Abstract-Sodium/calcium (Na ϩ /Ca 2ϩ ) exchange (NCX) overexpression is common to human heart failure and heart failure in many animal models, but its specific contribution to the cellular Ca 2ϩ ([Ca 2ϩ ] i ) handling deficit is unclear. Here, we investigate the effects of exchange inhibitory peptide (XIP) on Ca 2ϩ handling in myocytes isolated from canine tachycardic pacing-induced failing hearts. Whole-cell patch-clamped left ventricular myocytes from failing hearts (F) showed a 52% decrease in steady-state sarcoplasmic reticulum (SR) Ca 2ϩ load and a 44% reduction in the amplitude of the [Ca 2ϩ ] i transient, as compared with myocytes from normal hearts (N). Intracellular application of XIP (30 mol/L) normalized the [Ca 2ϩ ] i transient amplitude in F (3.86-fold increase), concomitant with a similar increase in SR Ca 2ϩ load. The degree of NCX inhibition at this concentration of XIP was Ϸ27% and was selective for NCX: L-type Ca 2ϩ currents and plasmalemmal Ca 2ϩ pumps were not affected. XIP also indirectly improved the rate of [Ca 2ϩ ] i removal at steady-state, secondary to Ca 2ϩ -dependent activation of SR Ca 2ϩ uptake. The findings indicate that in the failing heart cell, NCX inhibition can improve SR Ca 2ϩ load by shifting the balance of Ca 2ϩ fluxes away from trans-sarcolemmal efflux toward SR accumulation. Hence, inhibition of the Ca 2ϩ efflux mode of the exchanger could potentially be an effective therapeutic strategy for improving contractility in congestive heart failure. (Ca 2ϩ ) handling is a key factor in the pathophysiology of heart failure. A typical failing heart cell shows a decrease in the ability of the internal stores (the sarcoplasmic reticulum [SR]) to load with Ca 2ϩ , and an increase in Ca 2ϩ extrusion from the cell by the sodium/ calcium exchanger (NCX). NCX overexpression is a component of altered Ca 2ϩ handling in human 1 and animal models, 2,3 but it is unclear whether it is compensatory or contributes to dysfunction. One widely held hypothesis is that NCX overexpression compensates for decreased Ca 2ϩ reuptake into the SR by increasing Ca 2ϩ extrusion from the cell, 4,5 which improves relaxation (positive lusitropic) but at the cost of a further depletion of SR Ca 2ϩ stores (negative inotropic). Further complicating the issue is the observation that NCX overexpression is also found in hypercontractile models with no SR dysfunction. 6 We studied the effect of partially correcting the NCX overexpression (by applying an exchange inhibitory peptide [XIP]) in a canine model of heart failure. Partial inhibition of NCX normalized both SR Ca 2ϩ release and re-uptake, arguing for a critical role for NCX overexpression in the Ca 2ϩ handling deficit as well as for its potential as a therapeutic target.
Materials and MethodsThese experiments were performed using a canine tachycardic pacing-induced heart failure model. We, 2,7,8 and others, 9 have previously demonstrated that this animal model reproduces a remarkable number of features of the human disease. Induction of heart failu...