title: 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-oxonapht halen-6- carbonitrile)] and levcromakalim were studied on the electrical and contractile responses induced by noradrenaline and KCl and on 86Rb+ 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 86Rb+ efflux. 5. UR-8225 and levcromakalim inhibited the contractions induced by Ca2+ in aortae incubated in Ca(2+)-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.
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Perez-Vizcaino
authors.forename: O
authors.initials: O
authors.lastname: Casis
authors.forename: R
authors.initials: R
authors.lastname: Rodriguez
authors.forename: L A
authors.initials: LA
authors.lastname: Gomez
authors.forename: J
authors.initials: J
authors.lastname: Garcia Rafanell
authors.forename: J
authors.initials: J
authors.lastname: Tamargo
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D019806:Cromakalim; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012413:Rubidium / Q000493:pharmacokinetics; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D001578:Benzopyrans; D009281:Naphthalenes; D015221:Potassium Channels; D011728:Pyridones; D011758:Pyrroles; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents; D019806:Cromakalim; C082407:UR 8225; D011189:Potassium Chloride; D012413:Rubidium; D002118:Calcium; D009638:Norepinephrine