A FURTHER STUDY OF THE VASODILATOR AND NEGATIVE INOTROPIC MECHANISMS OF ACTION OF NICORANDIL AND ITS CONGENERS IN THE CANINE HEART

The vasodilator and negative inotropic mechanisms of action of nicoran dil and its congeners (SG-209, SG-103, and SG-86) were investigated in isolated canine papillary muscle preparations cross-circulated throug h the anterior septal artery with support dogs. SG-209, SG-103, and SG -86 were obtained by replacement of the nitroxyl group of nicorandil b y acetoxyl, nicotinoyloxyl, and hydroxyl groups, respectively. Nicoran dil(0.03-10 mu mol), SG-209 (0.1-10 mu mol), SG-103 (1-30 mu mol), and SG-86 (3-100 mu mol) all produced an increase in coronary blood flow through the anterior septal artery. Both nicorandil and SG-209 produce d a near-maximal increase in coronary blood flow, the latter being abo ut 5.5 times less potent than the former. SG-103 and SG-86 were far le ss potent than SG-209 in that order. The vasodilator actions of nicora ndil and SG-209 were antagonized by glibenclamide given IV to support dogs, but those of SG-103 and SG-86 were nob. The pK(B) values of glib enclamide were 6.34 toward nicorandil and 6.49 toward SG-209. Develope d tension of the papillary muscle was reduced by nicorandil, SG-209, a nd SG-103, but not by SG-86. In this respect SG-209 was about 4.7 time s less potent than nicorandil, and SG-103 was much less potent than SG -209. The negative inotropic effects of nicorandil and SG-209 were ant agonized by glibenclamide, but that of SG-103 was not. These results i ndicate that both nicorandil and SG-209 act as It-channel openers in c oronary resistance vessels and in ventricular myocardium, and that the nitroxyl and the acetoxyl group at C2 of the parent structure of nico randil and its congeners, i.e., N-ethylnicotinamide, play a pivotal ro le in making these compounds act as It-channel openers. In this respec t, the nitroxyl group is about five times more potent than the acetoxy l group.