Effect of Nifekalant, a Class III Anti-Arrhythmic Agent, on Ca2+ Waves in Rat Intact Trabeculae

Abstract

Nifekalant, a class III anti-arrhythmic agent, has been used clinically at serum concentrations of 1-10 micromol/L in patients with ventricular arrhythmias. However, the effect of nifekalant on triggered arrhythmias has not yet been established. Trabeculae were dissected from the right ventricles of 16 rat hearts. The force was measured using a silicon strain gauge, the membrane potential using ultra-compliant microelectrodes, and the regional intracellular Ca2+ ([Ca2+]i) using electrophoretically microinjected fura-2 and an image intensified CCD camera at a sarcomere length of 2.1 microm. Rapid cooling contractures (RCCs) were measured to estimate the Ca2+ content in the sarcoplasmic reticulum. Ca2+ waves and aftercontractions were measured after the induction of reproducible Ca2+ waves. Nifekalant at 1, 10 and 250 micromol/L increased significantly the action potential duration, the peak [Ca2+]i, the developed force and the amplitude of RCCs in a concentration-dependent manner (stimulus interval = 2 s, [Ca2+]o = 0.7 mmol/L, 26.0+/-0.2 degrees C). Nifekalant at 10 and 250 micromol/L increased significantly the velocity of Ca2+ waves with an enhancement of the aftercontractions (stimulus interval = 0.5 s for 7.5 s, [Ca2+]o = 1.8+/-0.1 mmol/L, 22.3+/-0.5 degrees C). Nifekalant, even at a therapeutic concentration, can increase muscle contraction, but may worsen triggered arrhythmias because of the acceleration of Ca2+ waves under Ca2+-overloaded conditions.