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

Abstract

Background Nifekalant, a class III anti-arrhythmic agent, has been used clinically at serum concentrations of 1-10 μmol/L in patients with ventricular arrhythmias. However, the effect of nifekalant on triggered arrhythmias has not yet been established. Methods and Results 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 μm. 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 μmol/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°C). Nifekalant at 10 and 250 μmol/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 °C). Conclusions 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. (Circ J 2005; 69: 739 - 745)