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

• Published in: British journal of pharmacology 1993-11, Vol.110 (3), p.1165-1171
• Main Authors: Perez‐Vizcaino, F., Casis, O., Rodriguez, R., Gomez, L.A., Rafanell, J. Garcia, Tamargo, J.
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - pharmacology; Benzopyrans - pharmacology; Biological and medical sciences; Calcium - pharmacology; Cardiovascular system; Cromakalim; Female; In Vitro Techniques; Ion Channel Gating - drug effects; levcromakalim; Male; Medical sciences; Membrane Potentials - drug effects; Muscle Contraction - drug effects; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiology; Naphthalenes - pharmacology; Norepinephrine - pharmacology; Pharmacology. Drug treatments; portal vein; Portal Vein - drug effects; Portal Vein - metabolism; Portal Vein - physiology; potassium channels; Potassium Channels - drug effects; Potassium Channels - physiology; Potassium Chloride - pharmacology; Pyridones - pharmacology; Pyrroles - pharmacology; rat aorta; Rats; Rats, Sprague-Dawley; Rubidium - pharmacokinetics; Rubidium Radioisotopes; UR‐8225; vascular smooth muscle; Vasodilator Agents - pharmacology; Vasodilator agents. Cerebral vasodilators
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1993.tb13936.x

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 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 × 10−6 m and 6.6 ± 1.3 × 10−7 m, respectively) or 30 mm KCl (IC50 = 1.4 ± 0.2 × 10−7 m and 9.4 ± 1.3 × 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 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 × 10−8 m and 1.5 ± 0.7 × 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.