Open AccessInflammatory factors that contribute to upregulation of ERG and cardiac arrhythmias are suppressed by CPU86017, a class III antiarrhythmic agent
Author(s) -
Du RongHui,
Yi HongWei,
Dai DeZai,
Tang WeiHua,
Dai Yin
Publication year - 2008
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1211/jpp.60.8.0015
Subject(s) - downregulation and upregulation , malondialdehyde , medicine , endocrinology , erg , nitric oxide , reactive oxygen species , propranolol , nitric oxide synthase , chemistry , pharmacology , oxidative stress , biochemistry , gene , retinal
The aim of this study was to verify whether exaggerated arrhythmogenesis is attributed to inflammatory factors actively involving an excess of reactive oxygen species (ROS), transforming growth factor (TGF)‐β and endothelin (ET). We hypothesized that CPU86017, derived from berberine, which possesses multi‐channel blocking activity, could suppress inflammatory factors, resulting in inhibition of over‐expression of ether‐a‐go‐go (ERG) and an augmented incidence of ventricular fibrillation (VF) in ischaemia/reperfusion (I/R). Rats with cardiomyopathy (CMP) induced by thyroxine (0.2 mg −1 kg −1 s.c. daily for 10 days) were treated with propranolol (10 mg kg −1 p.o.) or CPU86017 (80 mg kg −1 p.o.) on days 6–10. On the 11th day, arrhythmogenesis of the CMP was evaluated by I/R. In the CMP control group, an increase in VF incidence was found with the I/R episode, accompanied by increased ROS, which manifested as an increased level of malondialdehyde and decreased activities of SOD, glutathione peroxidase and catalase in the myocardium. Levels of inducible nitric oxide synthase and TGF‐β mRNA were increased in association with upregulation of preproET‐1 and ET‐ converting enzyme. We found increased levels of ERG, which correlated well with arrhythmogenesis. Treatment with CPU86017 or propranolol reversed these changes. These experiments verified our hypothesis that the inflammatory factors ROS, iNOS, TGF‐β and ET‐1 are actively involved in upregulation of ERG and arrhythmogenesis. CPU86017 and propranolol reduced VF by suppressing these inflammatory factors in the myocardium.