DIAZEPAM POTENTIATES THE POSITIVE INOTROPIC EFFECTS OF HISTAMINE AND FORSKOLIN IN GUINEA-PIG PAPILLARY-MUSCLES

There have been diverse reports on the effects of diazepam on cardiac contractility. The purpose of this study was to examine whether diazep am modifies the inotropic response elicited by histamine on an isolate d guinea-pig papillary muscle, The responses of electrically driven pa pillary muscle to histamine and cyclic AMP-related inotropic agents we re recorded in the absence and in the presence of diazepam, Histamine and forskolin, which directly stimulate adenylate cyclase, significant ly increased the contractile force in the papillary muscle in a concen tration-dependent manner. A histaminergic H-2-receptor antagonist, cim etidine, but not a Hi-receptor antagonist, diphenhydramine, at 10 mu M produced a rightward shift in the concentration-response curve for hi stamine. Diazepam (10 mu M) shifted the concentration-response curve f or histamine and forskolin to the left by 1.8 and 1.6 times, respectiv ely. Neither a central type (fulmazenil) nor a peripheral type (PK1119 5) of benzodiazepine receptor antagonist modified the effect of diazep am on the histaminergic-evoked contraction, Phosphodiesterase blockade by 3-isobutyl-1-methylxanthine shifted the concentration-dependent cu rve for histamine to the left. A combination of 3-isobutyl-1-methylxan thine also produced a leftward shift of the curve. However, there was no significant difference between the 3-isobutyl-1-methylxanthine only group and the combination group. These results indicate that diazepam potentiates the positive inotropic effect produced by histamine, prob ably mediated via an increase in cyclic AMP levels induced by histamin e.