ABSTRACT
The effects of benazepril hydrochloride (CGS 14824 A, CAS 86541-74-4), a novel angiotension I converting enzyme inhibitor, on the central nervous systems, were studied in experimental animals. Benazepril hydrochloride (3 or 10 mg/kg/d, p.o. for 14 days) dose-dependently inhibited the increase in the blood pressure caused by continuous norepinephrine (NE) infusion in spontaneously hypertensive rats (SHR) and suppressed in seizures induced by a monoamine oxidase inhibitor, tranylcypromine in NE infused SHR. Benazepril hydrochloride transiently increased spontaneous motor activity in mice, tended to inhibit acetic acid-induced writhing in mice and decreased fast wave sleep and slow wave deep sleep on EEG in cats at a high dose of 100 mg/kg p.o. However, benazepril hydrochloride at the same dose showed no effect on other central nervous and sensory systems in experimental animals.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Benzazepines/pharmacology , Central Nervous System/drug effects , Neurons, Afferent/drug effects , Acetates/antagonists & inhibitors , Acetic Acid , Animals , Anticonvulsants , Avoidance Learning/drug effects , Body Temperature/drug effects , Electroencephalography , Male , Methamphetamine/antagonists & inhibitors , Mice , Mice, Inbred Strains , Motor Activity/drug effects , Postural Balance/drug effects , Rats , Rats, Inbred SHR , Reflex/drug effects , Reserpine/antagonists & inhibitors , Tranylcypromine/antagonists & inhibitors , Tremorine/antagonists & inhibitorsABSTRACT
Cicletanine, a drug which affects membrane ion transport, induces a marked increase of the liberation of PGI2 as demonstrated by the increase of the stable metabolites in the plasma following intravenous administration of arachidonic acid. Furthermore, the inhibiting effect of tranylcypromine on prostacyclin synthetase is completely removed by this pharmacon. These observations are suggestive that this drug presents a scope for treatment of thrombotic disorders as well as hypertension.
Subject(s)
Diuretics/pharmacology , Prostaglandin-Endoperoxide Synthases/metabolism , Pyridines , Animals , Antihypertensive Agents , Biological Transport, Active/drug effects , Cyclooxygenase Inhibitors , Epoprostenol/blood , Ions , Male , Rabbits , Rats , Rats, Inbred Strains , Thrombosis/drug therapy , Tranylcypromine/antagonists & inhibitors , Tranylcypromine/pharmacologyABSTRACT
The isolated right rat atrium was used to investigate the chronotropic effects of dl-tranylcypromine and its d- and l-isomers. The concentration-effect curves of the three compounds were similar. The response of the preparation to the three drugs was completely blocked by pretreatment of the animal with reserpine, thus indicating an indirect effect of the drugs by the release of the natural mediator. Cocaine present in the bathing fluid partially antagonized the effect of dl-tranylcypromine and its isomers. It is concluded that the accumulation of the different forms of the drug by neural structures and the subsequent release of the neurotransmitter are not stereospecific processes. Furthermore it is suggested that the efflux of the neurotransmitter in the rat atrium may be carrier-mediated, and that this process is inhibited by cocaine.
Subject(s)
Heart Atria/drug effects , Tranylcypromine/metabolism , Animals , Cocaine/pharmacology , Heart Rate/drug effects , Male , Rats , Rats, Inbred Strains , Reserpine/pharmacology , Stereoisomerism , Tranylcypromine/antagonists & inhibitors , Tranylcypromine/pharmacologySubject(s)
Monoamine Oxidase Inhibitors/pharmacology , Oxazoles/pharmacology , Oxazolidinones , Animals , Brain/enzymology , Clorgyline/antagonists & inhibitors , Drug Interactions , Liver/enzymology , Male , Monoamine Oxidase Inhibitors/antagonists & inhibitors , Myocardium/enzymology , Oxazoles/antagonists & inhibitors , Rats , Serotonin/metabolism , Time Factors , Tranylcypromine/antagonists & inhibitorsABSTRACT
Injection of rats with tranylcypromine and L-dopa increased brain dopamine concentrations and produced a behavioural syndrome that includes hyperactivity. It also elevated caudate nucleus cyclic AMP concentrations by approximately 50% in vivo, probably by stimulating dopamine receptors. Pretreatment with chlorpromazine inhibited both the tranylcypromine/L-dopa-induced behaviour and elevated cyclic AMP concentrations in a dose-dependent manner. Haloperidol and alpha-flupenthixol also inhibited both effects, while beta-flupenthixol and pimozide were without effect. Since none of these drugs altered the tranylcypromine/L-dopa-induced rise of brain dopamine, it is likely that they produced their effect by inhibiting dopamine-sensitive adenylate cyclase. A good correlation was found to exist between the neuroleptic inhibition of both the increased behavioural activity and the increased caudate nucleus cyclic AMP concentrations produced by tranylcypromine and L-dopa.
Subject(s)
Antipsychotic Agents/pharmacology , Caudate Nucleus/metabolism , Cyclic AMP/metabolism , Levodopa/antagonists & inhibitors , Motor Activity/drug effects , Tranylcypromine/antagonists & inhibitors , Animals , Brain Chemistry/drug effects , Dopamine/analysis , Levodopa/pharmacology , Male , Norepinephrine/analysis , Rats , Tranylcypromine/pharmacologySubject(s)
Brain/drug effects , Cycloheximide/pharmacology , Motor Activity/drug effects , Nerve Tissue Proteins/biosynthesis , Tranylcypromine/antagonists & inhibitors , Tryptophan/antagonists & inhibitors , Animals , Brain/metabolism , Cycloheximide/administration & dosage , Injections, Spinal , Liver/metabolism , Male , Rats , Tranylcypromine/pharmacology , Tryptophan/pharmacologyABSTRACT
Hospitalized bipolar and unipolar endogenously depressed patients who showed an antidepressant response to the monoamine oxidase (MAO) inhibitor, tranylcypromine sulfate, relapsed (ie, depression returned) when relatively small doses of parachlorophenylalanine (PCPA) were added for brief periods. Considered together with our findings that PCPA similarly reversed the antidepressant effects of the tricyclic drug, imipramine hydrochloride, implications are (1) serotonergic mechanisms are likely involved in the antidepressant effects of both the tricyclic drugs and MAO inhibitors in man and (2) this indolamine may also play a role in the endogenous clinical state of depression.
