EFFECTS OF THE NOVEL POTASSIUM CHANNEL OPENER, UR-8225, ON CONTRACTILE RESPONSES IN RAT ISOLATED SMOOTH-MUSCLE

1 The effects of UR-8225 [(1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphthalen-6-carbonitrile)] and levcromakalim were studied on the electrical and contractile responses induced by noradrenaline and KCl and on Rb-86+ efflux in rat aortic rings and on spontaneous mechanical activity in rat portal vein segments. 2 UR-8225 and levcromakalim, 10-(9) M-10(-5) M, relaxed the contractile responses induced by noradrenaline (IC50 = 2.7 +/- 0.4 x 10(-6) M and 6.6 +/- 1.3 x 10(-7) M, respectively) or 30 mM KCl (IC50 = 1.4 +/- 0.2 x 10(-7) M and 9.4 +/- 1.3 x 10(-8) M, respectively) more effectively than those induced by 80 mM KCl. The relaxant effect on noradrenaline-induced contractions was independent of the presence or absence of functional endothelium. 3 The vasorelaxant effect of UR-8225 and levcromakalim can be competitively antagonized by glibenclamide, an ATP-sensitive K+ channel blocker. There were no differences in the calculated pA2 values for glibenclamide to inhibit UR-8225- and levcromakalim-induced relaxations (7.61 +/- 0.08 and 7.69 +/- 0.10, respectively). The slope of the Schild plot yielded values not significantly different from unity (0.95 +/- 0.06 and 0.96 +/- 0.05, respectively). 4 UR-8225 (10(-5) M) hyperpolarized the resting aortic membrane potential from -50.7 +/- 0.7 mV to -66.0 +/- 2.0 mV and stimulated Rb-86+ efflux. 5 UR-8225 and levcromakalim inhibited the contractions induced by Ca2+ in aortae incubated in Ca2+-free PSS containing methoxyverapamil in the presence of noradrenaline. 6 Both drugs inhibited the amplitude of spontaneous activity in portal veins (IC50 = 5.1 +/- 1.4 x 10(-8) M and 1.5 +/- 0.7 x 10(-8) M, respectively), this effect being competitively antagonized by glibenclamide. 7 These results indicated that UR-8225 exhibited qualitatively similar. but slightly less potent, vasorelaxant effects than those exerted by levcromakalim, which suggests that they can be related to its ability to activate ATP-sensitive K+ channels in vascular smooth muscle cells.