The heart is a major locus for the toxic and lethal effects of cocaine. Cocaine ingestion leads to increases in heart rate and blood pressure, and at higher levels a number of serious cardiovascular consequences can result. These include depression of cardiac contractility, arrhythmia, ischemia, myocardial infarction and sudden death. Chronic cocaine abuse is also associated with cardiomyopathy. The complex cardiovascular effects of cocaine are believed to be a function of both its sympathomimetic action and its local anesthetic effects. We have demonstrated that cocaine has a direct effect on cardiac muscle cells to depress contractility, and that this results from inhibition of the cytosolic Ca2+ transients that underlie excitation-contraction coupling. Our preliminary data suggest that the major targets of cocaine involved in this action are sarcolemmal ion channels. We plan to continue our studies by investigating how the effects of cocaine on these ion channels contribute to the cocaine-induced depression of myocardial function. The direct effects of cocaine on myocardial cells occur against a background of elevated catecholamines in vivo. Since cocaine interacts with ion channels that are important targets for the adrenergic control of cardiac contractility, we will also investigate how cocaine modifies the regulation of these channels by catecholamines. The best characterized of the cardiac targets of cocaine is the Na+ channel, and it is likely that this contributes to both the depression of cardiac contractility and the altered conduction properties of the myocardium. We will investigate the mechanism of cocaine block using cloned Na+ channels from human and rat heart expressed in a mammalian cell line. This system will also be used for site-directed mutagenesis studies designed to characterize the molecular components involved in cocaine binding to the cardiac Na+ channel. The work proposed in this application will utilize a combination of fluorescent Ca2+ indicator, electrophysiology and molecular biology approaches. The long-term aim of these studies is to elucidate the role of the direct effects of cocaine on heart muscle cells in terms of the overall responses of the cardiovascular system to this drug in vivo.
