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(Circulation Research. 1998;83:1192-1204.)
© 1998 American Heart Association, Inc.

Original Contributions

Bay K 8644 Increases Resting Ca²⁺ Spark Frequency in Ferret Ventricular Myocytes Independent of Ca Influx

Contrast With Caffeine and Ryanodine Effects

Hiroshi Satoh, Hideki Katoh, Patricio Velez, Michael Fill, Donald M. Bers

From the Department of Physiology and Cardiovascular Institute, Loyola University Chicago, Maywood, Ill.

Correspondence to Donald M. Bers, Department of Physiology, Loyola University Medical School, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}luc.edu

Abstract—Bay K 8644, an L-type Ca²⁺ channel agonist, was shown previously to increase resting sarcoplasmic reticulum (SR) Ca²⁺ loss and convert post-rest potentiation to decay in dog and ferret ventricular muscle. Here, the effects of Bay K 8644 on local SR Ca²⁺ release events (Ca²⁺ sparks) were measured in isolated ferret ventricular myocytes, using laser scanning confocal microscopy and the fluorescent Ca²⁺ 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 466±90% of control at constant SR Ca²⁺ 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 Ca²⁺ spark frequency induced by Bay K 8644 was not affected by superfusion with Ca²⁺-free solution (with 10 mmol/L EGTA) but was suppressed by the addition of 10 µmol/L nifedipine (which by itself did not alter resting Ca²⁺ spark frequency). This suggests that the effect of Bay K 8644 on Ca²⁺ sparks is mediated by the sarcolemmal dihydropyridine receptor but is also independent of Ca²⁺ 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 Ca²⁺ signals. This may indicate long-lasting openings of SR Ca²⁺ release channels and a lack of local SR Ca²⁺ 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 Ca²⁺ release at rest, independent of Ca²⁺ influx and perhaps through a functional linkage between the sarcolemmal dihydropyridine receptor and the SR ryanodine receptor. In contrast, caffeine and ryanodine modulate Ca²⁺ sparks by a direct action on the SR Ca²⁺ release channels.

Key Words: dihydropyridine receptor • sarcoplasmic reticulum • confocal microscopy • fluo-3