title: Inflammatory factors that contribute to upregulation of ERG and cardiac arrhythmias are suppressed by CPU86017, a class III antiarrhythmic agent.
abstract: 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)-beta 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 mgkg(-1) p.o.) or CPU86017 (80 mgkg(-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-beta 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-beta 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.
authors.affiliation: Medical college of Nanjing University, Nanjing, 210093, China.
authors.forename: Rong-Hui
authors.initials: RH
authors.lastname: Du
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Yi
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Tang
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D009202:Cardiomyopathies / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013974:Thyroxine; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
chemical_list: C400084:4-chlorobenzyltetrahydroberberine; D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D019332:Endothelin-1; D051638:Ether-A-Go-Go Potassium Channels; D018836:Inflammation Mediators; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D001599:Berberine; D009569:Nitric Oxide; D011433:Propranolol; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D013974:Thyroxine