Shi Hong, Wang Huizhen, Li Danshi, Nattel Stanley, Wang Zhiguo
Research Center, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada.
Cell Physiol Biochem. 2004;14(1-2):31-40. doi: 10.1159/000076924.
Parasympathetic tone and congestive heart failure (CHF) are two of promoting factors in initiation and perpetuation of atrial fibrillation (AF). Recent studies indicate co-existence of multiple muscarinic acetylcholine receptor subtypes (mAChRs) that mediate several distinct K+ currents in the heart; inward rectifier K+ current IKACh by the M2, and two delayed rectifier K+ currents IKM3 and IK4AP by the M3 and M4 receptors, respectively. We studied the alterations of atrial mAChRs and their coupled K+ channels in the setting of AF in dogs with ventricular tachypacing-induced CHF. Whole-patch-clamp recordings showed that the current densities of IKACh (induced by 1 mM acetylcholine) and IK4AP (induced by 1 mM 4-aminopyridine) were ñ45% and ñ55% lower, respectively, while that of IKM3 (induced by 10 mM choline) was ñ75% higher, at a plateau voltage of 0 mV in atrial myocytes from CHF than those from healthy hearts. In healthy hearts, IKACh comprised >60%, and IKM3 and IK4AP <30%, of the total outward K+ currents mediated by mAChRs at depolarized potentials (between -20 mV and +50 mV). In AF atria of CHF dogs, however, the contribution of IKM3 increased to approximately 50%, exceeding those of IKACh or IK4AP. Western blot analyses with atrial membrane protein samples indicated that receptor densities of the M2 and M4 subtypes decreased by approximately 33% and approximately 22%, respectively, whereas that of the M3 subtype increased by approximately 2.3 folds, in parallel to the alterations of the corresponding K+ currents. We conclude that differential alterations of mAChR subtypes underlie differential alterations of their coupled K+ channels in AF atria and these differential alterations may contribute to atrial remodeling in AF induced in the setting of CHF.
迷走神经张力和充血性心力衰竭（CHF）是心房颤动（AF）起始和持续存在的两个促进因素。最近的研究表明，心脏中存在多种毒蕈碱型乙酰胆碱受体亚型（mAChRs），它们介导几种不同的钾电流；M2受体介导内向整流钾电流IKACh，M3和M4受体分别介导两种延迟整流钾电流IKM3和IK4AP。我们研究了心室快速起搏诱导的CHF犬房颤情况下心房mAChRs及其偶联钾通道的变化。全细胞膜片钳记录显示，在CHF犬心房肌细胞中，IKACh（由1 mM乙酰胆碱诱导）和IK4AP（由1 mM 4-氨基吡啶诱导）的电流密度在0 mV平台电压下分别比健康心脏低约45%和55%，而IKM3（由10 mM胆碱诱导）的电流密度高约75%。在健康心脏中，在去极化电位（-20 mV至+50 mV之间），由mAChRs介导的总外向钾电流中，IKACh占>60%，IKM3和IK4AP占<30%。然而，在CHF犬的房颤心房中，IKM3的贡献增加到约50%，超过了IKACh或IK4AP。对心房膜蛋白样品进行的蛋白质印迹分析表明，M2和M4亚型的受体密度分别降低了约33%和约22%，而M3亚型的受体密度增加了约2.3倍，这与相应钾电流的变化平行。我们得出结论，mAChR亚型的差异改变是其在房颤心房中偶联钾通道差异改变的基础，这些差异改变可能导致CHF情况下诱导的房颤中的心房重塑。
