Abstract
The effect of ranolazine (10 μM) on local Ca2+ regulation was studied in isolated rat ventricular myocytes. Cells were loaded with fluo-4 AM and Ca2+ was detected using line-scan confocal imaging. Ranolazine increased Ca2+ spark frequency by 57.8 ± 17% (p<0.05, n=29). This was accompanied by significant (p<0.05) decreases in Ca2+ spark amplitude (44.5 ± 0.1%), duration (16.5 ± 1.9%) and width (5.6 ± 1.7%) resulting in a decrease in the calculated ‘spark mass’ of 41.3 ± 5.4% (data from 15-29 cells). In cells initially paced at 0.2 Hz in the presence of forskolin (10 μM), cessation of stimulation was followed by spontaneous diastolic Ca2+ waves. After introduction of ranolazine (but not in its absence), the frequency of spontaneous Ca2+ waves decreased markedly over 10-15 minutes and waves were completely abolished in 5 of 11 cells. Inhibition of Ca2+ waves also occurred in permeabilized cells, suggesting an intracellular site of action. We propose that the ranolazine-induced decrease in Ca2+ spark mass may contribute to inhibition of pro-arrhythmic Ca2+ waves by reducing the probability of saltatory propagation between Ca2+ release sites.
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