Qing Zhang1, Ji-Hua Ma2, Hong Li3, Xiao-Hong Wei1, Jie Zheng2, Gang Li1, Cheng-Yu Wang1, Ying Wu2, Qi-Hua He4, Lin Wu5. 1. Department of Cardiology, Peking University First Hospital, Beijing, China. 2. Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China. 3. Amgen Inc, Thousands Oaks, California. 4. Centre of Medical and Health Analysis, Peking University Health Science Center, Beijing, China. 5. Department of Cardiology, Peking University First Hospital, Beijing, China; Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China. Electronic address: Lin_wu@163.com.
Abstract
BACKGROUND: Increased CO2 levels in the general circulation and/or in the myocardium are common under pathologic conditions. OBJECTIVE: The purpose of this study was to test the hypothesis that an increase in CO2 levels, and not just the subsequent extra- or intracellular acidosis, would augment late sodium current (INa,L) and contribute to arrhythmogenesis in hearts with reduced repolarization reserve. METHODS: Monophasic action potential durations at 90% completion of repolarization (MAPD90) from isolated rabbit hearts, INa,L, and extra- (pHo) and intracellular pH (pHi) values from cardiomyocytes using the whole-cell patch-clamp techniques and 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM), respectively, were measured. RESULTS: Increasing CO2 levels from 5% to 10% and 20% and administration of 1 nM sea anemone toxin (ATX)-II increased INa,L and prolonged both epicardial and endocardial MAPD90 (n = 7 and 10, respectively) without causing arrhythmic activities. Compared to 5% CO2, 10% and 20% CO2 decreased pHo and pHi in hearts treated with 1 nM ATX-II, caused greater prolongation of MAPD90, and elicited ventricular tachycardias. Increasing CO2 levels from 5% to 10% and 20% with pHo maintained at 7.4 produced smaller changes in pHi (P <.05) but similar increases in INa,L, prolongation of MAPD90, and incidence of ventricular tachycardias (n = 8). Inhibition of INa,L reversed the increase in INa,L, suppressed MAPD90 prolongations, and ventricular tachycardias induced by 20% CO2. Increased phospho-calmodulin-dependent protein kinase II-δ (CaMKIIδ) and phospho-NaV1.5 protein levels in hearts treated with 20% CO2 was attenuated by eleclazine. CONCLUSION: Increased CO2 levels enhance INa,L and are proarrhythmic factors in hearts with reduced repolarization reserve, possibly via mechanisms related to phosphorylation of CaMKIIδ and NaV1.5.
BACKGROUND: Increased CO2 levels in the general circulation and/or in the myocardium are common under pathologic conditions. OBJECTIVE: The purpose of this study was to test the hypothesis that an increase in CO2 levels, and not just the subsequent extra- or intracellular acidosis, would augment late sodium current (INa,L) and contribute to arrhythmogenesis in hearts with reduced repolarization reserve. METHODS: Monophasic action potential durations at 90% completion of repolarization (MAPD90) from isolated rabbit hearts, INa,L, and extra- (pHo) and intracellular pH (pHi) values from cardiomyocytes using the whole-cell patch-clamp techniques and 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM), respectively, were measured. RESULTS: Increasing CO2 levels from 5% to 10% and 20% and administration of 1 nM sea anemone toxin (ATX)-II increased INa,L and prolonged both epicardial and endocardial MAPD90 (n = 7 and 10, respectively) without causing arrhythmic activities. Compared to 5% CO2, 10% and 20% CO2 decreased pHo and pHi in hearts treated with 1 nM ATX-II, caused greater prolongation of MAPD90, and elicited ventricular tachycardias. Increasing CO2 levels from 5% to 10% and 20% with pHo maintained at 7.4 produced smaller changes in pHi (P <.05) but similar increases in INa,L, prolongation of MAPD90, and incidence of ventricular tachycardias (n = 8). Inhibition of INa,L reversed the increase in INa,L, suppressed MAPD90 prolongations, and ventricular tachycardias induced by 20% CO2. Increased phospho-calmodulin-dependent protein kinase II-δ (CaMKIIδ) and phospho-NaV1.5 protein levels in hearts treated with 20% CO2 was attenuated by eleclazine. CONCLUSION: Increased CO2 levels enhance INa,L and are proarrhythmic factors in hearts with reduced repolarization reserve, possibly via mechanisms related to phosphorylation of CaMKIIδ and NaV1.5.
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