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

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