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

摘要

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.