Study of negative chronotropic action of a novel Russian class III antiarrhythmic drug nibentan in mammalian atria in vitro and in vivo

Nibentan is a novel class III antiarrhythmic drug with anticholinergic acti on. In the isolated rabbit sino-atrial node nibentan in doses 0,023, 0,23 a nd 2,3 mu M/l dose-dependently prolonged sinus cycle length (by 6+/-2, 23+/ -4 and 47+/-4%, respectively, p<0,05) at the account of increase of action potential duration (by 12+/-1, 32+/-3% and 59+/-9%, respectively, p<0,05). Moreover 0,23 and 2,3 mu M/l of nibentan decreased the slope of phase 4 dia stolic depolarization by 29+/-4 and 45+/-6%, respectively (p<0,05). During cholinergic stimulation with carbachol (0,03 mu M/l) prolongation of the si nus cycle length induced by nibentan was less pronounced (by 2+/-1% after 0 ,023 mu M/l, NS, and by 14+/-3% after 0,23 mu M/l, p<0,05). In open-chest d ogs intravenous administration of nibentan (0,063, 0,125 and 0,250 mg/kg) s ignificantly decreased frequency of sinus rhythm (by 20+/-4, 26+/-4 and 32/-4%, respectively, p<0,05). Herewith nibentan-induced sinus cycle length p rolongation was significantly less pronounced during stimulation of the vag us nerve. Atrial activation mapping (224 unipolar electrodes) showed that n ibentan at doses of 0,063, 0,125 and 0,250 mg/kg induced a shift of pacemak er localization mostly toward to inferior vena cava by 20% (NS), 50 (NS) an d 80% (p<0,05), respectively. The caudal shift of pacemaker localization ma y account for negative chronotropic effect of nibentan.