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

Rimantas Treinys,Rodolphe Fischmeister,Jonas Jurevičius,Giedrius Kanaporis

doi:10.3390/ijms20061501

Abstract

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 (ICaL) in human and rat cardiac myocytes: an initial increase of ICaL 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 ICaL 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 ICaL in single cardiac myocytes. The initial increase of ICaL was induced by a wide range of metabolic inhibitors (FCCP, 2,4-DNP, rotenone, antimycin A). In rat cardiomyocytes, the initial increase of ICaL 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 ICaL 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 ICaL when Ca2+ was replaced by Ba2+, eliminating CDI of LTCCs. We conclude that the initial increase in ICaL 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.

Highlights

The L-type Ca2+ channels (LTCCs) provide Ca2+ for the initiation and regulation of cell contraction and play a main role in cardiac muscle contraction
Metabolic inhibition was induced by the application of mitochondrial uncoupler carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) to isoprenaline stimulated human atrial cells and changes of ICaL were monitored
In most of the tested human atrial cells, FCCP induced a biphasic effect on ICaL, i.e., a rapid initial stimulation of ICaL that was followed by a strong inhibition of ICaL

Summary

Introduction

The L-type Ca2+ channels (LTCCs) provide Ca2+ for the initiation and regulation of cell contraction and play a main role in cardiac muscle contraction. The increase of intracellular Ca2+ concentration in the vicinity of closely associated Ca2+ channels and RyRs leads to calcium dependent inactivation (CDI) of LTCCs [2] and reduction of ICaL [3]. The close functional interaction between plasmalemma and SR means that LTCCs and RyRs can change the activity of each other and alter the balance of cellular Ca2+, which directly activates the contraction of myofilaments. Malfunction of LTTCs and RyRs interaction may affect the contractility of myocardium and, as a consequence, the main function of the heart, to pump blood, may be altered

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Conclusion