Diazepam enhances inotropic responses to dopamine in rat ventricular myocardium.
Diazepam inhibits phosphodiesterase type 4 and enhances the effect of some 3',5'-cyclic adenosine monophosphate (cAMP)-dependent positive inotropic drugs. We sought to determine whether diazepam and the selective phosphodiesterase type 4 inhibitor rolipram enhances the contractile response and cAMP levels induced by dopamine in rat myocardium. Dopamine (3-100 microM) produced concentration-dependent positive inotropic effects (-log EC50 = 5.21 +/- 0.2, n = 5), which were augmented in the presence of 10 microM diazepam (-log EC50 = 5.40 +/- 0.08, n = 6, P < 0.05) or 1 microM rolipram (-log EC50 = 5.41 +/- 0.1, n = 6, P < 0.05). The effect of diazepam was not mimicked by 100 microM gamma-aminobutyric acid nor it was antagonized by a 5 microM concentration of the blockers of central and peripheral type benzodiazepine receptors, flumazenil and PK 11195. cAMP levels (pmol/g) produced by dopamine (744.4 +/- 111.8, n = 5) in this tissue were enhanced by the presence of diazepam (1073 +/- 97.7, n = 6, P < 0.05) or rolipram (1034.0 +/- 245.2, n = 5, P < 0.05). Therefore, diazepam, like rolipram, augments the inotropic and biochemical effects of dopamine in rat myocardium. This effect is not mediated by benzodiazepine receptors but is probably the consequence of the phosphodiesterase type 4 inhibitory activity of diazepam.
Departmento de Farmacologia, Facultad de Medicina, Murcia, Spain.
María Jesús
MJ
Juan-Fita
María Luisa
ML
Vargas
Jesús
J
Hernández
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004298:Dopamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function
D002316:Cardiotonic Agents; D003975:Diazepam; D004298:Dopamine