Phase 1 repolarization rate defines Ca dynamics and contractility on intact mouse hearts.

In the heart, Ca influx through L-type Ca channels triggers Ca release from the sarcoplasmic reticulum. In most mammals, this influx occurs during the ventricular action potential (AP) plateau phase 2. However, in murine models, the influx through L-type Ca channels happens in early repolarizing phase 1. The aim of this work is to assess if changes in the open probability of 4-aminopyridine (4-AP)-sensitive Kv channels defining the outward K current during phase 1 can modulate Ca currents, Ca transients, and systolic pressure during the cardiac cycle in intact perfused beating hearts. Pulsed local-field fluorescence microscopy and loose-patch photolysis were used to test the hypothesis that a decrease in a transient K current (I) will enhance Ca influx and promote a larger Ca transient. Simultaneous recordings of Ca transients and APs by pulsed local-field fluorescence microscopy and loose-patch photolysis showed that a reduction in the phase 1 repolarization rate increases the amplitude of Ca transients due to an increase in Ca influx through L-type Ca channels. Moreover, 4-AP induced an increase in the time required for AP to reach 30% repolarization, and the amplitude of Ca transients was larger in epicardium than endocardium. On the other hand, the activation of I with NS5806 resulted in a reduction of Ca current amplitude that led to a reduction of the amplitude of Ca transients. Finally, the 4-AP effect on AP phase 1 was significantly smaller when the L-type Ca current was partially blocked with nifedipine, indicating that the phase 1 rate of repolarization is defined by the competition between an outward K current and an inward Ca current.