Partial inhibition of sodium/calcium exchange restores cellular calcium handling in canine heart failure

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

Research output: Contribution to journalArticle

Abstract

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+ ([Ca 2+]i) handling deficit is unclear. Here, we investigate the effects of exchange inhibitory peptide (XIP) on Ca2+ handling in myocytes isolated from canine tachycardie 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 2+ load and a 44% reduction in the amplitude of the [Ca 2+]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.

Original languageEnglish (US)
Pages (from-to)292-299
Number of pages8
JournalCirculation research
Volume95
Issue number3
DOIs
StatePublished - Aug 6 2004

Keywords

  • Calcium transient
  • Exchange inhibitor peptide
  • Excitation-contraction coupling
  • XIP

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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