Cocaine is still widely used despite increasing reports of apparent idiosyncratic myocardial toxicity. At present, we are unable to identify individuals at risk for cocaine-related cardiac disease. Individuals vary in their susceptibility to toxic responses yet no animal model for cocaine-induced cardiac disease had been described reflecting this variability. Using measurements of several cardiovascular variables (e.g. cardiac output, systemic vascular resistance, stroke volume, and heart rate), we have identified variability in response characteristics that is related to variability in cocaine-induced cardiomyopathies but not to pressor responses. In most of our studies, we have separated the population into two groups to facilitate our analysis using cardiac output (CO) responses. Cocaine administration elicits consistent decreases in CO in vascular responders (formerly named responders). Vascular responders have a greater incidence of ultrastructural myocardial abnormalities (eg., dilated sarcoplasmic reticulum, myofibrillar and mitochondrial abnormalities and focal myocytolysis) after repeated cocaine administration while these changes are less severe or absent in rats without a decrease in CO (mixed responders, formerly nonresponders). Vascular responders also have smaller increases in heart rate and greater increases in systemic vascular resistance (SVR). Several agents alter the CO and arterial pressure responses independently suggesting that different mechanisms are involved. In this application, we propose to focus on two aspects of our findings; the variability in cardiovascular and in cardiomyopathic responsiveness. First, we will determine the specific cause of the decrease in CO and enhanced increase in SVR by measuring specific parameters that could be responsible for the variability such as contractility, coronary and skeletal muscle vascular responsivity and sympathetic nerve activity. In addition, we will examine the relative contribution of parasympathetic and sympathetic tone before and after cocaine and the possible causes of differential cardiac sensitivity to adrenergic agents. These studies will define causes of the CO and SVR variability. Second, we will perform morphometry to characterize the ultrastructural alterations in the myocardium of cocaine-treated rats and compare these to catecholamine and CNS stimulation-induced cardiomyopathies. The causes of ultrastructural changes will be examined directly using selective antagonists and cardiac denervation. Our results will characterize the causes of differential sensitivity to cocaine-induced cardiovascular responses and myocardial disease and may provide specific treatments for patients sensitive to cocaine-induced cardiac disease. Furthermore, our studies offer a novel model by which individuals at greater risk for cocaine- or stress-related heart disease may be identified.
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