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.L), suggesting that the effects of repolarization on excitation-contraction coupling occur primarily via changes in I_Ca.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.L. Isoproterenol application enhanced and largely resynchronized SR Ca²⁺ release, while it increased the magnitude and shortened the time to peak of I_Ca.L. Our data demonstrate that membrane repolarization modulates the recruitment and synchronization of SR Ca²⁺ release via I_Ca.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 replarization can be overcome by β-adrenergic stimulation.