Volatile anesthetics are potent depressants of the cardiovascular system. In combination with calcium antagonists they can cause cardiac arrest and peripheral vascular collapse. Their combined effects on the heart may be difficult to interpret in the intact animal or human because of many variables such as drug disposition and baroreceptor induced reflex regulation. In isolated heart and in cardiac tissue preparations we have demonstrated the following: a) there is a pronounced interaction between enflurane and calcium antagonists on depressing cardiac function and A-V conduction; b) halothane improves functional recovery of isolated hearts from a hypoxic episode; c) the slow inward calcium current (ICa) is depressed by the three anesthetics, halothane, isoflurane and enflurane, at clinically relevant concentrations, and d) isoflurane depresses contractile force less than does halothane or enflurane at equipotent doses and does not cause a parallel depression of the intracellular Ca++ transient. This proposal is aimed to specifically study the following: a) direct and interactive effects of volatile anesthetics and calcium antagonists on transient (T) and long (L) components of the ICa using whole-cell voltage clamp experiments in freshly isolated ventricular cells obtained by enzymatic dissociation; b) direct and interactive effects of inhalational anesthetics and calcium antagonists on myofibrilla calcium sensitivity utilizing the Ca++ sensitive bioluminescent protein aequorin in isolated ventricular tissue; and c) effects of volatile anesthetics on reducing calcium overload to assess a role for reducing myocardial damage and the incidence of ventricular dysrhythmias during reperfusion following graded transient ischemia in the isolated heart. We will directly test the hypotheses that: 1) in the presence of calcium antagonists the volatile anesthetics differentially suppress the , 2) volatile anesthetics and calcium antagonists differentially alter myofibrilla responsiveness to Ca++; and 3) volatile anesthetics reduce myocardial damage during transient ischemia and reperfusion by directly modifying the influx and translocation of calcium. Our long term objective is to examine the molecular mechanisms of Ca++ fluxes as they apply to volatile anesthetics, and to examine the specific actions of various volatile anesthetics with calcium antagonists. These studies are designed to better understand the clinically observed cardiac effects of volatile anesthetics and calcium antagonists.