Effect of nifekalant, a class III anti-arrhythmic agent, on Ca²⁺ waves in rat intact trabeculae

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⁺ ([Ca ²⁺]_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 Ca ²⁺ 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.