These two authors contributed equally to this work.
The Multiple Ion Channel Blocker CPUY11018 Prevents Aconitine-Induced Arrhythmias
Article first published online: 18 MAY 2012
© 2012 Wiley Periodicals, Inc.
Drug Development Research
Volume 73, Issue 4, pages 214–221, June 2012
How to Cite
Tang, Y.-Q., Yu, P., Zhao, N., Yang, Q., Yin, Y.-M., Le, X.-Y., Guo, X., Wang, M.-H., Zhong, H. and You, Q.-D. (2012), The Multiple Ion Channel Blocker CPUY11018 Prevents Aconitine-Induced Arrhythmias. Drug Dev. Res., 73: 214–221. doi: 10.1002/ddr.21009
- Issue published online: 19 JUN 2012
- Article first published online: 18 MAY 2012
- Manuscript Accepted: 7 APR 2012
- Manuscript Received: 8 FEB 2012
- Natural Science Foundation of Jiangsu Province. Grant Number: BK 2010434
- National “Key Program for New Drug Research Development“. Grant Number: 2009 ZX09103-088
- sodium channels;
- calcium channels;
- ventricular myocytes;
|Strategy, 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 IV|
In the present study, the potential antiarrhythmic activities of a new multiple ion channel blocker, CPUY11018 (Y18) were investigated. The effects of Y18 on ICa,L and INa 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 ICa,L and INa in rat ventricular myocytes with IC50 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.