Sudden death associated with ischemic heart disease is primarily a result of disturbances in cardiac rhythm leading to ventricular fibrillation. The proposed research is directed at further delineating the biochemical and electrophysiologic mechanisms responsible for the arrhythmogenic effects of catecholamines during myocardial ischemia and reperfusion. During the current grant interval, a major influence of alpha 1-adrenergic stimulation on arrhythmogenesis, during both ischemia and reperfusion, has been recognized, associated with a 2-fold reversible increase in alpha 1-adrenergic receptors. More recently, the sarcolemmal accumulation of endogenous long-chain acylcarnitines has been linked to the increase in alpha 1-adrenergic receptors. The proposed research is aimed at further characterizing this mechanism to determine if other amphiphiles, including lysophosphatides, known to accumulate in the ischemic heart, alter the exposure of alpha 1-adrenergic receptors, and whether the increase in receptor number is coupled to an increase in inositol trisphosphate (IP3) and stimulation of protein kinase C. The influence of stimulation of these exposed receptors on increases in intracellular Ca2+ will be evaluated using spectrofluorimetric analysis of fura-2. Analogous experiments will be performed in isolated human myocytes to determine whether alpha 1-adrenergic receptors exist on human myocytes, whether they increase in number in response to hypoxia through mechanisms analogous to that seen in canine and feline myocytes and whether stimulation of the receptors are coupled to phosphatidylinositol turnover and accumulation of intracellular Ca2+ measured with fura-2. The influence of hypoxia on the exposure of beta-adrenergic receptors and their coupling to adenylate cyclase will also be investigated. During the current grant interval, we have demonstrated that both reentrant and non- reentrant mechanisms contribute to arrhythmogenesis in the ischemic heart. The rapid acceleration of the non-reentrant mechanism is critical to the conversion of ventricular tachycardia to ventricular fibrillation. The cellular electrophysiologic effects of stimulation of alpha 1- and beta-adrenergic receptors under the above conditions in which the receptors are altered will be investigated using transmembrane action potential recordings in isolated myocytes. Analogous studies will be performed in vivo to determine the influence of both alpha 1- and beta-adrenergic stimulation on the reentrant and non-reentrant mechanisms occurring in the ischemic and reperfused heart using unique 3-dimensional mapping procedures.
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