摘要
目的：探讨心肌内向整流钾通道（Kir）激动剂zacopride缺血后适应对大鼠缺血/再灌注性心律失常的影响及可能的电生理学机制。方法：SD大鼠Langendorff离体灌流心脏和在体麻醉大鼠冠状动脉左前降支结扎15 min后松扎15 min诱发缺血/再灌注性心律失常。在冠状动脉左前降支松扎前3 min给予zacopride,观察缺血后适应对再灌注性心律失常的影响。胶原酶法分离大鼠单个心室肌细胞,应用全细胞膜片钳技术观察zacopride对心室肌细胞缺氧/复氧致延迟后除极的影响和对细胞膜表面ATP敏感性钾通道（KATP）的影响。结果：大鼠离体心脏再灌注时预先给予0.1～10μmol/L zacopride可有效抑制再灌注性心律失常的发生。其中0.1μmol/L zacopride为最大效应浓度,可使期前收缩数减少,室速和室颤发生率均下降,持续时间均缩短;再灌前3 min将1μmol/L BaCl2和0.1μmol/L zacopride同时灌流心脏,BaCl2可部分逆转zacopride的保护效应（P〈0.01）,表明zacopride的后适应保护与其增强Kir电流的作用有关。在1.5～5μg/kg剂量范围内,zacopride对大鼠在体再灌注诱发的室速和室颤有明显抑制效应,但对期前收缩数无明显影响。1.5μg/kg zacopride抗心律失常的效应与阳性对照药利多卡因（7.5 mg/kg）相似。进一步研究发现zacopride可有效抑制缺氧/复氧所致心室肌细胞延迟后除极,降低其发生率（P〈0.01）。Zacopride的上述效应与K（ATP）无关。结论：Zacopride对大鼠缺血/再灌注性心律失常的抑制作用是由激活心肌细胞Kir介导的。激活Kir并消除延迟后除极所诱发的触发性活动可能是zacopride缺血后适应的主要机制。
AIM： To investigate the effects of postconditioning of zacopride,a specific agonist of inwardly rectifying potassium channel（ Kir）,on ischemia/reperfusion-induced arrhythmias and the involved electrophysiological mechanisms. METHODS： Langendorff-perfused SD rat hearts or anesthetized rats were subjected to coronary artery occlusion for15 min followed by 15 min of reperfusion to induce ischemia / reperfusion arrhythmias. Zacopride was applied 3 min before reperfusion. Various arrhythmias were monitored and compared in different groups. The single rat ventricular myocyte was isolated by collagenase digestion. The effects of zacopride on hypoxia / reoxygenation-induced delayed afterdepolarizations（ DADs） and ATP-sensitive potassium channel（ K（ATP）） were observed by the technique of whole-cell patch clamping. RESULTS： Post-conditioning of 0. 1 ～ 10 μmol / L zacopride significantly prevented the hearts from reperfusion arrhythmias.During reperfusion,0. 1 μmol / L zacopride showed the maximum effect,with decreasing the number of premature ventricu-lar beats（ PVB）,reducing the incidences of ventricular tachycardia（ VT） and ventricular fibrillation（ VF）,and shortening the duration of VT and VF（ P〈0. 01）. The postconditioning effects were partly reversed by 1 μmol / L BaCl2（ P〈0. 01）,suggesting that the antiarrhythmic effect of zacopride was mediated by Kir. In the in vivo study,1. 5 ～ 5 μg /kg zacopride had positive effects on reperfusion-induced VT and VF and negative effect on PVB. At the dose of 1. 5 μg / kg,zacopride showed the most potent antiarrhythmic effect,which compared favourably with that of a classical antiarrhythmic agent,lidocaine. Furthermore, zacopride significantly inhibited hypoxia / reoxygenation-induced DADs（ P〈0. 01）.Zacopride had no effect on K ATP. CONCLUSION： The inhibitory effect of zacopride on ischemia / reperfusion-induced arrhythmias is mediated by the activation of Kir. Augmentation of Kir cuvrent,thus diminishing the DADs,might be the critical mechanisms underlying postconditioning of zacopride.
出处
《中国病理生理杂志》
CAS
CSCD
北大核心
2016年第11期1921-1927,共7页
Chinese Journal of Pathophysiology
基金
国家自然科学基金资助项目(No.31200864)
中央高校基本科研业务费专项资金资助课题(No.2015SYS008)
山西医科大学创新基金(No.01201107)
关键词
Zacopride
心律失常
后适应
内向整流钾通道
延迟后除极
Zacopride
Arrhythmia
Postconditioning
Inwardly rectifying potassium channel
Delayed afterdepolarizations
