The Direct Effects of Diazepam and Midazolam on Myocardial Depression in Cultured Rat Ventricular Myocytes

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Abstract
We examined the direct myocardial depressant effects of diazepam and midazolam 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 rat ventricular myocytes. Ventricular myocytes of neonatal rats were obtained by enzymatic digestion with collagenase and cultured for 6-7 days. The myocytes were stabilized in serum-free medium, and the spontaneous beating rate and amplitude were measured by determining displacement with a fiberoptic sensor. Myocytes were exposed to either diazepam or midazolam at concentrations of 0.1, 1, 10, and 100 micro M. The beating rate and amplitude were measured 4 min after diazepam or midazolam administration. In other cells, either diazepam or midazolam was administered at each concentration in the presence of flumazenil or Bay K 8644. Midazolam and diazepam decreased the beating rate and amplitude concentration-dependently. These myocardial depressant effects were prevented by Bay K 8644 and, to a lesser degree, by flumazenil. Thus, the 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 contraction using cultured rat ventricular heart cells. Both of these drugs have a direct myocardial depressant effect at the cellular level, which is mainly mediated by an inhibition of the sarcolemmal L-type Ca2+ channel. (Anesth Analg 1997;85:729-33)