Effects of the novel potassium channel opener, UR‐8225, on contractile responses in rat isolated smooth muscle

Abstract

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 KCI and on 86Rb+ efflux in rat aortic rings and on spontaneous mechanical activity in rat portal vein segments.2 UR-8225 and levcromakalim, 10-9M-10-SM, relaxed the contractile responses induced by noradrenaline (IC50 = 2.7 ± 0.4 x 10-6 M and 6.6 ± 1.3 x I0-M, respectively) or 30mM KCI (IC, = 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 KCI. 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 86Rb+ 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.

Vasodilator effects of sodium nitroprusside, levcromakalim and their combination in isolated rat aorta

“…In the rat aorta, EDHF appears to play a minor role in endothelium‐dependent relaxation (Chen et al ., 1988; Shimokawa et al ., 1996). However, hyperpolarization induced by potassium channel openers is very effective in inducing vasodilatation in this tissue (Pérez‐Vizcaíno et al ., 1993). The role of the endothelium in modulating the relaxant effects of potassium channel openers in vascular smooth muscle is controversial because enhanced, unchanged or reduced relaxant responses have been reported after endothelium removal (White & Hilley, 1998a; Cavero et al ., 1989; Drieu La Rochelle et al ., 1992; Feleder & Adler‐Graschinsky, 1997).…”

“…One holder served as anchor and the other was attached to an isometric force‐displacement transducer coupled to a signal amplifier (Model PRE 206‐4, Cibertec, Madrid, Spain) and connected to a computer via an A/D interface. Contractile tension was recorded by a REGXPC computer program (Cibertec, Madrid, Spain) as previously described (Pérez‐Vizcaíno et al ., 1993; 1998). Each ring was stretched to a resting tension of 2 g and allowed to equilibrate for 60–90 min.…”

Pharmacology of UR‐8225, a New Potassium Channel Opener

“…The pharmacological effects of UR-8225 can be related, as previously suggested with levcromakalim (36,45,47), to this drugs ability to activate ATP-sensitive K + channels in cardiac and vascular smooth muscle cells (17,35,43). The evidence for this is five-fold: 1) As previously described for other PCOs (20), UR-8225 inhibited the contractile responses induced by norepinephrine or low KCl concentrations ( s 3 0 mM), while those induced by high KCl (80 mM) concentrations were almost unaffected.…”

“…UR-8225 and levcromakalim inhibited the amplitude of spontaneous myogenic contractions in rat portal veins (K5, = 0.05 5 0.01 p M and 0.015 2 0.007 pM, respectively) (6,17,35). The sulfonylurea glyburide, a selective inhibitor of ATP-sensitive K + channels in vascular smooth muscle (2,13), shifted rightward the curve for UR-8225 and levcromakalim (Fig.…”

“…Furthermore, UR-8225 inhibited the tonic contractile responses induced by addition of 2 mM Ca2+ in aortic rings previously incubated in Ca2+-free solution containing 10 JAM D600 and 0.03 mM EDTA in the presence of 10 pM norepinephrine (35). At 1 and 10 p M , UR-8225 inhibited this tonic contraction by 17.0% and 38.9%, respectively.…”