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. 1993 Nov;110(3):1165–1171. doi: 10.1111/j.1476-5381.1993.tb13936.x

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

F Perez-Vizcaino 1, O Casis 1, R Rodriguez 1, L A Gomez 1, J Garcia Rafanell 1, J Tamargo 1
PMCID: PMC2175824  PMID: 8298804

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.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Bray K. M., Newgreen D. T., Small R. C., Southerton J. S., Taylor S. G., Weir S. W., Weston A. H. Evidence that the mechanism of the inhibitory action of pinacidil in rat and guinea-pig smooth muscle differs from that of glyceryl trinitrate. Br J Pharmacol. 1987 Jun;91(2):421–429. doi: 10.1111/j.1476-5381.1987.tb10297.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bray K. M., Weston A. H., Duty S., Newgreen D. T., Longmore J., Edwards G., Brown T. J. Differences between the effects of cromakalim and nifedipine on agonist-induced responses in rabbit aorta. Br J Pharmacol. 1991 Feb;102(2):337–344. doi: 10.1111/j.1476-5381.1991.tb12175.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cauvin C., Malik S. Induction of Ca++ influx and intracellular Ca++ release in isolated rat aorta and mesenteric resistance vessels by norepinephrine activation of alpha-1 receptors. J Pharmacol Exp Ther. 1984 Aug;230(2):413–418. [PubMed] [Google Scholar]
  4. Chiu P. J., Tetzloff G., Ahn H. S., Sybertz E. J. Effects of BRL 34915, a putative K channel opener, on transmembrane 45Ca movements in rabbit aortic smooth muscle. Eur J Pharmacol. 1988 Oct 18;155(3):229–237. doi: 10.1016/0014-2999(88)90508-0. [DOI] [PubMed] [Google Scholar]
  5. Cook N. S. The pharmacology of potassium channels and their therapeutic potential. Trends Pharmacol Sci. 1988 Jan;9(1):21–28. doi: 10.1016/0165-6147(88)90238-6. [DOI] [PubMed] [Google Scholar]
  6. Delpón E., Valenzuela C., Pérez O., Tamargo J. Electrophysiological effects of CRE-1087 in guinea-pig ventricular muscles. Br J Pharmacol. 1992 Oct;107(2):515–520. doi: 10.1111/j.1476-5381.1992.tb12776.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Donaldson S. K., Goldberg N. D., Walseth T. F., Huetteman D. A. Voltage dependence of inositol 1,4,5-trisphosphate-induced Ca2+ release in peeled skeletal muscle fibers. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5749–5753. doi: 10.1073/pnas.85.15.5749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Edwards G., Weston A. H. Structure-activity relationships of K+ channel openers. Trends Pharmacol Sci. 1990 Oct;11(10):417–422. doi: 10.1016/0165-6147(90)90149-3. [DOI] [PubMed] [Google Scholar]
  9. Escande D., Cavero I. K+ channel openers and 'natural' cardioprotection. Trends Pharmacol Sci. 1992 Jul;13(7):269–272. doi: 10.1016/0165-6147(92)90083-i. [DOI] [PubMed] [Google Scholar]
  10. Hamilton T. C., Weston A. H. Cromakalim, nicorandil and pinacidil: novel drugs which open potassium channels in smooth muscle. Gen Pharmacol. 1989;20(1):1–9. doi: 10.1016/0306-3623(89)90052-9. [DOI] [PubMed] [Google Scholar]
  11. Hirst G. D., Edwards F. R. Sympathetic neuroeffector transmission in arteries and arterioles. Physiol Rev. 1989 Apr;69(2):546–604. doi: 10.1152/physrev.1989.69.2.546. [DOI] [PubMed] [Google Scholar]
  12. Ito S., Kajikuri J., Itoh T., Kuriyama H. Effects of lemakalim on changes in Ca2+ concentration and mechanical activity induced by noradrenaline in the rabbit mesenteric artery. Br J Pharmacol. 1991 Sep;104(1):227–233. doi: 10.1111/j.1476-5381.1991.tb12411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lawson K., Cavero I. Effects of Ca2+ antagonists and K+-channel activators on K+-induced contractions in the rat aorta. J Auton Pharmacol. 1989 Oct;9(5):329–336. doi: 10.1111/j.1474-8673.1989.tb00069.x. [DOI] [PubMed] [Google Scholar]
  14. Nelson M. T., Standen N. B., Brayden J. E., Worley J. F., 3rd Noradrenaline contracts arteries by activating voltage-dependent calcium channels. Nature. 1988 Nov 24;336(6197):382–385. doi: 10.1038/336382a0. [DOI] [PubMed] [Google Scholar]
  15. Pacaud P., Loirand G., Baron A., Mironneau C., Mironneau J. Ca2+ channel activation and membrane depolarization mediated by Cl- channels in response to noradrenaline in vascular myocytes. Br J Pharmacol. 1991 Dec;104(4):1000–1006. doi: 10.1111/j.1476-5381.1991.tb12540.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Pérez-Vizcaino F., Duarte J., Tamargo J. Effects of flecainide on isolated vascular smooth muscles of rat. Br J Pharmacol. 1991 Nov;104(3):726–730. doi: 10.1111/j.1476-5381.1991.tb12495.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pérez-Vizcaíno F., Carrón R., Delpón E., Duarte J., Tamargo J. Effects of (S)-nafenodone on 45Ca2+ fluxes and contractions in rat isolated vascular smooth muscle. Eur J Pharmacol. 1993 Feb 23;232(1):105–111. doi: 10.1016/0014-2999(93)90734-y. [DOI] [PubMed] [Google Scholar]
  18. Quast U., Cook N. S. Moving together: K+ channel openers and ATP-sensitive K+ channels. Trends Pharmacol Sci. 1989 Nov;10(11):431–435. doi: 10.1016/S0165-6147(89)80003-3. [DOI] [PubMed] [Google Scholar]
  19. Sanguinetti M. C. Modulation of potassium channels by antiarrhythmic and antihypertensive drugs. Hypertension. 1992 Mar;19(3):228–236. doi: 10.1161/01.hyp.19.3.228. [DOI] [PubMed] [Google Scholar]
  20. Standen N. B., Quayle J. M., Davies N. W., Brayden J. E., Huang Y., Nelson M. T. Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science. 1989 Jul 14;245(4914):177–180. doi: 10.1126/science.2501869. [DOI] [PubMed] [Google Scholar]
  21. Weir S. W., Weston A. H. Effect of apamin on responses to BRL 34915, nicorandil and other relaxants in the guinea-pig taenia caeci. Br J Pharmacol. 1986 May;88(1):113–120. doi: 10.1111/j.1476-5381.1986.tb09477.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Weston A. H., Longmore J., Newgreen D. T., Edwards G., Bray K. M., Duty S. The potassium channel openers: a new class of vasorelaxants. Blood Vessels. 1990;27(2-5):306–313. doi: 10.1159/000158823. [DOI] [PubMed] [Google Scholar]
  23. Yanagisawa T., Teshigawara T., Taira N. Cytoplasmic calcium and the relaxation of canine coronary arterial smooth muscle produced by cromakalim, pinacidil and nicorandil. Br J Pharmacol. 1990 Sep;101(1):157–165. doi: 10.1111/j.1476-5381.1990.tb12106.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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