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Effects of Na⁺/Ca²⁺ exchange induced by SR Ca²⁺ release on action potentials and afterdepolarizations in guinea pig ventricular myocytes

Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21224

Submitted 25 March 2003 ; accepted in final form 15 August 2003

In cardiac cells, evoked Ca²⁺ releases or spontaneous Ca²⁺ waves activate the inward Na⁺/Ca²⁺ exchange current (I_NaCa), which may modulate membrane excitability and arrhythmogenesis. In this study, we examined changes in membrane potential due to I_NaCa elicited by sarcoplasmic reticulum (SR) Ca²⁺ release in guinea pig ventricular myocytes using whole cell current clamp, fluorescence, and confocal microscopy. Inhibition of I_NaCa by Na⁺-free, Li⁺-containing Tyrode 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 Na⁺/Ca²⁺ exchange inhibitor KB-R7943 (5 µM) or after inhibition of 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 the myocytes were returned to Na⁺-containing solution, the potentiated intracellular Ca²⁺ concentration ([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 I_NaCa activation by spontaneous SR Ca²⁺ release/oscillations, depending on the timing, can account for both DADs and EADs during SR Ca²⁺ overload.

early afterdepolarization; delayed afterdepolarization; flash photolysis; Ca²⁺ overload; triggered arrhythmia; ischemia-reperfusion arrhythmia; sarcoplasmic reticulum

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