ICaL inhibition prevents arrhythmogenic Ca2+ waves caused by abnormal Ca2+ sensitivity of RyR or SR Ca2+ accumulation

Abstract

AimsArrhythmogenic Ca2+ waves result from uncontrolled Ca 2+ release from the sarcoplasmic reticulum (SR) that occurs with increased Ca2+ sensitivity of the ryanodine receptor (RyR) or excessive Ca2+ accumulation during β-adrenergic stimulation. We hypothesized that inhibition of the L-type Ca2+ current (I CaL) could prevent such Ca2+ waves in both situations.Methods and resultsCa2+ waves were induced in mouse left ventricular cardiomyocytes by isoproterenol combined with caffeine to increase RyR Ca2+ sensitivity. ICaL inhibition by verapamil (0.5 M) reduced Ca2+ wave probability in cardiomyocytes during electrostimulation, and during a 10 s rest period after ceasing stimulation. A separate type of Ca2+ release events occurred during the decay phase of the Ca2+ transient and was not prevented by verapamil. Verapamil decreased Ca2+ spark frequency, but not in permeabilized cells, indicating that this was not due to direct effects on RyR. The antiarrhythmic effect of verapamil was due to reduced SR Ca2+ content following ICaL inhibition. Computational modelling supported that the level of ICaL inhibition obtained experimentally was sufficient to reduce the SR Ca2+ content. Ca2+ wave prevention through reduced SR Ca2+ content was also effective in heterozygous ankyrin B knockout mice with excessive SR Ca2+ accumulation during β-adrenergic stimulation.ConclusionICaL inhibition prevents diastolic Ca 2+ waves caused by increased Ca2+ sensitivity of RyR or excessive SR Ca2+ accumulation during β-adrenergic stimulation. In contrast, unstimulated early Ca2+ release during the decay of the Ca2+ transient is not prevented, and merits further study to understand the full antiarrhythmic potential of ICaL inhibition. © 2012 The Author.