ETHANOL AND CARDIOPROTECTION FROM ISCHEMIA--NMR STUDIES

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Recent studies have indicated that moderate ethanol consumption induces a chronic state of cardio-protection which results in reduced ischemia/reperfusion injury. The mechanisms for this protection are largely unknown but may overlap with those induced by ischemic preconditioning. The understanding of the mechanisms by which ethanol induces a stable state of cardioprotection are of great interest in regards to the eventual implementation of such protection in the clinical arena. The final effector mechanisms for the cardioprotection induced by either ischemic preconditioning or ethanol consumption are poorly understood. Little data is available in the ethanol protected heart, which address metabolic variables involved with ischemic injury, and how they may be altered. Guinea pigs will be given 10 percent ethanol for a period of 6 weeks, and compared to age matched controls. Hearts will be isolated and Langendorff perfused; function will be measured by left ventricular balloon. Specific Aim I is to investigate the cationic and energetic effects of regular ethanol consumption during subsequent myocardial ischemia/reperfusion, in order to evaluate the involvement of such effects in the concomitant improvement of postischemic function in the ethanol protected heart. Intracellular Na+, pH and high energy phosphates will be assessed during ischemia/reperfusion in the perfused guinea pig heart using interleaved 23Na+ and 31P NMR spectroscopy. 19F NMR spectroscopy and atomic absorption techniques will be used to measure changes in cytosolic free Ca2+ and tissue Ca2+, respectively. Lactate dehydrogenase release will be measured. These experiments will test the hypothesis that the functional improvement (and decreased cell death) observed with regular moderate alcohol consumption is associated with an altered pattern of energetic depletion and cation overload during ischemia and/or reperfusion In addition, the project will investigate the role of the ATP dependent K+ (KATP) channel in ethanol-induced cardioprotection. This KATP channel which is normally only activated under ischemic conditions, has been shown to play a clinical role in cardioprotection arising from ischemic preconditioning. It's role in ethanol induced preconditioning is unknown. Specific Aim 2 is to test the hypothesis that KATP channel activation is required for the improvement of postischemic function in ethanol protected myocardium, as well as the associated alterations in the cationic and energetic state during ischemia and/or reperfusion. This will be accomplished by administration of a specific KATP channel inhibitor, 5-hydroxydecanoate.