Abstract
Large-conductance calcium and voltage-activated potassium channels (BK Ca ) are heterogeneously expressed in a wide array of cells. In adult ventricular cardiomyocytes, activation of mitochondrial BK Ca channels is implicated in cardioprotection against ischemia-reperfusion (IR) injury. However, plasma membrane BK Ca channel activity has never been detected in adult ventricular cardiomyocytes. In this study, we report the presence of the BK Ca channel in the plasma membrane and mitochondria of neonatal murine and rodent cardiomyocytes. In neonatal cardiomyocyte (NCM), whole-cell potassium currents measured were sensitive to iberiotoxin (IbTx), suggesting the presence of BK Ca channels in the plasma membrane. Moreover, the open probability of single-channel recording decreased in presence of IbTx by 46+5% (n=10) and 32+5% (n=10) for rats and mice, respectively. Ex vivo studies with isolated neonatal hearts (p6) subjected to ischemia and post-conditioned with NS1619 during reoxygenation increased (58+3% as opposed to 48+5% for control, n>5 pups) the myocardial infarction whereas IbTx reduced (32+2%) the infarct size. In agreement, isolated NCM also presented increased apoptosis on treatment with NS1619 during hypoxia-reoxygenation (HR), whereas IbTx reduced TUNEL positive cells. In NCMs, activation of BK Ca channels increased the intracellular reactive oxygen species post HR injury. Electrophysiological characterization of NCMs indicated that NS1619 increased the beat period, field, and action potential duration, and decreased the conduction velocity and spike amplitude. In contrast, IbTx had no impact on the electrophysiological properties of NCMs. Taken together, our data established that inhibition of plasma membrane BK Ca channels in the neonates protects the heart/cardiomyocytes from IR injury. Furthermore, the functional disparity observed towards the cardioprotective activity of BK Ca channels in adults compared to neonatal heart could be attributed to their differential localization.
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