HNS-32 [N(1),N(1)-dimethyl-N(2)-(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 (Vmax) 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.