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

DÍAZ-ZEGARRA, LEANDRO; CELY-ORTIZ, DIANA CATALINA ALEJANDRA; FELICE, JUAN IGNACIO; VALVERDE, CARLOS ALFREDO; LASCANO, ELENA CATALINA; NEGRONI, JORGE ANTONIO; MATTIAZZI, RAMONA ALICIA; AIELLO, ERNESTO ALEJANDRO

Congreso; Reunión Anual de Sociedades de Biociencias; 2020

Sociedad Argentina de Investigación Clínica (SAIC), Sociedad Argentina de Inmunología (SAI) y Sociedad Argentina de Fisiología (SAFIS)

It has been described that one of the triggers of awide 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 ofrefractoriness between heartbeats, known as Ca2+ release restitution(CRR). Although the control of CRR has been associated with the sarcoplasmicreticulum (SR) Ca2+ loading and ryanodine receptor (RyR2) Ca2+sensitivity, an intriguing point is whether the restitution of the actionpotential (AP) and/or the L-type calcium current (ICa) are involved in thedetermination of CRR. To assess these interrogates, we used mouse isolatedcardiac 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, 4mMexternal Ca2+ concentration). Restitution of cytosolic Ca2+transient (Fura-2 AM), L-type Ca2+ current (ICa, patch-clamp) andaction potential (AP, microelectrodes) were evaluated with a two-pulse protocol(S1/S2). CRR, ICa and AP restitution percentages increased as a function of thecoupling interval (S2-S1), following an exponentialcurve. 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+-dependentinactivation induced by the enhanced RyR2 release of Ca2+. However,whereas ICa and AP restitution did not differ between PLNKO vs. WT myocytes, theywere slightly but significantly accelerated in WT myocytes at 4 vs. 2 mM Ca2+.Similar results were obtained with a mathematical model of human myocyte. Weconclude that an acceleration of ICa restitution recovery may influence but isnot a requisite for the occurrence of a faster CRR.