Facilitation of L-type calcium currents by diastolic depolarization in cardiac cells: impairment in heart failure

Objective: Decay kinetics of the voltage-gated L-type Ca2+ current (I-CaL) control the magnitude of Ca2+ influx during the cardiac action potential. W e investigated the influence of changes in diastolic membrane potential on I-CaL decay kinetics in cardiac cells. Methods: Cells were isolated enzymat ically from rat ventricles, human right atrial appendages obtained during c orrective heart surgery and left ventricles from end-stage failing hearts o f transplant recipients. The whole-cell patch-clamp technique was used to e voke I-CaL by a 100-ms depolarizing test pulse to -10 mV. Conditioning pote ntials between -80 and 0 mV were applied for 5 s prior to the test pulse. R esults: Depolarizing the cells between -80 and -50 mV prior to the test pul se slowed the early inactivation of I-CaL both in rat ventricular and human atrial cells. This slowing resulted in a significant increase of Ca2+ infl ux. This type of facilitation was not observed when the sarcoplasmic reticu lum (SR) Ca2+ content was depleted using ryanodine which reduced the rate o f inactivation of I-CaL, or when Ba2+ replaced Ca2+ as the permeating ion. Facilitation was favored by intracellular cAMP-promoting agents that, in ad dition to increasing current peak amplitude, enhanced the fast Ca2+-depende nt inactivation of I-CaL. Facilitation was impaired in atrial and ventricul ar human failing hearts. Conclusion: Decay kinetics of I-CaL are regulated by the diastolic membrane potential in rat and human cardiomyocytes. This r egulation, which associates slowing of I-CaL inactivation with reduced SR C a2+ release and underlies facilitation of Ca2+ channels activity, may have profound physiological relevance for catecholamines enhancement of Ca2+ inf lux. It is impaired in failing hearts, possibly due to lowered SR Ca2+ rele ase. (C) 2000 Elsevier Science B.V. All rights reserved.