Phase 1 repolarization rate defines Ca 2+ dynamics and contractility on intact mouse hearts

LÓPEZ ALARCÓN, MARÍA MICAELA; RODRÍGUEZ DE YURRE, AINHOA; FELICE, JUAN IGNACIO; MEDEI, EMILIANO; ESCOBAR, ARIEL L.

JOURNAL OF GENERAL PHYSIOLOGY

ROCKEFELLER UNIV PRESS

Año: 2019

0022-1295

In the heart, Ca2+influx through L-type Ca2+ channels triggers Ca2+ releasefrom the sarcoplasmic reticulum. In most mammals, this influx occurs during theventricular action potential (AP) plateau phase 2. However, in murine models,the influx through L-type Ca2+ channels happens in earlyrepolarizing phase 1. The aim of this work is to assess if changes in the openprobability of 4-aminopyridine (4-AP)?sensitive Kv channels defining theoutward K+ current during phase 1 can modulate Ca2+currents, Ca2+ transients, and systolic pressure during the cardiaccycle in intact perfused beating hearts. Pulsed local-field fluorescencemicroscopy and loose-patch photolysis were used to test the hypothesis that adecrease in a transient K+ current (Ito) will enhance Ca2+influx and promote a larger Ca2+ transient. Simultaneous recordingsof Ca2+ transients and APs by pulsed local-field fluorescencemicroscopy and loose-patch photolysis showed that a reduction in the phase 1repolarization rate increases the amplitude of Ca2+ transients dueto an increase in Ca2+ influx through L-type Ca2+channels. Moreover, 4-AP induced an increase in the time required for AP toreach 30% repolarization, and the amplitude of Ca2+ transients waslarger in epicardium than endocardium. On the other hand, the activation of Itowith NS5806 resulted in a reduction of Ca2+ current amplitude thatled to a reduction of the amplitude of Ca2+ transients. Finally, the4-AP effect on AP phase 1 was significantly smaller when the L-type Ca2+current was partially blocked with nifedipine, indicating that the phase 1 rateof repolarization is defined by the competition between an outward K+current and an inward Ca2+ current.