Modulation of Ca2+ release in cardiac myocytes by changes in repolarization rate -: Role of phase-1 action potential repolarization in excitation-contraction coupling

The early rate of action potential (AP) repolarization varies in the mammalian heart regionally, during development, and in disease. We used confocal microscopy to assess the effects of changes in repolarization rate on spatially resolved sarcoplasmic reticulum (SR) Ca2+ release. The kinetics and peak amplitude of Ca2+ transients were reduced, and the amplitude, frequency, and temporal synchronization of Ca2+ spikes decreased as the rate of repolarization was slowed. The first latencies and temporal dispersion of Ca2+ spikes tracked closely with the time to peak and the width of the L-type Ca2+ current (I-Ca,I-L), suggesting that the effects of repolarization on excitation-contraction coupling occur primarily via changes in I-Ca,I-L. Next, we examined the effect of changes in the rapid early repolarization rate (phase 1) of a model human AP on SR Ca2+ release by varying the amount of transient outward K+ current. Slowing of phase-1 repolarization also caused a loss of temporal synchrony and recruitment of Ca2+-release events, associated with a reduced amplitude and lengthened time to peak of I-Ca,I-L. Isoproterenol application enhanced and largely resynchronized SR Ca2+ release, while it increased the magnitude and shortened the time to peak of I-Ca,I-L. Our data demonstrate that membrane repolarization modulates the recruitment and synchronization of SR Ca2+ release via I-Ca,I-L and illustrate a physiological role for the phase-1 notch of the AP in optimizing temporal summation and recruitment of Ca2+-release events. The effects of slowing phase-1 repolarization can be overcome by beta-adrenergic stimulation.