Changes in intra-luminal calcium during spontaneous calcium waves following sensitization of ryanodine receptor channels

Abstract

Cardiac contraction during systole is dependent on action potential-triggered Ca2+ release from the sarcoplasmic reticulum (SR) through ryanodine receptor (RyR) channels. SR Ca2+ release can also occur spontaneously during diastole, which causes a decrease in Ca2+ content within the SR and contributes to arrhythmogenesis. Here, we use measurements of cytosolic Ca2+ and intra-SR Ca2+ ([Ca 2+]SR) to examine how RyR sensitization alters spontaneous SR Ca 2+ release events in rabbit ventricular myocytes. RyR sensitization with caffeine (250 μM) increased the open probability of single RyR channels, increased the initial frequency and amplitude of local SR Ca2+ release events (Ca2+ sparks), and decreased the [Ca2+]SR level where Ca2+ sparks terminated. In intact myocytes, caffeine applied during rest after steady-state electrical stimulation increased the frequency of spontaneous Ca2+ waves and decreased the [Ca 2+]SR level where waves terminated. These effects caused a marked loss of SR Ca2+ content. Therefore, increasing RyR activity has complex effects on cardiac function. Increased RyR activity during systole is beneficial as it increases SR Ca2+ release and contractile strength. However, increased RyR activity during diastole produces spontaneous, arrhythmogenic Ca2+ release events that lower SR Ca2+ content and subsequently decrease contractility. © 2010 Landes Bioscience.