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Cardiovascular Research 2000 47(2):336-349; doi:10.1016/S0008-6363(00)00107-3
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

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

Stéphanie Barrère-Lemaire, Christophe Piot, Florence Leclercq, Joël Nargeot and Sylvain Richard*

Institut de Génétique Humaine, CNRS, UPR 1142, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France

* Corresponding author. Tel.: +33-499-61-9939; fax: +33-499-61-9901 srichard{at}igh.cnrs.fr

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.

KEYWORDS Adrenergic (ant)agonists; Ca-channel; Heart failure; Membrane potential; Myocytes; Serotonin (5HT)


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