Molecular basis of downregulation of G-protein-coupled inward rectifying K+ current (IK,ACh) in chronic human atrial fibrillation -: Decrease in GIRK4 mRNA correlates with reduced IK,ACh and muscarinic receptor-mediated shortening of action potentials
Molecular basis of downregulation of G-protein-coupled inward rectifying K+ current (IK,ACh) in chronic human atrial fibrillation -: Decrease in GIRK4 mRNA correlates with reduced IK,ACh and muscarinic receptor-mediated shortening of action potentials
复制标题
DOI：
10.1161/hc4601.099466
复制
发表时间：
2001-11-20
期刊：
影响因子：
37.8
通讯作者：
Ravens, U
中科院分区：
文献类型：
--
作者：
Dobrev, D;Graf, E;Ravens, U
背景-临床和实验证据表明，副交感神经系统参与心房颤动（AF）的发病机制。然而，目前尚不清楚G蛋白耦合内向整流K+电流（I-K，I-ACh）的变化是否导致慢性AF。方法和结果-在本研究中，我们使用电生理记录和竞争性逆转录聚合酶链反应来研究离体人心房肌细胞和39例窦性心律和心律失常患者的心房组织中I-K，I-ACh和I-K，I-Ach GIRK4亚基水平的变化。 24名慢性房颤患者。与窦性心律患者相比，AF 患者的肌细胞中 I-K、I-Ach 密度大约减少 50%，并且伴随着 GIRK4 mRNA 水平的降低。 AF 期间内向整流 K+ 电流 (I-K1) 的电流密度比窦性心律时大 2 倍，这与 Kir2.1 mRNA 的增加相对应。 AF 中较大的 I-K1 与 AF 患者右心房小梁中更多的负膜电位一致。此外，AF时动作电位持续时间缩短，毒蕈碱受体刺激产生的动作电位缩短减弱，表明I-K1和I-K、I-ACh的变化在功能上相关。结论：慢性人类AF诱导转录介导的I-K1上调，但I-K、I-ACh下调，并减弱毒蕈碱受体介导的心房动作电位缩短。这表明心房肌细胞通过下调 I-K、I-ACh 来适应长期高速率，以抵消由于电重塑导致的心房有效不应期的缩短。
Background-Clinical and experimental evidence suggest that the parasympathetic nervous system is involved in the pathogenesis of atrial fibrillation (AF). However, it is unclear whether changes in G-protein-coupled inward rectifying K+ current (I-K,I-ACh) contribute to chronic AF.Methods and Results-In the present study, we used electrophysiological recordings and competitive reverse-transcription polymerase chain reaction to study changes in I-K,I-ACh and the level of the I-K,I-Ach GIRK4 subunit in isolated human atrial myocytes and the atrial tissue of 39 patients with sinus rhythm and 24 patients with chronic AF. The density of I-K,I-Ach was approximate to 50% smaller in myocytes from patients with AF compared with those in sinus rhythm, and this was accompanied by decreased levels of GIRK4 mRNA. The current density of the inward rectifying K+ current (I-K1) was 2-fold larger during AF than in sinus rhythm, in correspondence with an increase in Kir2.1 mRNA. The larger I-K1 in AF is consistent with more negative membrane potentials in right atrial trabeculae from AF patients. Moreover, action potential duration was reduced in AF, and the action potential shortening produced by muscarinic receptor stimulation was attenuated, indicating that the changes of I-K1 and I-K,I-ACh were functionally relevant.Conclusions-Chronic human AF induces transcriptionally mediated upregulation of I-K1 but downregulation Of I-K,I-ACh and attenuates the muscarinic receptor-mediated shortening of atrial action potentials. This suggests that atrial myocytes adapt to a chronically high rate by downregulating I-K,I-ACh to counteract the shortening of the atrial effective refractory period due to electrical remodeling.