hyperactivity following administration of the 5-HT agonist 5-methoxy N,N-dimethyltryptamine was enhanced by repeated (10 day) ECS, suggesting altered post-synaptic responses to 5-HT receptor stimulation. 5 Repeated ECS enhanced locomotor activity following tranylcypromine and L-DOPA. It did not alter brain noradrenaline or dopamine concentrations. 6 The latent period before a pentylenetetrazol-induced convulsion was shortened by repeated ECS. 7 Following repeated ECS there appears to be increased neuronal sensitivity to certain stimuli producing centrally mediated behavioural stimulation. This is discussed in relation to the mechanism by which electroconvulsive therapy (ECT) produces its therapeutic effect. (+info)
Synthesis of prostaglandin I2 (prostacyclin) by cultured human and bovine endothelial cells.
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Cultured endothelial cells derived from human umbilical veins or bovine aorta produce a potent inhibitor of platelet aggregation. The inhibitor is synthesized from sodium arachidonate or or prostaglandin endoperoxides by a microsomal enzyme system. Tranylcypromine, a specific antagonist of prostacyclin synthetase, suppresses production of the inhibitor by endothelial cells. The inhibitor, which is ether extractable, has been identified using a two-step thin-layer radiochromatographic procedure and a synthetic prostaglandin I2 standard. With this procedure, we have shown that human and bovine endothelial cells convert sodium [3H]arachidonate to radiolabeled prostaglandin I2 and 6-keto-prostaglandin F1alpha, as wellas prostaglandin E2. Thus, endothelial cells may be non-thrombogenic in vivo because they synthesize and release prostaglandin I2, a potent inhibitor of platelet aggregation. (+info)
Involvement of central serotonergic mechanisms in the cough reflex.
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To determine the role of central serotonergic systems in modulating the cough reflex, the effects of serotonergic agonists on the respiration and the cough reflex were comparatively studied. Male and female cats were anesthetized with sodium pentobarbital. Respiration and cough reflex were measured using a pneumotachograph via a cannula inserted into the trachea. The cough reflex was elicited by electrical stimuli to the superior laryngeal nerve. Tranylcypromine, a MAO inhibitor, in a dose of 5 mg/kg, i.v., increased the respiration, but depressed the cough reflex. The serotonin precursor 5-hydroxytryptophan (5 mg/kg, i.v.) depressed the respiration and the cough reflex. Haloperidol (2 mg/kg, i.v.) abolished the tranylcypromine-stimulated respiratory responses, and it intensified the tranylcypromine induced cough depression. It is concluded that the increase in serotonin levels in the brain has a depressant influence on the central generating mechanisms of the cough reflex. Furthermore, central dopaminergic mechanisms seem to play a modulating role on the cough reflex. (+info)
Effect of a prostaglandin E1 derivative (OP-1206) and acetylsalicylic acid on electrically induced thrombosis in guinea-pig mesenteric artery and its modification by an inhibitor of prostaglandin I2 synthetase, tranylcypromine.
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The antithrombotic effect of a prostaglandin E1 derivative, OP-1206 (17S-20-dimethyl-trans-delta 2-PGE1) X alpha-cyclodextrin clathrate (OP-1206 X alpha-CD), was compared with that of acetylsalicylic acid (ASA) in a electrically induced thrombosis model of guinea-pig mesenteric arteries using intact animals and animals subjected to the superfusion of tranylcypromine (TC, 15 mM) over their mesentery. The drug-effect was assessed by the change of the threshold voltage for the thrombus formation. 1) TC (1.5-15 mM) lowered the threshold voltage, and the effect was comparable to its inhibitory effect on PGI2 formation in vitro, suggesting that PGI2 generated in mesenteric arteries acts to prevent thrombus formation. 2) In intact animals, OP-1206 X alpha-CD at doses of 0.01-0.3 mg/kg, p.o. (as OP-1206), significantly and dose-dependently elevated the threshold voltage. ASA (30-1000 mg/kg, p.o.) significantly elevated the threshold voltage, but the effect reached to its maximum at 100 mg/kg and lessened with further increase of ASA. 3) In TC-treated animals, OP-1206 X alpha-CD elevated the threshold voltage dose-dependently, but the elevation of threshold voltage by ASA reached to its plateau level which was significantly lower than that obtained with OP-1206 X alpha-CD at 0.3 mg/kg, indicating that the antithrombotic effect of ASA is incomplete in this model.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)