Intracellular Ca (Cai) overload is a well-known arrhythmogenic factor which contributes to focal arrhythmias by promoting automaticity and triggered activity, and to reentry by facilitating cellular uncoupling and slow conduction. As a sequela of myocardial ischemia and reperfusion, Cai overload contributes to cellular injury and arrhythmias, including ventricular fibrillation. However, the cellular mechanisms responsible for Cai overload during ischemia/reperfusion remain incompletely understood. The objective of this proposal is to characterize the subcellular mechanisms by which metabolic inhibition and components of the ischemia environment alter Cai regulation in isolated ventricular myocytes. Cai (using fura-2), membrane current and voltage, and cell shortening will be monitored simultaneously in isolated rabbit and guinea pig ventricular myocytes under whole cell patch clamp conditions during exposure to metabolic inhibitors (combined or selective inhibition of glycolysis and oxidative metabolism) and to various components of the ischemic environment (e.g. oxygen free radicals and amphiphiles). Using a rapid extracellular solution exchange device to facilitate pharmacologic interventions and ionic substitutions, we will characterize in detail the effects of these interventions on individual components of excitation-contraction coupling responsible for regulating Cai, including the Ca current (L and T types), Na-Ca exchange, the sarcoplasmic reticulum, mitochondria and the sarcolemmal Ca pump. We will also perform studies in giant excised membrane patches to assess the effects of components of the ischemic environment on Na-Ca exchange. A second major goal is to explore the mechanisms by which Cai overload causes arrhythmias. In particular, we will test a hypothesis predicted from the computer simulations of the cardiac action potential described in Project 3; namely that, by delaying or accelerating diastolic depolarization, delayed afterdepolarizations due to Cai overload are capable of producing a chaotic arrhythmia in a single myocyte. If a chaotic arrhythmia can be produced in the isolated myocyte, it may be amenable to 'chaos control' using the pacing algorithm described in Project 3, which will allow us to study the mechanisms of chaos control at a cellular and subcellular level using patch-clamp and fluorescent indicator techniques. These studies will provide important new information about pathogenesis of abnormal Cai regulation relevant to myocardial ischemia/reperfusion, and its arrhythmogenic consequences.
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