ROLE OF K-GMP IN THE VASORELAXANT EFFECTS OF NICORANDIL IN ISOLATED PIGLET PULMONARY AND MESENTERIC-ARTERIES - RELATIVE EFFICACY AND INTERACTIONS BETWEEN BOTH PATHWAYS( CHANNEL OPENING AND STIMULATION OF CYCLIC)

1 The effects of the K+ channel opener levcromakalim, the guanylate cy clase stimulant nitroprusside and the dual drug nicorandil (K+ channel opener and guanylate cyclase stimulant) were analysed in piglet isola ted endothelium-denuded pulmonary (PA) and mesenteric (MA) arteries st imulated by noradrenaline (NA) or by the thromboxane Al mimetic U46619 . 2 Nicorandil, levcromakalim and verapamil were less potent in PA tha n in MA, the efficacy of levcromakalim was also reduced in PA. The eff ects of nicorandil and levcromakalim were similar in arteries pre-cont racted by NA and U46619, whereas verapamil was more potent in arteries precontracted by NA. Nitroprusside was equipotent in MA pre-contracte d by either NA or U46619 and in PA pre-contracted by NA whereas in PA pre-contracted by U46619, nitroprusside showed lower potency and effic acy. 3 The relaxant effects of levcromakalim and nitroprusside were in hibited by 10(-5) M glibenclamide and 10(-6) M ODQ, respectively. Nico randil-induced relaxation was inhibited by ODQ in all experimental con ditions, whereas glibenclamide had inhibitory effects in PA and MA pre -contracted by U46619, had no effect in PA pre-contracted by NA and in MA pre-contracted by NA it was only inhibitory in the presence of ODQ . 4 No apparent interactions were found between nitroprusside and levc romakalim as indicated by the lack of effects of pretreatment with one of them (producing 20-35% relaxation) on the potency of the relaxant response to the other. However, in PA pre-contracted by U46619, where nitroprusside or levcromakalim induced only partial relaxation, the co mbination of both mechanisms (either by combining nitroprusside plus l evcromakalim or by nicorandil) was able to induce full vasodilatation. 5 In conclusion, K+ channel opening and guanylate cyclase stimulation are independent pathways that induce additive vasorelaxation in pigle t PA and MA. The mechanism of action of nicorandil is dependent on the artery and on the nature of the agonist employed to precontract the a rtery. The relative efficacy of K+ channel opening vs guanylate cyclas e stimulation may partially explain the preferential contribution of e ach mechanism to the relaxant effects of nicorandil.