title: Reduced inotropic effect of nifekalant in failing hearts in rats.
abstract: Class III antiarrhythmic agents have been widely used to suppress ventricular tachyarrhythmias in patients with heart failure because they have been shown to have positive inotropic effects as well. However, it remains to be examined whether those agents also exert positive inotropic effects in failing hearts. We addressed this important issue in a rat model of heart failure. We used Nifekalant as a representative class III antiarrhythmic agent. Four weeks after a s.c. injection of 60 mg/kg monocrotaline (MCT) or vehicle (Ctr) into rats, we obtained trabeculae from right ventricles and measured the developed force and intracellular Ca(2+) ([Ca(2+)](i)) by the fura-2 microinjection method. The sarcoplasmic reticulum (SR) Ca(2+) content was assessed by the rapid-cooling contracture (RCC) technique. MCT rats exhibited right ventricular hypertrophy induced by pressure overload. The protein expression of SR Ca(2+) ATPase type 2 (SERCA2) and the SERCA2/phospholamban ratio in MCT rats was lower with a slower decline of Ca(2+) transients and a reduced amplitude of RCCs. Nifekalant concentration-dependently increased the force, peak [Ca(2+)](i), and the amplitude of RCCs in Ctr rats but not in MCT rats with identical prolongation of the action potential. Under the SR inhibited with cyclopiazonic acid and ryanodine, Nifekalant increased the force in Ctr rats but not in MCT rats. These results indicate that the positive inotropic effects of Nifekalant is reduced in failing hearts, probably due to the depressed SR Ca(2+) uptake and reduced reserve of the trans-sarcolemmal Ca(2+) transport, warranting a caution in the antiarrhythmic therapy with a class III antiarrhythmic agent in heart failure.
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8574, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Endo
authors.forename: Masahito
authors.initials: M
authors.lastname: Miura
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirose
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wakayama
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Sugai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kagaya
authors.forename: Jun
authors.initials: J
authors.lastname: Watanabe
authors.forename: Kunio
authors.initials: K
authors.lastname: Shirato
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D016686:Monocrotaline; D009200:Myocardial Contraction / Q000187:drug effects*; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D011744:Pyrimidinones; C076259:nifekalant; D016686:Monocrotaline; D002118:Calcium