THE DIRECT EFFECTS OF DIAZEPAM AND MIDAZOLAM ON MYOCARDIAL DEPRESSIONIN CULTURED RAT VENTRICULAR MYOCYTES

We examined the direct myocardial depressant effects of diazepam and m idazolam and determined whether a benzodiazepine receptor antagonist, flumazenil, or an L-type Ca2+ channel agonist, Bay K 8644, affects the myocardial depression induced by diazepam and midazolam in cultured r at ventricular myocytes. Ventricular myocytes of neonatal rats were ob tained. by enzymatic digestion with collagenase and cultured for 6-7 d ays. The myocytes were stabilized in serum-free medium, and the sponta neous beating rate and amplitude were measured by determining displace ment with a fiberoptic sensor. Myocytes were exposed to either diazepa m or midazolam at concentrations of 0.1, 1, 10, and 100 mu M. The beat ing rate and amplitude were measured 4 min after diazepam or midazolam administration. In other cells, either diazepam or midazolam was admi nistered at each concentration in the presence of flumazenil or Bay K 8644. Midazolam and diazegam decreased the beating rate and amplitude concentration-dependently. These myocardial depressant effects were pr evented by Bay K 8644 and, to a lesser degree, by flumazenil. Thus, th e L-type Ca2+ channel is important in the direct myocardial depression caused by diazepam and midazolam. Implications: This study describes the direct effect of midazolam and diazepam on intrinsic myocardial co ntraction using cultured rat ventricular heart cells. Both of these dr ugs have a direct myocardial depressant effect at the cellular level, which is mainly mediated by an inhibition of the sarcolemmal L-type Ca 2+ channel.