title: Potential therapeutic value of antioxidants for abnormal prolongation of QT interval and the associated arrhythmias in a rabbit model of diabetes.
abstract: Abnormal QT prolongation is the major cardiac electrical disorder and a predictor of mortality in diabetic patients. Our previous studies suggest that dysfunction of delayed rectifier K(+) current (I(Kr)) is the main cause for the problem. Here we report the potential therapeutic role and mechanisms of vitamin E in the rabbit model of diabetes. The QT interval and action potential duration were considerably prolonged with frequent occurrence of ventricular tachyarrhythmias in diabetic rabbits. Administration of vitamin E corrected the abnormal QT prolongation and abolished the arrhythmic incidence. I(Kr) was found markedly reduced resulting in slowing of cardiac repolarization thereby QT prolongation in diabetic hearts. The diabetic depression of I(Kr) is primarily ascribed to oxidative damages to the cardiac membrane and proteins, as indicated by the overproduction of reactive oxygen species leading to severe lipid peroxidation and protein oxidation. Moreover, I(Kr) depression is most likely due to the dysfunction of HERG K(+) channel, the major subunit underlying native I(Kr), in response to oxidative stress, for peroxide anion-generating system produced similar depression of HERG channels. Vitamin E restored the depressed I(Kr) and HERG by its antioxidant actions which likely underlie its beneficial effects on diabetic QT prolongation and the associated arrhythmias. The data indicate that an antioxidant is sufficient for reversing the I(Kr)/I(HERG) dysfunction and the consequent electrical disorders in diabetic hearts. Our study also conceptually simplifies the complex nature of diabetic electrical disorders to primarily oxidative stress, and should stimulate interest in antioxidants as a therapeutic strategy for diabetic QT prolongation.
authors.affiliation: Research Center, Montreal Heart Institute, Montreal, Canada.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xuelin
authors.initials: X
authors.lastname: Sun
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jingxiong
authors.initials: J
authors.lastname: Wang
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D004195:Disease Models, Animal; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000502:physiology; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D051638:Ether-A-Go-Go Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species; D014810:Vitamin E