Block of cardiac Na channels is considered to be one of the primary mechanisms underlying both the therapeutic and cardiotoxic effects of Class I antiarrhythmic and local anesthetic agents. However, the molecular mechanisms by which these drugs exert their effects on cardiac Na channels is still poorly understood, and a matter of current debate. One of the major goals of this research proposal is to further elucidate the cellular basis by which local anesthetic-like agents exert their inhibitory affects on cardiac Na channels, and to define how the state-dependent interaction of local anesthetic-like agents are modified by physiological variables such as beta-adrenergic stimulation, pH and stage of development. This goal will be achieved by investigation of the Na channel blocking properties of Class I antiarrhythmic drugs and local anesthetics in isolated cardiac myocytes using the whole-cell voltage clamp technique. A second major goal of this proposal is to further define the mechanisms underlying cocaine cardiotoxicity using a combination of in vitro and in vivo techniques. Within the past decade cocaine use has become a major medical problem in the United States such that cocaine related deaths now account for a large fraction of emergency room deaths. Recent clinical reports strongly suggest that cocaine intoxication can precipitate life- threatening cardiac events, even in young healthy individuals. However, because there have been no systematic studies of the direct effects of cocaine on the heart in vivo, the mechanisms responsible for cocaine cardiotoxicity remain poorly understood. Therefore a second goal of this proposal will be to elucidate the major mechanisms underlying acute cocaine cardiac toxicity. The time course of drug effects on coronary blood flow, ventricular contractility, cardiac output, and cardiac electrophysiological properties (ECG) will be defined during drug infusions to delineate the mechanism(s) underlying cocaine cardiotoxicity in vivo. In addition, a combination of in vitro and in vivo experiments will also be performed to assess how the cardiotoxic effects of cocaine are modified by physiological derangements known to occur during severe cocaine intoxication (e.g. hypoxia/acidosis, tachycardia, hyperthermia, and elevated plasma catecholamine levels). Knowledge of the ways in which cocaine compromises cardiac function should provide insight into new ways to reverse or treat cocaine-induced cardiotoxicity. An additional goal of this proposal is to test the hypothesis that administration of lidocaine can improve cardiac conduction in vivo when conduction has been depressed by cocaine. The test of this hypothesis is of relevance to the clinical treatment of local anesthetic overdose.