Cardioprotective effects of sarcolemmal and mitochondrial K-ATP channel openers in an experimental model of autoimmune myocarditis. Role of the reduction in calcium overload during acute heart failure.
It has been reported that K-ATP channel openers have a cardioprotective effect in acute ischemia as a pharmacological preconditioning effect. In the present study, the chronic effects of clinical K-ATP channel openers, ie, nicorandil (Nic) and mexiletine (Mex), on cardiac function were evaluated in a rat model of experimental autoimmune myocarditis (EAM). Nicorandil (3 or 10 mg/kg/day) or Mex (10 or 25 mg/kg/day) was administered to the EAM rats, and the effects were compared with those in untreated EAM rats (control EAM) and sham rats without EAM on day 21 (acute phase) or day 60 (chronic phase). In the acute phase, the control EAM rats exhibited a reduced left ventricular ejection fraction (LVEF) and prolonged monophasic action potential duration (MAPD). Neither drug had an affect on the LVEF or degree of myocarditis, but Mex 25 mg suppressed the MAPD prolongation. In the chronic phase, EAM+Nic and EAM+Mex 25 mg exhibited a higher LVEF than the control EAM. Although the control EAM exhibited sustained MAPD prolongation, the other groups showed recovery of the MAPD in the chronic phase. The mitochondorial redox state was lower in the control EAM than in the sham, and EAM+Nic exhibited a similar level of the redox state as the sham in the chronic phase. Nicorandil exhibited a cardioprotective effect through the protection of mitochondrial function. Mexiletine exhibited a cardioprotective effect possibly through a reduction in the calcium overload by shortening the MAPD in the acute phase.
Department of Cardio-Angiology, Kitasato University School of Medicine, Kanagawa, Japan.
Shinichi
S
Niwano
Shoji
S
Hirasawa
Hiroe
H
Niwano
Sae
S
Sasaki
Ray
R
Masuda
Kiyotaka
K
Sato
Takashi
T
Masuda
Tohru
T
Izumi
D000200:Action Potentials / Q000187:drug effects; D000208:Acute Disease; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000378:metabolism / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism*; D004452:Echocardiography; D004594:Electrophysiology; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D054086:KATP Channels / Q000187:drug effects*; D008801:Mexiletine / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects; D009205:Myocarditis / Q000378:metabolism / Q000517:prevention & control*; D020108:Nicorandil / Q000494:pharmacology*; D051381:Rats; D012508:Sarcolemma / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D054086:KATP Channels; D008801:Mexiletine; D020108:Nicorandil; D002118:Calcium