This proposed research project is part of a continuing investigation of the effects of adenosine and pyruvate on cardiac function in both normal and stunned myocardium. The studies are designed to expand the observation that adenosine and pyruvate play an important role in modulating the tolerance of the heart to ischemia as a result of adenosine A/1 receptor stimulation and enhancement of the myocardial phosphorylation potential, respectively. These agents are attractive candidates for preventing and treating reversible postischemic myocardial dysfunction because they are endogenous compounds which are rapidly metabolized and their salutary effects on cardiac function occur during both ischemia and reperfusion. Experiments will be performed in isolated myocytes and sarcoplasmic reticulum (SR) vesicles using electrophysiological and biochemical techniques, and in the intact pig subjected to regional and global myocardial ischemia.
The specific aims of the proposed research are to investigate: 1) the cellular and subcellular mechanisms of adenosine and pyruvate mediated attenuation of myocardial stunning. Normal and metabolically de- energized freshly harvested rat ventricular myocytes will be used to determine the effect of adenosine and pyruvate on: (a) the slow inward calcium current (I/Ca), (b) intracellular calcium concentration ([Ca+2]]/i), (c) the ATP dependent potassium channel (K/ATP) current, and (d) SR calcium handling (SR 45/Ca2+ uptake and SR Ca2+-ATPase activity). 2) the efficacy of adenosine and pyruvate as therapeutic agents to reduce or eliminate the level of requisite inotropic support by dobutamine using in vivo porcine models of regional and global myocardial stunning. Dose- related effects of adenosine/pyruvate and adenosine A/1 receptor agonists on the stunned heart will be compared to dobutamine by measuring end systolic pressure wall thickness relationships (ESPTR), cardiac output, left ventricular dP/dt, coronary blood flow, myocardial oxygen consumption, myocardial phosphorylation potential, interstitial fluid purine accumulation, and myocardial purine release before, during, and after ischemia in normal and acutely injured hearts. The proposed experiments are designed to elucidate the cellular mechanisms underlying the salutary effects of adenosine and pyruvate with the intent to further enhance their efficacy. The findings should lead to the development of new and specific therapeutic strategies to improve hemodynamic performance and therefore survival in patients with critical but reversible postischemic myocardial dysfunction.
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