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(Circulation Research. 2004;95:292.)
© 2004 American Heart Association, Inc.

Cellular Biology

Partial Inhibition of Sodium/Calcium Exchange Restores Cellular Calcium Handling in Canine Heart Failure

Ion A. Hobai, Christoph Maack, Brian O’Rourke

From the Johns Hopkins University Institute of Molecular Cardiobiology, Department of Medicine, Baltimore, Md.

Correspondence to Brian O’Rourke, PhD, The Johns Hopkins University, Institute of Molecular Cardiobiology, 720 Rutland Ave, 844 Ross Bldg, Baltimore, MD 21205-2195. E-mail bor{at}jhmi.edu

Sodium/calcium (Na⁺/Ca²⁺) exchange (NCX) overexpression is common to human heart failure and heart failure in many animal models, but its specific contribution to the cellular Ca²⁺ ([Ca²⁺]_i) handling deficit is unclear. Here, we investigate the effects of exchange inhibitory peptide (XIP) on Ca²⁺ 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) Ca²⁺ load and a 44% reduction in the amplitude of the [Ca²⁺]_i transient, as compared with myocytes from normal hearts (N). Intracellular application of XIP (30 µmol/L) normalized the [Ca²⁺]_i transient amplitude in F (3.86-fold increase), concomitant with a similar increase in SR Ca²⁺ load. The degree of NCX inhibition at this concentration of XIP was 27% and was selective for NCX: L-type Ca²⁺ currents and plasmalemmal Ca²⁺ pumps were not affected. XIP also indirectly improved the rate of [Ca²⁺]_i removal at steady-state, secondary to Ca²⁺-dependent activation of SR Ca²⁺ uptake. The findings indicate that in the failing heart cell, NCX inhibition can improve SR Ca²⁺ load by shifting the balance of Ca²⁺ fluxes away from trans-sarcolemmal efflux toward SR accumulation. Hence, inhibition of the Ca²⁺ efflux mode of the exchanger could potentially be an effective therapeutic strategy for improving contractility in congestive heart failure.

Key Words: exchange inhibitor peptide • XIP • excitation–contraction coupling • calcium transient

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