title: Antiarrhythmic efficacy of CPUY102122, a multiple ion channel blocker, on rabbits with ischemia/reperfusion injury.
abstract: BACKGROUND
  The antiarrhythmic potential of a novel multichannel blocker CPUY102122 (CY22) was investigated in the present study.
  
  
  METHODS
  The effect of CY22 on rapid delayed rectifier potassium channel current (IKr) was studied using whole-cell patch clamp techniques in Chinese Hamster Ovary cells stably expressing human Ether-à-go-go-Related Gene. We further evaluated the antioxidant effects of CY22 and demonstrated the reversal of connexin down-regulation in the development of cardiac ventricular arrhythmias, which was produced using coronary ligation/reperfusion in rabbits. CY22 and Amiodarone were administered 30min prior to the procedure. Next, electrocardiograms were recorded, protein expression of left ventricular Connexin43 (Cx43), non-phosphorylation-Cx43 (np-Cx43), Rac-1 and gp-91[phox] were assayed using Western blot analysis, microstructural changes in the myocardium were observed and redox system activity was assayed.
  
  
  RESULTS
  CY22 inhibited IKr in a concentration-dependent manner with IC50 value of 2.8±0.8μmol/L. CY22 treatment significantly decreased T-wave amplitude and QTc arrhythmic scores and ameliorated the shape of the infarcted myocardium compared to the model group. CY22 decreased the serum levels of creatine kinase, lactate dehydrogenase, and myocardial levels of malondialdehyde, as well as increased superoxide dismutase activity. Cx43 expression in the left ventricle was significantly increased by CY22 treatment, which significantly decreased np-43 expression, Rac-1 activity and gp-91[phox] protein expression.
  
  
  CONCLUSIONS
  These results indicated that CY22 has both antiarrhythmic and cardiovascular protective effects partly by blocking IKr, the production of antioxidants and protection of Cx43.
authors.affiliation: Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China; Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, China. Electronic address: wmh_yjs@163.com.
authors.forename: Minhui
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. Electronic address: zixinzizu@126.com.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Shan
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China. Electronic address: cpuyangqian816@163.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. Electronic address: myword3477@163.com.
authors.forename: Xianglei
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. Electronic address: jss393900019@163.com.
authors.forename: Sisi
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China. Electronic address: kexin95@126.com.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China. Electronic address: youqidong@gmail.com.
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.affiliation: Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. Electronic address: tyq@cpu.edu.cn.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D016466:CHO Cells; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology; D018031:Connexin 43 / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D020128:Inhibitory Concentration 50; D009203:Myocardial Infarction / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D011817:Rabbits
chemical_list: D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D002316:Cardiotonic Agents; D018031:Connexin 43; D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D000638:Amiodarone
keywords: Antiarrhythmic; Antioxidant; CPUY102122; Connexin 43; Rapidly activating component of delayed rectifier K(+) current