Published online before print June 12, 2003, doi: 10.1161/01.RES.0000080932.98903.D8
© 2003 American Heart Association, Inc.
Cellular Biology |
Role of Sodium-Calcium Exchanger in Modulating the Action Potential of Ventricular Myocytes From Normal and Failing Hearts
From The Johns Hopkins University, School of Medicine, Institute of Molecular Cardiobiology (A.A.A., I.A.H., G.F.T., B.O.’R.) and the Whitaker Biomedical Engineering Institute (A.A.A., R.L.W.), Baltimore, Md.
Correspondence to Brian O’Rourke, PhD, The Johns Hopkins University, School of Medicine, Institute of Molecular Cardiobiology, 844 Ross Bldg, 720 Rutland Ave, Baltimore, MD 21205-2195. 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 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.
Key Words: heart failure • Na+-Ca2+ exchanger • reversal potential • Ca2+ transients
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