Reports of cardiovascular problems, such as myocardial infarction, temporally related to cocaine use are increasing. Many cases have occurred in young individuals without pre-existing heart disease. Although at least two of the pharmacologic actions of cocaine (i.e. inhibition of neuronal catecholamine uptake and local anesthesia) are well established, the mechanism(s) of its cardiovascular actions are not understood. Clearly, the above two actions would be expected to have opposite effects on the cardiovascular system (i.e., cardiac stimulation and vasoconstriction vs. cardiac depression and vasodilation, respectively). At present the relationship between the dose-response curves for these two actions of cocaine on the cardiovascular system has not been well established. Thus, both quantitatively and qualitatively, the cardiovascular effects of cocaine probably depend upon its dose and any pre-existing factors which modify either of its established actions. The proposed studies are designed to; 1) investigate the mechanism(s) by which cocaine exerts its cardiac and vascular actions in vivo: 2) study the effects of cocaine on coronary blood flow in a region of myocardial ischemia; 3) evaluate the time-course of the apparent acute tolerance to the cardiovascular actions of cocaine and its relationship to cocaine plasma concentration; 4) assess the effects (beneficial and/or detrimental) of other drugs on the actions of cocaine and 5) study the effects of cocaine on isolated coronary and peripheral arterial rings, including the internal mammary artery, which is frequently utilized for coronary bypass. The first group of studies will determine the relative importance of cocaine actions in the CNS vs the peripheral autonomic nervous system to ists cardiovascular effects. To define the role of the CNS in the cardiovascular actions of cocaine, a key experiment which we will employ will be the classical cross-perfused head preparation, which allows separation of cerebral from systemic blood circulation, while leaving innervation intact. The relative contributions of sympathetic neuronal activity and adrenal medullary activity to the actions of cocaine will also be studied. The relative contributions of adrenergic and local anesthetic actions on myocardial function and the relationship between myocardial oxygen supply and demand will also be studied. All studies will be performed in chronically instrumented conscious dogs, where appropriate. In experiments requiring anesthesia, urethane, and anesthetic demonstrated not to interfere with the cardiovascular actions of cocaine will be used.
