Alterations of L-type calcium current and the Action Potential restitution do not constitute a requisite for CRR.

DIAZ ZEGARRA LA; CELY ORTIZ A; FELICE JI; VALVERDE CA; LESCANO EA; NEGRONI J; MATTIAZZI A; AIELLO EA

Mar del Plata

Congreso; Reunión de Sociedades de Biociencias 2020. Reunión Anual de la Sociedad Argentina de Fisiología (SAFIS); 2020

It has been described that one of the triggers of a wide spectrum of ventricular arrhythmias is the abnormal intracellular Ca2+ handling during the excitation-co-contraction coupling (ECC) in the cardiomyocyte. One of the possible abnormalities is the alteration of the recovery of refractoriness between heartbeats, known as Ca2+ release restitution (CRR). Although the control of CRR has been associated with the sarcoplasmic reticulum (SR) Ca2+ loading and ryanodine receptor (RyR2) Ca2+ sensitivity, an intriguing point is whether the restitution of the action potential (AP) and/or the L-type calcium current (ICa) are involved in the determination of CRR. To assess these interrogates, we used mouse isolated cardiac myocytes with higher CRR velocities respect to control myocytes (WT, 2mM external Ca2+ concentration), obtained by increasing SR Ca2+ load by using two different maneuvers, 1. ablation of phospholamban (PLNKO myocytes) and 2. Increasing extracellular Ca2+ concentration (WT myocytes, 4mM external Ca2+ concentration). Restitution of cytosolicCa2+ transient (Fura-2 AM), L-type Ca2+ current (ICa, patch-clamp) and action potential (AP, microelectrodes) were evaluated with a two-pulse protocol (S1/S2). CRR, ICa and AP restitution percentages increased as a function of the coupling interval (S2-S1), following an exponential curve. CRR was accelerated in PLNKO vs. WT myocytes and in WT myocytes at 4 vs. 2 mM Ca. In both cases there was a greater ICa Ca2+-dependent inactivation induced by the enhanced RyR2 release of Ca2+. However, whereas ICa and AP restitution did not differ between PLNKO vs. WT myocytes, they were slightly but significantly accelerated in WT myocytes at 4 vs. 2 mM Ca2+. Similar results were obtained with a mathematical model of human myocyte. We conclude that an acceleration of ICa restitution recovery may influence but is not a requisite for the occurrence ofa faster CRR.