The sarcoplasmic reticulum and the Na+Ca2+ exchanger both contribute to the Ca2+ transient of failing human ventricular myocytes

Our objective was to determine the respective roles of the sarcoplasmic ret iculum (SR) and the Na+/Ca2+ exchanger in the small, slowly decaying Ca2+ t ransients of failing human ventricular myocytes. Left ventricular myocytes were isolated from explanted hearts of patients with severe heart failure ( n=18), Cytosolic Ca2+, contraction, and action potentials were measured by using indo-1, edge detection, and patch pipettes, respectively. Selective i nhibitors of SR Ca2+ transport (thapsigargin) and reverse-mode Na+/Ca2+ exc hange activity (No. 7943, Kanebo Ltd) were used to define the respective co ntribution of these processes to the Ca2+ transient. Ca2+ transients and co ntractions induced by action potentials (AP transients) at 0.5 Hz exhibited phasic and tonic components. The duration of the tonic component was deter mined by the action potential duration. Ca2+ transients induced by caffeine (Caf transients) exhibited only a phasic component with a rapid rate of de cay that was dependent on extracellular Na+. The SR Ca2+-ATPase inhibitor t hapsigargin abolished the phasic component of the AP Ca2+ transient and of the Caf transient but had no significant effect on the tonic component of t he AP transient. The Na+/Ca2+ exchange inhibitor No. 7943 eliminated the to nic component of the AP transient and reduced the magnitude of the phasic c omponent. In failing human myocytes, Ca2+ transients and contractions exhib it an SR-related, phasic component and a slow, reverse-mode Na+/Ca2+ exchan ge-related tonic component. These findings suggest that Ca2+ influx via rev erse-mode Na+/Ca2+ exchange during the action potential may contribute to t he slow decay of the Ca2+ transient in failing human myocytes.