Cocaine is a potent central nervous system stimulant and local anesthetic with limited clinical usefulness that has become one of the most widely abused drugs in the U.S. Due to the lack of sufficient scientific data, cocaine is generally considered a """"""""safe"""""""" drug with minimal side effects amongst the estimated 10 to 20 million people who misuse cocaine. Studies describing the cardiovascular effects of cocaine have noted a modest pressor response and tachycardia presumably due to direct potentiation of catecholaminergic activity and indirect (CNS-mediated) sympathoexcitation. Clinical reports suggest that cocaine may cause cardiac myopathies in humans. The incidence of such reports is increasing as is the use of free base cocaine (""""""""crack""""""""), a more potent form of cocaine. We believe this necessitates detailed studies to define the effects of acute and chronic cocaine administration under controlled conditions and to determine the mechanisms by which cocaine elicits its effects on the vasculature and myocardium. The vascular effects of cocaine will be analyzed in awake, freely-moving rats instrumented for measurement of arterial pressure, heart rate and regional blood flows in the mesenteric and hindquarter vascular beds. The mechanisms by which specific cardiovascular effects are caused will be identified using selective receptor antagonists, local anesthetics and adrenalectomy after acute or chronic cocaine. Furthermore, tissue catecholamine turnover will be estimated after chronic cocaine administration to identify sustained alterations in sympathetic nerve activity. The incidence and severity of cardiomyopathies will be determined functionally by measuring cardiac output, levels of myocardial creatine phosphokinase and anatomically by postmortem, light and electron microscopic analysis of the myocardium. The mechanisms by which cardiac ischemia are produced will be deduced using selective antagonists for vasospasm and thrombotic occlusion. The effect of cocaine on baroreflex function will be determined in unanesthetized normal and baro-denervated rats by recording sympathetic nerve activity and heart rate responses to cocaine. CNS sites affecting baroreflex activity will also be examined. Finally, the effect of """"""""free base"""""""" cocaine on cardiovascular function will be compared to that of cocaine hydrochloride. The proposed studies represent a comprehensive approach utilizing the combined expertise of three investigators. This approach will be instrumental in determining mechanisms whereby cocaine affects vascular tone, on the functional and pathological effects of cocaine on the myocardium, on the proposed role of cocaine as a centrally acting sympathoexcitatory agent, on rational drug therapy for toxicity and on the relative dangers of free base cocaine.
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