Partial inhibition of sodium/calcium exchange restores cellular calcium handling in canine heart failure.
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 micromol/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.
Hobai
Ion A
IA
Johns Hopkins University Institute of Molecular Cardiobiology, Department of Medicine, Baltimore, Md 21205-2195, USA.
Maack
Christoph
C
O'Rourke
Brian
B
D000595:Amino Acid Sequence; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000502:physiology; D013610:Tachycardia / Q000150:complications
D002316:Cardiotonic Agents; D010455:Peptides; D019831:Sodium-Calcium Exchanger; C066745:exchanger inhibitory peptide; D002110:Caffeine; D000252:Calcium-Transporting ATPases; D002118:Calcium