Role of sodium-calcium exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts

Increased Na⁺-Ca²⁺ exchange (NCX) activity in heart failure and hypertrophy may compensate for depressed sarcoplasmic reticular Ca²⁺ uptake, provide inotropic support through reverse-mode Ca²⁺ entry, and/or deplete intracellular Ca²⁺ stores. NCX is electrogenic and depends on Na⁺ and Ca²⁺ 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 Ca²⁺ 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.