Role of Sodium-Calcium Exchanger in Modulating the Action Potential of Ventricular Myocytes From Normal and Failing Hearts

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Abstract
Increased Na + -Ca 2+ exchange (NCX) activity in heart failure and hypertrophy may compensate for depressed sarcoplasmic reticular Ca 2+ uptake, provide inotropic support through reverse-mode Ca 2+ entry, and/or deplete intracellular Ca 2+ stores. NCX is electrogenic and depends on Na + and Ca 2+ transmembrane gradients, making it difficult to predict its effect on the action potential (AP). Here, we examine the effect of [Na + ] i on the AP in myocytes from normal and pacing-induced failing canine hearts and estimate the direction of the NCX driving force using simultaneously recorded APs and Ca 2+ transients. AP duration shortened with increasing [Na + ] i and was correlated with a shift in the reversal point of the NCX driving force. At [Na + ] i ≥10 mmol/L, outward NCX current during the plateau facilitated repolarization, whereas at 5 mmol/L [Na + ] i , NCX had a depolarizing effect, confirmed by partially inhibiting NCX with exchange inhibitory peptide. Exchange inhibitory peptide shortened the AP duration at 5 mmol/L [Na + ] i and prolonged it at [Na + ] i ≥10 mmol/L. With K + currents blocked, total membrane current was outward during the late plateau of an AP clamp at 10 mmol/L [Na + ] i and became inward close to the predicted reversal point for the NCX driving force. The results were reproduced using a computer model. These results indicate that NCX plays an important role in shaping the AP of the canine myocyte, helping it to repolarize at high [Na + ] i , especially in the failing heart, but contributing a depolarizing, potentially arrhythmogenic, influence at low [Na + ] i .