Received for publication February 13, 2006.
Revised May 29, 2006.
Accepted for publication May 30, 2006.

Reduced Inotropic Effect of Nifekalant in Failing Hearts in Rats

Abstract

Class III anti-arrhythmic agents have been widely used to suppress ventricular tachyarrhythmias in patients with heart failure as 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 anti-arrhythmic agent. Four weeks after a subcutaneous injection of 60 mg/kg monocrotaline (MCT-rats) or vehicle (Ctr-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 type2 (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 anti-arrhythmic therapy with a class III anti-arrhythmic agent in heart failure.

Key words: Anti-arrhythmic agent, Calcium handling, Heart Failure, Inotropic effect, Nifekalant, Sarcoplasmic reticulum