PT  - JOURNAL ARTICLE
AU  - Hideaki Endo
AU  - Masahito Miura
AU  - Masanori Hirose
AU  - Jun Takahashi
AU  - Makoto Nakano
AU  - Yuji Wakayama
AU  - Yoshinao Sugai
AU  - Yutaka Kagaya
AU  - Jun Watanabe
AU  - Kunio Shirato
AU  - Hiroaki Shimokawa
TI  - Reduced Inotropic Effect of Nifekalant in Failing Hearts in Rats
AID  - 10.1124/jpet.106.102780
DP  - 2006 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1102--1107
VI  - 318
IP  - 3
4099  - http://jpet.aspetjournals.org/content/318/3/1102.short
4100  - http://jpet.aspetjournals.org/content/318/3/1102.full
SO  - J Pharmacol Exp Ther2006 Sep 01; 318
AB  - 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 Ca2+ ([Ca2+]i) by the fura-2 microinjection method. The sarcoplasmic reticulum (SR) Ca2+ 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 Ca2+ ATPase type 2 (SERCA2) and the SERCA2/phospholamban ratio in MCT rats was lower with a slower decline of Ca2+ transients and a reduced amplitude of RCCs. Nifekalant concentration-dependently increased the force, peak [Ca2+]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 Ca2+ uptake and reduced reserve of the trans-sarcolemmal Ca2+ transport, warranting a caution in the antiarrhythmic therapy with a class III antiarrhythmic agent in heart failure. The American Society for Pharmacology and Experimental Therapeutics