Negative inotropic effect of diazepam in isolated guinea pig heart

The inotropic effect of diazepam, a benzodiazepine derivative, and its mech anism of action were examined using guinea pig heart and single ventricular cell preparations. In Langendorff hearts and right ventricular free-wall p reparations, diazepam (10 to 100 muM) produced a monophasic negative inotro pic effect in a concentration dependent manner. Neither a central type (flu mazenil 1 muM) nor a peripheral type (PK11195 10 muM) of benzodiazepine rec eptor antagonist antagonized the monophasic negative inotropic effects of d iazepam. Diazepam (10 to 100 muM) shortened action potential duration of pa pillary muscle in a concentration dependent manner. In isolated single vent ricular cells, diazepam (30 and 100 muM) inhibited the calcium current (I-C a) in a concentration dependent manner. Diazepam produced a significant dec rease in I-Ca elicited by first depolarizing pulses, however, the decrease of I-Ca was not augmented during a train of depolarizing pulses. Thus, diaz epam appears to produce a tonic block of cardiac calcium channels and the m ode of inhibition is clearly different from the use-dependent block of vera pamil. From these results, it was concluded that diazepam produces a monoph asic negative inotropic effect that is independent of the benzodiazepine re ceptor, and is probably mediated through an inhibition of I-Ca in guinea pi g heart preparations.