Résumé
Objective: Decay kinetics of the voltage-gated L-type Ca2+ current (ICaL) control the magnitude of Ca2+ influx during the cardiac action potential. We investigated the influence of changes in diastolic membrane potential on ICaL decay kinetics in cardiac cells. Methods: Cells were isolated enzymatically from rat ventricles, human right atrial appendages obtained during corrective heart surgery and left ventricles from end-stage failing hearts of transplant recipients. The whole-cell patch-clamp technique was used to evoke ICaL by a 100-ms depolarizing test pulse to −10 mV. Conditioning potentials between −80 and 0 mV were applied for 5 s prior to the test pulse. Results: Depolarizing the cells between −80 and −50 mV prior to the test pulse slowed the early inactivation of ICaL both in rat ventricular and human atrial cells. This slowing resulted in a significant increase of Ca2+ influx. This type of facilitation was not observed when the sarcoplasmic reticulum (SR) Ca2+ content was depleted using ryanodine which reduced the rate of inactivation of ICaL, or when Ba2+ replaced Ca2+ as the permeating ion. Facilitation was favored by intracellular cAMP-promoting agents that, in addition to increasing current peak amplitude, enhanced the fast Ca2+-dependent inactivation of ICaL. Facilitation was impaired in atrial and ventricular human failing hearts. Conclusion: Decay kinetics of ICaL are regulated by the diastolic membrane potential in rat and human cardiomyocytes. This regulation, which associates slowing of ICaL inactivation with reduced SR Ca2+ release and underlies facilitation of Ca2+ channels activity, may have profound physiological relevance for catecholamines enhancement of Ca2+ influx. It is impaired in failing hearts, possibly due to lowered SR Ca2+ release.