The basic mechanisms of the actions and interactions of ethanol and cocaine on the heart, and the possible role of their metabolite ethylcocaine, are still poorly understood. Even less is known about the influence of chronic ethanol ingestion on these actions and interactions. The goal of this proposal is to investigate the effects of chronic ethanol ingestion on the acute in vitro cardiac actions on ethanol and cocaine alone, or in combination, and of ethylcocaine. Rat litter-mates isocalorically pair-fed two different regimens of a liquid diet for 30 weeks will be used: a control diet without ethanol, and an experimental diet containing ethanol. A third litter mate will be allowed to consume solid and water ad libitum. Sinoatrial preparations and papillary muscles will be isolated from the study and the experimental animals to perform parallel experiments. Intracellular microelectrodes will be used to study: (a) the actions of the drugs on sinus node automaticity and atrial and ventricular membrane potentials and (b) their possible anti-arrhythmic or actions. The inotropic actions will be studied in papillary muscles using a force transducer. Specific protocols will be utilized to study the effects of the drugs (a) on preparations driven at a constant rate, and (b) on the force-interval relationship. Specific interventions will be employed to probe the mechanisms of the actions of ethanol, cocaine, and ethylcocaine under different inotropic states or drug enhancement or inhibition of particular cellular processes. The data collected will provide important information on the effects of chronic ethanol ingestion on the acute actions of ethanol and cocaine, and their metabolite ethylcocaine.
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