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

DIAZ-ZEGARRA, LEANDRO A.; VALVERDE, CARLOS A; MATTIAZZI, RAMONA ALICIA; CELY ORTIZ, D.C. ALEJANDRA; LASCANO, ELENA CATALINA; AIELLO, ERNESTO A.; FELICE, JUAN IGNACIO; NEGRONI, JORGE ANTONIO

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It has been described that one of the triggers of a wide spectrum ofventricular arrhythmias is the abnormal intracellular Ca2+ handlingduring the excitation-co-contraction coupling (ECC) in the cardiomyocyte.One of the possible abnormalities is the alteration of therecovery of refractoriness between heartbeats, known as Ca2+ releaserestitution (CRR). Although the control of CRR has been associatedwith the sarcoplasmic reticulum (SR) Ca2+ loading and ryanodinereceptor (RyR2) Ca2+ sensitivity, an intriguing point is whetherthe restitution of the action potential (AP) and/or the L-type calciumcurrent (ICa) are involved in the determination of CRR. To assessthese interrogates, we used mouse isolated cardiac myocytes withhigher CRR velocities respect to control myocytes (WT, 2mM externalCa2+ concentration), obtained by increasing SR Ca2+ load by usingtwo different maneuvers, 1. ablation of phospholamban (PLNKOmyocytes) and 2. Increasing extracellular Ca2+ concentration (WTmyocytes, 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 atwo-pulse protocol (S1/S2). CRR, ICa and AP restitution percentagesincreased as a function of the coupling interval (S2-S1), followingan exponential curve. CRR was accelerated in PLNKO vs.WT myocytes and in WT myocytes at 4 vs. 2 mM Ca. In both casesthere was a greater ICa Ca2+-dependent inactivation induced by theenhanced RyR2 release of Ca2+. However, whereas ICa and AP restitutiondid not differ between PLNKO vs. WT myocytes, they wereslightly but significantly accelerated in WT myocytes at 4 vs. 2 mMCa2+. Similar results were obtained with a mathematical model ofhuman myocyte. We conclude that an acceleration of ICa restitutionrecovery may influence but is not a requisite for the occurrence ofa faster CRR.