Diazepam potentiates the effects of endogenous catecholamines on contractility and cyclic AMP levels in rat ventricular myocardium.
Diazepam has phosphodiesterase (PDE) inhibitory activity and potentiates the effect of some 3',5'-cyclic adenosine monophosphate (cAMP)-dependent positive inotropic agents. The present study was undertaken to determine whether diazepam enhances the contractile responses and cAMP levels induced by endogenous catecholamines in electrically driven rat right ventricular strips, and the effects are compared with that of the PDE inhibitor 3-isobutylmethylxantine (IBMX). Noradrenaline (10 nM(-1) microM), adrenaline (50 nM-500 microM) and tyramine (5-100 microM) produced concentration-dependent positive inotropic effects that were potentiated by the presence of 10 microM diazepam or IBMX. The diazepam-induced potentiation of the contractile effect of the sympathomimetic agents was not mimicked by 100 microM GABA nor was it antagonized by a 5 microM concentration of the blockers of central and peripheral type benzodiazepine receptors, flumazenil and PK 11195. The beta(2)-adrenergic receptor agonist salbutamol (0.1-300 microM) also produced a concentration-dependent positive inotropic effect which was potentiated by the presence of 10 microM diazepam or 10 microM IBMX. However, the contractile effect of salbutamol, either alone or in the presence of diazepam or IBMX, was not affected by 50 nM ICI 118551, an antagonist of beta(2)-adrenergic receptors, but was virtually abolished by a 0.3 microM concentration of CGP 20712A, an antagonist of beta(1)-adrenergic receptors. Diazepam and IBMX also potentiated the increase in cAMP levels caused by these three sympathomimetic agents in this tissue. [(3)H]Noradrenaline release elicited by electrical stimulation or by tyramine was not affected by diazepam. The results demonstrate that diazepam, like the phosphodiesterase inhibitor IBMX, produces an inotropic and biochemical potentiation of the effects of endogenous catecholamines in rat myocardium. This effect is not due to the release of noradrenaline at the presynaptic level nor is it mediated by beta(2)-adrenergic receptors or benzodiazepine receptors of the central or peripheral type. The effect is probably consequential upon the phosphodiesterase inhibitory activity of diazepam.
Marín
J
J
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Hernández
J
J
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002395:Catecholamines / Q000502:physiology*; D000242:Cyclic AMP / Q000096:biosynthesis*; D003975:Diazepam / Q000494:pharmacology*; D004357:Drug Synergism; D004558:Electric Stimulation; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical; D016276:Ventricular Function
D002395:Catecholamines; D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D003975:Diazepam; D015056:1-Methyl-3-isobutylxanthine