Metabolic Inhibition Induces Transient Increase of L-type Ca 2+ Current in Human and Rat Cardiac Myocytes.

Metabolic inhibition is a common condition observed during ischemic heart disease and heart failure. It is usually accompanied by a reduction in L-type Ca ²⁺ 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 Ca ²⁺ from the sarcoplasmic reticulum (SR). Similar results were obtained when Ca ²⁺ 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 Ca ²⁺ was replaced by Ba ²⁺ , 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 Ca ²⁺ release from SR resulting in reduced CDI of LTCCs.