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

Abstract

S-551, a class III anti-arrhythmic agent, with a pyrimidinedione structure, inhibits the rapiddelayed rectifier K + currents (IKr) at therapeutic concentrations of 1-10 mol/L 1 and, furthermore, inhibits several other K + channels at concentrations above 10 mol/L. [2][3][4][5][6] The blocking of K + channels can prolong the duration of the action potential 4,7 and consequently prolong the myocardial refractory period, 4,[6][7][8][9] suggesting that the chief anti-arrhythmic action of nifekalant comes from the suppressive action against re-entrant arrhythmias. 7,9 By this blocking of K + channels, nifekalant exerts a clinically potent suppressive action against ventricular tachyarrhythmias. [9][10][11] To achieve optimal anti-arrhythmic effects with drugs, the clinician needs to avoid the pro-arrhythmic actions of the drug. In the case of nifekalant, one may anticipate that the drug will increase the cellular Ca 2+ load because of the prolongation of the action potential and thereby induce triggered premature beats and triggered arrhythmias. 12 been observed as a propagation of regional increases in intracellular Ca 2+ ([Ca 2+ ]i) with aftercontractions and delayed afterdepolarizations (DADs), 12 start from damaged regions within both rat ventricular 15 and human atrial cardiac muscle. 12 The velocity of Ca 2+ waves ranges from 0.34 to 5.47 mm/s, 12 depending on both [Ca 2+ ]i and Ca 2+ loading in the sarcoplasmic reticulum (SR). 14 The acceleration of Ca 2+ waves caused by the increase in the cellular Ca 2+ loading can increase the amplitude of DADs 16 and finally induce triggered arrhythmias. 17 Such triggered arrhythmias from DADs have been reported to play an important role in the occurrence of tachyarrhythmias in heart diseases such as heart failure, 18,19 cardiac hypertrophy 20 and digitalis intoxication.Therefore, in this study, we investigated: (i) the effect of nifekalant on the action potential, Ca 2+ transient, and developed force of rat myocardium to determine whether nifekalant increases muscle contraction with an increase in cellular Ca 2+ loading; and (ii) the effect of nifekalant on the velocity of Ca 2+ waves and aftercontractions to evaluate whether nifekalant can affect triggered arrhythmias as well as re-entrant arrhythmias. Methods Dissection and Mounting of Rat Ventricular TrabeculaeThe experiments were performed according to the guidelines for the care and use of laboratory animals of Tohoku University. Trabeculae were obtained as previously described. 14,17 Sprague -Dawley rats (250-300 g) were anesthetized and hearts were excised. Sixteen trabeculae (length = Background Nifekalant, a class III anti-arrhythmic agent, has been used clinically at serum concentrations of 1-10 mol/L in patients with ventricular arrhythmias. However, the effect of nifekalant on triggered arrhythmiashas not yet been established. Methods and ResultsTrabeculae were dissected from the right ventricles of 16 rat hearts. The force was measured using a silicon strain gauge, the membrane potential using ultra-complian...

Reduced Inotropic Effect of Nifekalant in Failing Hearts in Rats

“…These discrepancies may be due to differences in the hemodynamic load, chamber geometry, and cell-cell or cell matrix connectivity between these preparations. Therefore, to fill the gap between isolated myocytes and whole hearts , we used in this study multicellular ventricular muscle with the original cell-cell and cell-matrix connectivity (Sys et al, 1998) and measured the contractile properties with the proper load at the sarcomere length of 2.1 m (Miura et al, 1999;Hirose et al, 2005).…”

“…The sarcomere length was measured using laser diffraction techniques (ter Keurs et al, 1980;Wakayama et al, 2005). Membrane potential was measured using ultracompliant glass microelectrodes, as described previously (Hirose et al, 2005). To estimate the duration of action potential, the time to 90% repolarization of the action potential (APD 90 ) was measured.…”

“…Rapid Cooling Contracture. SR Ca 2ϩ content was estimated using a rapid cooling contracture (RCC) technique as described previously (Hirose et al, 2005). The perfusion line filled with a warm solution (ϳ24°C) was instantly replaced by another perfusion line that was jacketed with ethylene glycol-water (1:3 at Ϫ5°C) in response to a voltage command from a personal computer.…”

“…It blocks the rapid-delayed rectifier current (I kr ) at therapeutic concentrations between 1 and 10 M (Shiga et al, 2001) and several other channels at concentrations above 10 M (Mori et al, 1995), thus exerting a clinically potent suppressive action against ventricular tachyarrhythmias. The K ϩ channels blocking effects of Nifekalant can prolong the duration of an action potential (Sen et al, 1998) and consequently increase the muscle contraction depending on the concentration in intact rat cardiac muscle (Hirose et al, 2005).…”

Emergency Treatment With Nifekalant, a Novel Class III Anti-Arrhythmic Agent, for Life-Threatening Refractory Ventricular Tachyarrhythmias Post-Marketing Special Investigation

“…It is suggested that nifekalant increased intracellular calcium concentration associated with the prolongation of action potential duration resulting in the increase of myocardial contraction. 13 …”