Arrhythmogenic coupling between the Na⁺-Ca^2 + exchanger and inositol 1,4,5-triphosphate receptor in rat pulmonary vein cardiomyocytes

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• 作者：Yosuke Okamoto^a ; Makoto Takano^b ; Takayoshi Ohba^a ; Kyoichi Ono^a ; ^{onok@med.akita-u.ac.jp}
• 关键词：Atrial fibrillation ; Pulmonary vein ; Na+&ndash ; Ca2  ; + exchanger ; Inositol 1 ; 4 ; 5-triphosphate receptor ; Automaticity
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2012
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：May, 2012
• 卷：52
• 期：5
• 页码：988-997
• 文件大小：1102 K

摘要

Atrial fibrillation, the most common sustained arrhythmia, is believed to be triggered by ectopic electrical activity originating in the myocardial sleeves surrounding the pulmonary veins (PVs). It has been reported that myocardial sleeves have the potential to generate automaticity in response to norepinephrine. This study investigated the cellular mechanisms underlying norepinephrine-induced automaticity in PV cardiomyocytes isolated from rats. Application of 10 渭M norepinephrine to PV cardiomyocytes induced repetitive and transient increases in intracellular Ca^2 + concentrations. The Ca^2 + transient was accompanied by depolarization, and induced automatic rhythmic action potentials at approximately 4 Hz in perforated patch clamp preparations in 27%of myocytes were observed. When the recording mode was switched from current-clamp to voltage-clamp mode during the continuous presence of automaticity, an oscillatory current was observed. The oscillatory current was always inward, irrespective of the membrane potential, indicating that the current was derived mainly from the Na⁺-Ca^2 + exchanger (NCX). The norepinephrine-induced automaticity was suppressed by blocking either the 尾₁- or 伪₁-adrenoceptor. Additionally, this automaticity was blocked by inhibitors of phospholipase C and the inositol 1,4,5-triphosphate receptor (IP₃R) but not by a protein kinase C inhibitor. We observed that the transverse-tubule system was enriched in cardiomyocytes in the PV, in contrast to those of the atrium, and that the NCX and IP₃R were co-localized along transverse tubules. These findings suggest that a functional coupling between the NCX and IP₃R causes arrhythmic excitability of the PV during the presence of combined 尾₁- and 伪₁-adrenoceptor stimulation.