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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 285; no. 6; pp. H2552 - H2562
• Main Authors: Spencer, C. Ian, Sham, James S. K
• Format: Journal Article
• Language: English
• Published: United States 01.12.2003
• Subjects: Acetates - pharmacology; Action Potentials - drug effects; Action Potentials - physiology; Animals; Calcium - metabolism; Calcium Signaling - physiology; Chelating Agents - pharmacology; Ethylenediamines - pharmacology; Guinea Pigs; Heart Ventricles - cytology; In Vitro Techniques; Isotonic Solutions - pharmacology; Lithium - pharmacology; Male; Myocytes, Cardiac - physiology; Photolysis; Sarcoplasmic Reticulum - metabolism; Sodium-Calcium Exchanger - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00274.2003

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 Ca 2+ releases or spontaneous Ca 2+ waves activate the inward Na + /Ca 2+ 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) Ca 2+ 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 (APD 90 ) by 50% and caused SR Ca 2+ overload. APD 90 was similarly abbreviated in myocytes exposed to the Na + /Ca 2+ exchange inhibitor KB-R7943 (5 µM) or after inhibition of SR Ca 2+ release with ryanodine (20 µM). In the absence of extracellular Na + , spontaneous SR Ca 2+ releases caused minimal changes in resting membrane potential. After the myocytes were returned to Na + -containing solution, the potentiated intracellular Ca 2+ concentration ([Ca 2+ ] i ) transients dramatically prolonged APD 90 and [Ca 2+ ] i oscillations caused delayed and early afterdepolarizations (DADs and EADs). Laser-flash photolysis of caged Ca 2+ mimicked the effects of spontaneous [Ca 2+ ] i oscillations, confirming that APD prolongation, DADs, and EADs could be ascribed to intracellular Ca 2+ release. These results suggest that Na + /Ca 2+ exchange is a major physiological determinant of APD and that I NaCa activation by spontaneous SR Ca 2+ release/oscillations, depending on the timing, can account for both DADs and EADs during SR Ca 2+ overload. early afterdepolarization; delayed afterdepolarization; flash photolysis; Ca 2+ overload; triggered arrhythmia; ischemia-reperfusion arrhythmia; sarcoplasmic reticulum Address for reprint requests and other correspondence: J. S. K. Sham, Div. of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (E-mail: jsks{at}welchlink.welch.jhu.edu ).