Metabolic Inhibition Induces Transient Increase of L-type Ca2+ Current in Human and Rat Cardiac Myocytes

International Journal of Molecular Sciences

Rodolphe Fischmeister¹  Jonas Jurevičius²  Rimantas Treinys²  Giedrius Kanaporis² 

[1] INSERM UMR-S 1180, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry F-92296, France;Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas LT-50162, Lithuania;

关键词: L-type Ca²⁺ current;    metabolic inhibition;    FCCP;    heart;    cardiac myocytes;    sarcoplasmic reticulum;    calcium dependent inactivation;   

DOI  :  10.3390/ijms20061501

来源: DOAJ

【 摘 要 】

Metabolic inhibition is a common condition observed during ischemic heart disease and heart failure. It is usually accompanied by a reduction in L-type Ca²⁺ channel (LTCC) activity. In this study, however, we show that metabolic inhibition results in a biphasic effect on LTCC current (I_CaL) in human and rat cardiac myocytes: an initial increase of I_CaL is observed in the early phase of metabolic inhibition which is followed by the more classical and strong inhibition. We studied the mechanism of the initial increase of I_CaL in cardiac myocytes during β-adrenergic stimulation by isoprenaline, a non-selective agonist of β-adrenergic receptors. The whole-cell patch–clamp technique was used to record the I_CaL in single cardiac myocytes. The initial increase of I_CaL was induced by a wide range of metabolic inhibitors (FCCP, 2,4-DNP, rotenone, antimycin A). In rat cardiomyocytes, the initial increase of I_CaL was eliminated when the cells were pre-treated with thapsigargin leading to the depletion of Ca²⁺ from the sarcoplasmic reticulum (SR). Similar results were obtained when Ca²⁺ release from the SR was blocked with ryanodine. These data suggest that the increase of I_CaL in the early phase of metabolic inhibition is due to a reduced calcium dependent inactivation (CDI) of LTCCs. This was further confirmed in human atrial myocytes where FCCP failed to induce the initial stimulation of I_CaL when Ca²⁺ was replaced by Ba²⁺, eliminating CDI of LTCCs. We conclude that the initial increase in I_CaL observed during the metabolic inhibition in human and rat cardiomyocytes is a consequence of an acute reduction of Ca²⁺ release from SR resulting in reduced CDI of LTCCs.

【 授权许可】

Unknown