During acute myocardial ischemia, extracellular K accumulation is a major factor predisposing the heart to the development of reentrant arrhythmias and VF. The mechanism, however, remains controversial. Two major hypotheses are: activation of metabolically-sensitive K channels such as ATP-sensitive K(KATP) channels, and K loss coupled to anion efflux (lactate and/or Pi) as a charge-balancing mechanism. The major goals of this project are to further elucidate the role of KATP channels in cellular K loss during hypoxia and ischemia, to characterize the biophysical, regulatory and pharmacologic properties of KATP channels in greater detail, and to evaluate mechanisms of transsarcolemmal lactate movement and its relationship to cation fluxes in heart. The effects of activation of KATP channels on cellular K loss will be studied in isolated arterially perfused rabbit interventricular septa loaded with 43K to measure unidirectional K efflux rate of tissue K content during exposure to KATP channel agonists. Our preliminary findings indicate that selective activation of KATP channels with cromakalim caused action potential shortening and an increase in unidirectional K efflux rate similar to hypoxia, but did not cause net K loss. In the proposed experiments we will activate the hypothesis that in addition to activation of KATP channels, enhancement of inward currents is required for net K loss to occur. Experimental findings in the rabbit septum will also be simulated in a computer model of the ventricular action potential to provide further insights. We will contribute to investigate the biophysical, regulatory and pharmacologic properties of KATP channels, using patch clamp techniques in isolated ventricular myocytes. We will attempt to delineate the mechanism by which glycolysis preferentially regulates KATP channel activity. We will test a novel hypothesis that surface charge plays an important physiologic role in regulating the ATP- sensitivity of KATP channels. We will explore our observation that c Ca- dependent process during severe metabolic inhibition irreversibly modified the ATP-sensitivity of KATP channels, and that treatment of the cytosolic surface of excised inside-out membrane patches with trypsin and other agents mimicked this effect. These observations will be investigated further to provide insight into channel regulation under pathophysiological conditions, and to gain insight into how proteolysis and chemical modification of KATP channels alters function. The final major goal is to evaluate the mechanisms of transmembrane lactate movement in heart and its relationship to cation (particularly K) fluxes. We have developed a novel method for studying transmembrane lactate movement in isolated patch-clamped cardiac myocytes using fluorescent indicators to monitor intracellular H, K and Na in response to lactate influx for this purpose. These studies should provide important new insights into the mechanisms of a major arrhythmogenic factor, extracellular K accumulation, contributing to sudden death during acute myocardial ischemia.
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