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The Multiple Ion Channel Blocker CPUY 11018 Prevents Aconitine‐Induced Arrhythmias
Author(s) -
Tang YiQun,
Yu Peng,
Zhao Na,
Yang Qian,
Yin YueMiao,
Le XiaoYong,
Guo Xiang,
Wang MinHui,
Zhong Hao,
You QiDong
Publication year - 2012
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21009
Subject(s) - aconitine , torsades de pointes , pharmacology , dofetilide , ventricular fibrillation , qt interval , channel blocker , medicine , anesthesia , calcium
trategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I‐III Regulatory, Quality, Manufacturing Postmarketing Phase IVIn the present study, the potential antiarrhythmic activities of a new multiple ion channel blocker, CPUY 11018 ( Y18 ) were investigated. The effects of Y18 on I Ca ,L and I Na were studied using whole‐cell patch clamp techniques in ventricular muscle cells from normal rats and guinea pigs. The antiarrhythmic effects were tested using a rat model of aconitine‐induced arrhythmias. The effects of Y18 on induction of QT prolongation and torsades de pointes ( TdP ) were investigated in anesthetized rabbits during stimulation with methoxamine. Y18 produced a concentration‐dependent inhibition of I Ca ,L and I Na in rat ventricular myocytes with IC 50 values of 88 μmol/l and 6.5 μmol/l, respectively. In the Y18 treatment group, the development of arrhythmias was significantly delayed. Doses of aconitine that induced ventricular fibrillation were decreased following treatment with 6 mg/kg Y18 (3.8 ± 0.4 μg/100 g vs 6.2 ± 1.3 μg/kg). A significant decrease in the occurrence of atrial fibrillation (100% to 33%; P < 0.05) occurred following Y18 administration. Y18 induction of TdP was significantly less than that seen with dofetilide and azimilide ( Az ). Thus, Y18 significantly inhibited the production of aconitine‐induced arrhythmias with a low potency for TdP induction. These results suggest that Y18 is a multiple channel blocker with promising antiarrhythmic potential.