摘要
血管紧张素转换酶抑制剂(ACE-I)改善对心肌梗死(MI)的和慢性心力衰竭患者的临床疗效。我们研究了潜在的抗心律失常(AA)在缺血性心衰小鼠模型的优点,并推测ACE-I通过舒张期Ca2+的正常化预防Ca2+依赖性对内整流性钾电流(IK1)减弱以及心律失常的发生。小鼠被随机分为三组:假手术组,MI组与MI-D组(心肌梗死24小时后用ACE抑制剂地拉普利治疗6周)。电生理分析表明地拉普利能减弱心肌梗死心电图参数(QRS波、QT间期延长、QTc间期)和减少希氏束心室传导时间,提高交感-迷走神经平衡(LF/HF)和减少房室块与室性心律失常。膜片钳测定技术表明,地拉普利能够预防IK1的减弱,IK1降低与细胞内Ca2+超载有关,当细胞内游离Ca2+保持在较低水平时,IK1减弱是无法观察到的。相反,假手术组在使用SERCA2a抑制剂毒胡萝卜素后增加细胞内游离Ca2+会减弱IK1。毒胡萝卜素对MI组动物没有影响但消除MI-D组小鼠中地拉普利对IK1的有利影响。地拉普利能防止两种由心肌梗死引起的触发性异常电活动-动作电位复极晚期延长和静息膜电位去极化的发生。总之,心梗后地拉普利早期慢性治疗能防止钙离子依赖性对内整流性钾电流减弱。这种机制有助于ACE-I对抗心律失常的治疗以及减轻病人心源性猝死的危险。
关键词: 心律失常,血管紧张素转换酶抑制剂,心脏衰竭,上游药物治疗,IK1。
Current Molecular Medicine
Title:ACE Inhibitor Delapril Prevents Ca2+-Dependent Blunting of IK1 and Ventricular Arrhythmia in Ischemic Heart Disease
Volume: 15 Issue: 7
Author(s): J. Thireau, S. Zalvidea, P. Meschin, J.-L. Pasquie, F. Aimond and S. Richard
Affiliation:
关键词: 心律失常,血管紧张素转换酶抑制剂,心脏衰竭,上游药物治疗,IK1。
摘要: Angiotensin-converting enzyme inhibitors (ACE-I) improve clinical outcome in patients with myocardial infarction (MI) and chronic heart failure. We investigated potential anti-arrhythmic (AA) benefits in a mouse model of ischemic HF. We hypothesized that normalization of diastolic calcium (Ca2+) by ACE-I may prevent Ca2+-dependent reduction of inward rectifying K+ current (IK1) and occurrence of arrhythmias after MI. Mice were randomly assigned to three groups: Sham, MI, and MI-D (6 weeks of treatment with ACE-I delapril started 24h after MI). Electrophysiological analyses showed that delapril attenuates MI-induced prolongations of electrocardiogram parameters (QRS complex, QT, QTc intervals) and conduction time from His bundle to ventricular activation. Delapril improved the sympatho-vagal balance (LF/HF) and reduced atrio-ventricular blocks and ventricular arrhythmia. Investigations in cardiomyocytes showed that delapril prevented the decrease of IK1 measured by patch-clamp technique. IK1 reduction was related to intracellular Ca2+ overload. This reduction was not observed when intracellular free-Ca2+ was maintained low. Conversely, increasing intracellular free-Ca2+ in Sham following application of SERCA2a inhibitor thapsigargin reduced IK1. Thapsigargin had no effect in MI animals and abolished the benefits of delapril on IK1 in MI-D mice. Delapril prevented both the prolongation of action potential late repolarization and the depolarization of resting membrane potential, two phenomena known to trigger abnormal electrical activities, promoted by MI. In conclusion, early chronic therapy with delapril after MI prevented Ca2+-dependent reduction of IK1. This mechanism may significantly contribute to the antiarrhythmic benefits of ACE-I in patients at risk for sudden cardiac death.
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J. Thireau, S. Zalvidea, P. Meschin, J.-L. Pasquie, F. Aimond and S. Richard , ACE Inhibitor Delapril Prevents Ca2+-Dependent Blunting of IK1 and Ventricular Arrhythmia in Ischemic Heart Disease, Current Molecular Medicine 2015; 15 (7) . https://dx.doi.org/10.2174/1566524015666150831131459
DOI https://dx.doi.org/10.2174/1566524015666150831131459 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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