Abstract
Tetracaine is commonly used to inhibit RyR-dependent SR Ca leak, however ability to do so in intact cardiac myocytes has not been fully characterized. In single RyR channel bilayer a significant portion of leak would not be inhibited even by low millimolar concentrations of tetracaine. In this study we investigated the effectiveness of tetracaine on RYR-dependent SR Ca leak in ventricular myocytes. Experiments were performed in isolated rabbit myocytes loaded with fluo-4. Myocytes were perfused with 2mM Ca NT with 200µM caffeine in order to increase basal SR Ca leak in the presence of varying concentrations of tetracaine (1, 10, 30, 100µM). Myocytes were then rapidly perfused with 0 Na, 0 Ca NT with 1mM tetracaine following washout with same solution but with varying amounts of tetracaine. SR Ca leak was quantified as the shift of Ca from the cytosol to the SR upon blockage of the RyR with high tetracaine. The EC50 for tetracaine is significantly reduced in intact myocytes compared to single RyR channel. Among the potential explanations for this effect is the possibility that Ca flux regulation makes the RyR clusters in the SR junction more sensitive to blockage of release.
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