Published online before print June 12, 2003, doi: 10.1161/01.RES.0000080932.98903.D8
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Submitted on July 24, 2002
Revised on May 29, 2003
Accepted on May 30, 2003
Role of Sodium-Calcium Exchanger in Modulating the Action Potential of Ventricular Myocytes From Normal and Failing Hearts
Antonis A. Armoundas ;
From The Johns Hopkins University, School of Medicine, Institute of Molecular Cardiobiology, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: bor{at}jhmi.edu.
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 (Em-ENCX, with E indicating equilibrium potential) 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. 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.
Key words: heart failure • Na+-Ca2+ exchanger • reversal potential • Ca2+ transients
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