Bay K 8644 Increases Resting Ca Spark Frequency in Ferret Ventricular Myocytes Independent of Ca Influx Contrast With Caffeine and Ryanodine Effects

Bay K 8644, an L-type Ca channel agonist, was shown previously to increase resting sarcoplasmic reticulum (SR) Ca loss and convert post-rest potentiation to decay in dog and ferret ventricular muscle. Here, the effects of Bay K 8644 on local SR Ca release events (Ca sparks) were measured in isolated ferret ventricular myocytes, using laser scanning confocal microscopy and the fluorescent Ca indicator fluo-3. The spark frequency under control conditions was fairly constant during 20 s of rest after interruption of electrical stimulation. Bay K 8644 (100 nmol/L) increased the spark frequency by 466690% of control at constant SR Ca load but did not change the spatial and temporal characteristics of individual sparks. The increase in spark frequency was maintained throughout the period of rest. The increase in Ca spark frequency induced by Bay K 8644 was not affected by superfusion with Ca-free solution (with 10 mmol/L EGTA) but was suppressed by the addition of 10 mmol/L nifedipine (which by itself did not alter resting Ca spark frequency). This suggests that the effect of Bay K 8644 on Ca sparks is mediated by the sarcolemmal dihydropyridine receptor but is also independent of Ca influx. Low concentrations of caffeine (0.5 mmol/L) increased both the average frequency and duration of sparks. Ryanodine (50 nmol/L) increased the spark frequency and also induced long-lasting Ca signals. This may indicate long-lasting openings of SR Ca release channels and a lack of local SR Ca depletion. In lipid bilayers, Bay K 8644 had no effect on either single-channel current amplitude or open probability of the cardiac ryanodine receptor. It is concluded that Bay K 8644 activates SR Ca release at rest, independent of Ca influx and perhaps through a functional linkage between the sarcolemmal dihydropyridine receptor and the SR ryanodine receptor. In contrast, caffeine and ryanodine modulate Ca sparks by a direct action on the SR Ca release channels. (Circ Res. 1998;83:1192-1204.)