© 2000 American Heart Association, Inc.
Cellular Biology |
Enhanced Ca2+-Activated Na+-Ca2+ Exchange Activity in Canine Pacing-Induced Heart Failure
From the Institute of Molecular Cardiobiology, Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, Md.
Correspondence to Brian O’Rourke, PhD, Johns Hopkins University, Department of Medicine, Division of Cardiology, 844 Ross Bldg, 720 Rutland Ave, Baltimore, MD 21205. E-mail bor{at}jhmi.edu
Abstract—Defective excitation-contraction coupling in heart failure is generally associated with both a reduction in sarcoplasmic reticulum (SR) Ca2+ uptake and a greater dependence on transsarcolemmal Na+-Ca2+ exchange (NCX) for Ca2+ removal. Although a relative increase in NCX is expected when SR function is impaired, few and contradictory studies have addressed whether there is an absolute increase in NCX activity. The present study examines in detail NCX density and function in left ventricular midmyocardial myocytes isolated from normal or tachycardic pacing–induced failing canine hearts. No change of NCX current density was evident in myocytes from failing hearts when intracellular Ca2+ ([Ca2+]i) was buffered to 200 nmol/L. However, when [Ca2+]i was minimally buffered with 50 µmol/L indo-1, Ca2+ extrusion via NCX during caffeine application was doubled in failing versus normal cells. In other voltage-clamp experiments in which SR uptake was blocked with thapsigargin, both reverse-mode and forward-mode NCX currents and Ca2+ transport were increased >2-fold in failing cells. These results suggest that, in addition to a relative increase in NCX function as a consequence of defective SR Ca2+ uptake, there is an absolute increase in NCX function that depends on [Ca2+]i in the failing heart.
Key Words: Na+-Ca2+ exchange • heart failure • tachycardia
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