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1 Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
* To whom correspondence should be addressed. E-mail: jsks{at}welchlink.welch.jhu.edu.
In cardiac cells, evoked Ca2+ releases or spontaneous Ca2+ waves activate inward Na+-Ca2+ exchange current (INaCa), which may modulate membrane excitability and arrhythmogenesis. In this study, we examined changes in membrane potential due to INaCa elicited by SR Ca2+ release in guinea pig ventricular myocytes, using whole-cell current clamp, fluorescence and confocal microscopy. Inhibition of INaCa by Na+-free, Li+-containing Tyrode's solution reversibly abbreviated the action potential duration at 90% repolarization (APD90) by 50% and caused SR Ca2+ overload. APD90 was similarly abbreviated in myocytes exposed to the inhibitor of Na+-Ca2+ exchange, KB-R7943 (5 µM), or after inhibiting SR Ca2+ release with ryanodine (20 µM). In the absence of extracellular Na+, spontaneous SR Ca2+ releases caused minimal changes in resting membrane potential. After returning the myocytes to Na+-containing solution, the potentiated [Ca2+]i transients dramatically prolonged APD90 and [Ca2+]i oscillations caused delayed and early afterdepolarizations (DADs and EADs). Laser-flash photolysis of caged Ca2+ mimicked the effects of spontaneous [Ca2+]i oscillations, confirming that APD prolongation, DADs and EADs could be ascribed to intracellular Ca2+ release. These results suggest that Na+-Ca2+ exchange is a major physiological determinant of APD, and that INaCa activation by spontaneous SR Ca2+ release/oscillations, depending on the timing, can account for both DADs and EADs during SR Ca2+ overload.
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