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The repolarization during phase-1 defines Ca2+ transients and contractility in perfused mouse hearts

Emiliano Medei, Maedeh Bazmi, Ariel L Escobar

In perfused hearts, Ca²⁺ influx through L-type Ca²⁺ channels triggers Ca²⁺ release from the sarcoplasmic reticulum. In nearly all mammals, the inflow which activates the sarcoplasmic reticulum Ca²⁺ release occurs during phase 2 of the action potential. Interestingly, in murine models, the triggering event occurs during phase 1 of the action potential. The objective of this review is to determine how much Ca²⁺ influx occurs during phase 1. Moreover, we want to determine how much Ca²⁺ gets into the myocytes when Kv4.3 is blocked with 4-aminopyridine (4-AP). Moreover, we will evaluate changes in the open probability of Kv 4.3 following blockage via 4-aminopyridine (4-AP). To test whether a decrease in a transient K+ current (Ito) will enhance Ca²⁺ influx across the plasma membrane and increase the amplitude of Ca²⁺ transients, pulsed local-field fluorescence microscopy, recordings using sharp microelectrodes, measurements of the developed pressure, and loose-patch photolysis were utilized. Furthermore, some experiments were performed using loose patch photolysis to evaluate the amplitude of the Ca²⁺ in intact beating hearts. Interestingly, 4-AP increased not only the time required for AP to reach 30% repolarization but also the amplitude of Ca²⁺ transients in the epicardium in comparison to the endocardium. Furthermore, the activation of Ito with N-[3,5-Bis(trifluoromethyl)phenyl]-N’-[2,4- dibromo-6-(2H-tetrazol-5-yl)phenyl]urea (NS5806) resulted in a reduction of Ca²⁺ current amplitude, which led to a reduction of the amplitude of Ca²⁺ transients.