Alcohol exerts a variety of actions on the cardiovascular system, the nervous system, and other organs. Clinical studies, have linked alcohol consumption with a number of asymptomatic and overt cardiovascular abnormalities, including cardiomyopathy, hypertension, arrhythmias, heart failure, and stroke. The mechanisms responsible for these various problems are not well understood. In the nervous system, voltage activated calcium channels and certain ligand-gated channels arc particularly sensitive targets of alcohol. These channels are suspected of being instrumental in acute intoxication and withdrawal. In cardiac tissues, calcium channels play a key role in rhythmicity, conduction, and excitation-contraction coupling. These channels are a major site of control by endogenous hormones and transmitters, and by therapeutic drugs. Calcium channels have been directly linked to a number of the actions of ethanol on the heart. Ethanol interferes with contractility in a variety of models, and it reduces electrically-stimulated calcium transients in ventricular myocytes. Our preliminary data with rat myocytes, and results from other laboratories, have confirmed that ethanol blocks L-type calcium channels in isolated cardiac cells. Defining how alcohol affects the physiology and regulation of these channels is essential in explaining immediate consequences of alcohol ingestion, as well as events that occur during prolonged periods of alcohol ethanol abuse. The overall objective of the proposed studies is to use whole-cell patch clamp techniques to analyze ethanol modulation of cardiac calcium channels. Ventricular myocytes will be dissociated from cardiac tissues of adult rats, and subjected to acute alcohol exposure. Biophysical and pharmacological experiments will evaluate calcium channel function under these conditions, and impossible mechanisms of channel modulation. Certain second messenger systems are known to exert regulatory control over calcium channel function in heart cells. Among these, the beta- adrenergic/cAMP/PKA pathway is a critical mechanism for enhancing L-type calcium channels and stimulating cardiac contractility. We will therefore test the hypothesis that ethanol alters regulation of channels through this signal transduction system. Our preliminary data have shown that ethanol not only blocks currents stimulated via the beta-adrenergic system, but it also inhibits desensitization of the coupling process. We have also just completed exciting new preliminary studies demonstrating that ethanol is capable of reversing or occluding nifedipine-induced channel block. This novel action may have major implications, given the widespread clinical use of dihydropyridines and other calcium channel antagonists. Drug interactions of this type will be an important focus of the project.
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