HNS-32

HNS-32, an azulene-1-carboxamidine derivative, is an originally synthesized antiarrhythmic compound. Its cardiovascular effects after oral administration (1-10 mg/kg) were assessed using the pentobarbital-anesthetized in vivo rat model in comparison with those of verapamil (3 mg/kg, p.o.). Verapamil decreased the heart rate and mean blood pressure and prolonged the PR interval without changing the QRS width (n = 6). Similar results were observed for HNS-32 except that the QRS width was prolonged by the highest dose and the effects occurred slowly and lasted longer. These results suggest that HNS-32 is an orally active slowly-acting calcium plus sodium channel blocker.

HNS‐32 [N1,N1‐dimethyl‐N2‐(2‐pyridylmethyl)‐5‐isopropyl‐3,8‐dimethylazulene‐1‐carboxamidine] (CAS Registry Number: 186086‐10‐2) is a newly synthesized azulene derivative. Computer simulation showed that its three dimensional structure is similar to that of the class Ib antiarrhythmic drugs, e.g., lidocaine or mexiletine. HNS‐32 potently suppressed ventricular arrhythmias induced by ischemia due to coronary ligation and/or ischemia‐reperfusion in dogs and rats. In the isolated dog and guinea pig cardiac tissues, HNS‐32 had negative inotropic and chronotropic actions, prolonged atrial‐His and His‐ventricular conduction time and increased coronary blood flow. In the isolated guinea pig ventricular papillary muscle, HNS‐32 decreased maximal rate of action potential upstroke (V̇max) and shortened action potential duration (APD). These findings suggest that HNS‐32 inhibits inward Na+ and Ca2+ channel currents. In the isolated pig coronary and rabbit conduit arteries, HNS‐32 inhibited both Ca2+ channel‐dependent and ‐independent contractions induced by a wide variety of chemical stimuli. HNS‐32 is a potent inhibitor of protein kinase C (PKC)‐mediated constriction of cerebral arteries. It is likely to block both, Na+ and Ca2+ channels expressed in cardiac and vascular smooth muscles. These multiple ion channel blocking effects are largely responsible for the antiarrhythmic and vasorelaxant actions of HNS‐32. This drug may represent a novel approach to the treatment of arrhythmias.