The Sarcoplasmic Reticulum and the Na + /Ca 2+ Exchanger Both Contribute to the Ca 2+ Transient of Failing Human Ventricular Myocytes

Abstract

Abstract —Our objective was to determine the respective roles of the sarcoplasmic reticulum (SR) and the Na + /Ca 2+ exchanger in the small, slowly decaying Ca 2+ transients of failing human ventricular myocytes. Left ventricular myocytes were isolated from explanted hearts of patients with severe heart failure (n=18). Cytosolic Ca 2+ , contraction, and action potentials were measured by using indo-1, edge detection, and patch pipettes, respectively. Selective inhibitors of SR Ca 2+ transport (thapsigargin) and reverse-mode Na + /Ca 2+ exchange activity (No. 7943, Kanebo Ltd) were used to define the respective contribution of these processes to the Ca 2+ transient. Ca 2+ transients and contractions induced by action potentials (AP transients) at 0.5 Hz exhibited phasic and tonic components. The duration of the tonic component was determined by the action potential duration. Ca 2+ transients induced by caffeine (Caf transients) exhibited only a phasic component with a rapid rate of decay that was dependent on extracellular Na + . The SR Ca 2+ -ATPase inhibitor thapsigargin abolished the phasic component of the AP Ca 2+ transient and of the Caf transient but had no significant effect on the tonic component of the AP transient. The Na + /Ca 2+ exchange inhibitor No. 7943 eliminated the tonic component of the AP transient and reduced the magnitude of the phasic component. In failing human myocytes, Ca 2+ transients and contractions exhibit an SR-related, phasic component and a slow, reverse-mode Na + /Ca 2+ exchange–related tonic component. These findings suggest that Ca 2+ influx via reverse-mode Na + /Ca 2+ exchange during the action potential may contribute to the slow decay of the Ca 2+ transient in failing human myocytes.