Effects of HNS-32, a novel antiarrhythmic drug, on ventricular arrhythmiasinduced by coronary artery occlusion and reperfusion in anesthetized rats

HNS-32 (N-1,N-1-dimethyl-N-2-(2-pyridylmethyl)-5-isopropyl-3, 8-dimethylazu lene-1-carboxamidine: CAS 186086-10-2) is a newly synthesized compound, and possesses antiarrhythmic properties with vasodilator action in dog hearts. The aim of this study was to investigate the dose-dependent effects of HNS -32 on ischemia- and/or reperfusion-induced ventricular arrhythmias in anes thetized rats in vivo and compared with those of mexiletine. Saline or drug s were administered intravenously 5 min prior to coronary artery occlusion. On the ischemia-induced ventricular arrhythmias, HNS-32 showed dose-depend ent reduction of total number of premature ventricular complexes (PVC) from 2091 +/- 225 to 656 +/- 116 and 286 +/- 69 beats/30 min (p < 0.05), the ve ntricular tachycardia (VT) duration from 183 +/- 33 to 28 +/- 9 and 4 +/- 2 sec (p < 0.05), the incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.0 5), and the incidence of ventricular fibrillation (VF) from 50 to 0 and 0% (p < 0.05) with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 936 +/- 159 beats/30 min (p < 0.05), 39 +/- 22 sec (p < 0.05) , 90% (n.s.) and 10% (n.s.), respectively. HNS-32 completely suppressed the late reperfusion-induced arrhythmias, however mexiletine did not affect th em. On the early reperfusion-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of VT duration from 126 +/- 34 to 37 +/- 12 and 3 +/- 2 sec (p < 0.05), incidence of VT from 100 to 90 (n.s.) and 40% (p < 0 .05), incidence of VF from 100 to 10 and 0% (p < 0.05), and mortality rate from 90 to 0 and 0% (p < 0.05), with 3 and 5 mg/kg, respectively. Mexiletin e also reduced these parameters to 16 +/- 9 sec (p < 0.05), 80 (n.s.), 50 ( p < 0.05), and 10% (p < 0.05), respectively. HNS-32 significantly reduced t he heart rate in a dose-dependent manner, from 399 +/- 14 to 350 +/- 8 and 299 +/- 10 beats/min (p < 0.05) with 3 and 5 mg/kg, respectively. The antia rrhythmic effects of HNS-32 were more potent than that of the similar dose of mexiletine against occlusion-induced and reperfusion-induced arrhythmias in in vivo rats.