Cocaine and crack cocaine abuse have been reported to produce clinically significant cardiac depression, which in some patients may present as acute heart failure with cardiogenic pulmonary edema. Recent studies in our laboratory indicate that the negative inotropic actions of cocaine are mediated in part by muscarinic stimulation of the cardiac myocyte and may occur at low doses devoid of local anesthetic effect; methylecgonidine (MEG, the principle pyrolysis product of crack cocaine smoking) is more potent than cocaine as a muscarinic agonist on myocardium. The major goals of the proposed experiments are to delineate the cellular and molecular mechanisms that are affected by cocaine and MEG stimulation of cardiac muscarinic receptors, evaluate their functional significance with regard to contractile performance, and identify approaches to prevent or reverse their acute and subacute myocardial depressant effect in vivo. A variety of molecular and cellular techniques will be employed to identify the type(s) and subtype(s) of muscarinic receptors affected by cocaine versus MEG, which physiologic data indicate may differ, and to delineate specific cellular sites of action. The physiological significance of our findings will be tested in a model of ischemia that we predict will demonstrate the potential for these agents to exacerbate post ischemic cardiac dysfunction, or stunning. Experiments will be performed with ferret myocardium and transfected cell lines; however, we will demonstrate their relevance to man by confirmatory experiments with human myocytes. Taken together, these studies should enhance our understanding of the cellular mechanisms and functional significance of cocaine and MEG interaction with the cardiac muscarinic receptors and identify potential therapeutic approaches to the cardiac depression that can occur with abuse of these substances, even in patients with normal hearts.
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