Summary
Potassium (K+) channel openers decrease intracellular free Ca2+ concentrations ([Ca2+]i) by hyperpolarizing the membrane and deactivating the Ca2+-channels. To examine whether the hyperpolarization produced by K+-channel openers has other effects on the mechanical activity of vascular smooth muscle, we investigated the effects of levcromakalim (BRL 38227) on membrane potential, [Ca2+]i, as measured with fura-2, and force of contraction induced by 30 mmol/l KCl-physiological salt solution (PSS), in canine coronary arteries. BRL 38227 hyperpolarized the membrane and reduced increases in [Ca2+]i and in contractile force induced by 30 mmol/l KCl-PSS. The [Ca2+]i-contractile force curve, determined in the presence of BRL 38227, was located to the right of the control curve determined by decreasing extracellular Ca2+ concentrations ([Ca2+]o) in 30 mmol/l KCl-PSS. The [Ca2+ i-contractile force curve, determined by decreasing extracellular K+ concentrations ([K+]o), was also located to the right of that determined by decreasing [Ca2+]o in 30 mmol/l KCl-PSS. The effect of BRL 38227, a reduction in the Ca 2+-sensitivity of contractile elements, was antagonized by the ATP-sensitive K+-channel blocker, glibenclamide (10−6 or 10−5 mol/1). These results suggest that the membrane hyperpolarization induced by BRL 38227, or the repolarization caused by reducing ([K+]o), decreases the Ca2+-sensitivity of contractile elements of vascular smooth muscle.
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References
Buckingham RE, Clapham JC, Coldwell MC, Hamilton TC, Hewlett DR (1986) Stereospecific mechanism of action of the novel anti-hypertensive agent, BRL 34915. Br J Pharmacol 87:78P
Buckingham RE, Hamilton TC, Hewlett DR, Mootoo S, Wilson C (1989) Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat. Br J Pharmacol 97:57–64
Casteels R, Kitamura K, Kuriyama H, Suzuki H (1977) The membrane properties of the smooth muscle cells of the rabbit main pulmonary artery. J Physiol (Lond) 271:41–61
Challiss RAJ, Patel N, Arch JRS (1992) Comparative effects of BRL 38227, nitrendipine and isoprenaline on carbachol- and histamine-stimulated phosphoinositide metabolism in airway smooth muscle. Br J Pharmacol 105:997–1003
Edwards G, Henshaw M, Miller M, Weston AH (1991) Comparison of the effects of several potassium-channel openers on rat bladder and rat portal vein in vitro. Br J Pharmacol 102:679–686
Eltze M (1989) Glibenclamide is a competitive antagonist of cromakalim, pinacidil and RP 49356 in guinea-pig pulmonary artery. Eur J Pharmacol 165:231–239
Gardner JP, Diecke FPJ (1988) Influence of pH on isometric force development and relaxation in skinned vascular smooth muscle. Pflügers Arch 412:231–239
Hamilton TC, Weir SW, Weston AH (1986) Comparison of the effects of BRL 34915 and verapamil on electrical and mechanical activity in rat portal vein. Br J Pharmacol 88:103–111
Harder DR, Coulson PB (1979) Estrogen receptors and effects of estrogen on membrane electrical properties of coronary vascular smooth muscle. J Cell Physiol 100:375–382
Himpens B, Somlyo AP (1988) Free-calcium and force transients during depolarization and pharmacomechanical coupling in guinea-pig smooth muscle. J Physiol (Lond) 395:507–530
Hof RP, Quast U, Cook NS, Blarer S (1988) Mechanism of action and systemic regional hemodynamics of the potassium channel activator BRL34915 and its enantiomers. Circ Res 62:679–686
Iino M (1981) Tension responses of chemically skinned fibre bundles of the guinea-pig taenia caeci under varied ionic environments. J Physiol (Lond) 320:449–467
Ito S, Kajikuri J, Itoh T, Kuriyama H (1991) Effects of lemakalim on changes in Ca2+ concentration and mechanical activity induced by noradrenaline in the rabbit mesenteric artery. Br J Pharmacol 104:227–233
Ito Y, Kuriyama H, Suzuki H (1978) The effects of diltiazem (CRD-401) on the membrane and mechanical properties of vascular smooth muscles of the rabbit. Br J Pharmacol 64:503–510
Kageyama M, Mori T, Yanagisawa T, Taira N (1991) Is staurosporine a specific inhibitor of protein kinase C in intact porcine coronary arteries? J Pharmacol Exp Ther 259:1019–1026
Kamouchi M, Xiong Z, Teramoto N, Kajioka S, Okabe K, Kitamura K (1991) Ionic currents involved in vasodilating actions of E4080, a newly synthesized bradycardia-inducing agent, in dispersed smooth muscle cells of the rabbit portial vein. J Pharmacol Exp Ther 259:1396–1403
Kanmura Y, Itoh T, Suzuki H, Ito Y, Kuriyama H (1983) Effects of nifedipine on smooth muscle cells of the rabbit mesenteric artery. J Pharmacol Exp Ther 226:238–248
Karaki H (1989) Ca2+ localization and sensitivity in vascular smooth muscle. Trends Pharmacol Sci 10:320–325
Kawamura T, Adachi H, Ogawa T (1991) Cardiovascular effects of E4080, a novel bradycardic agent with coronary vasodilating properties, in anesthetized dogs. Eur J Pharmacol 203:399–404
Konishi M, Olson A, Hollingworth S, Baylor SM (1988) Myoplasmic binding of fura-2 investigated by steady-state fluorescence and absorbance measurements. Biophys J 54:1089–1104
Maelicke A (1992) An ion channel-gated adenylate cyclase. Trends Biochem Sci 17:51
Mori T, Yanagisawa T, Taira N (1990) Phorbol 12,13-dibutyrate increases vascular tone but has a dual action on intracellular calcium levels in porcine coronary arteries. Naunyn Schmiedebergs Arch Pharmacol 341:251–255
Mrwa U, Achtig I, Rüegg JC (1974) Influences of calcium concentration and pH on the tension development and ATPase activity of the arterial actomyosin contractile system. Blood Vessels 11:277–286
Nelson MT, Patlak JB, Worley JF, Standen NB (1990) Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. Am J Physiol 259:C3-C18
Noack T, Deitmer P, Edwards G, Weston AH (1992) Characterization of potassium currents modulated by BRL 38227 in rat portal vein. Br J Pharmacol 106:717–726
Okada Y, Yanagisawa T, Taira N (1991) An analysis of the nitrate-like and K channel opening actions of KRN2391 in canine coronary arterial smooth muscle. Br. J Pharmacol 104:829–838
Okada Y, Yanagisawa T, Taira N (1992) E4080 has a dual action, as a K+ channel opener and a Ca2+ channel blocker, in canine coronary arterial smooth muscle. Eur J Pharmacol 218:259–264
Quast U, Baumlin Y (1991) Cromakalim inhibits contractions of rat isolated mesenteric bed induced by noradrenaline but not caffeine in Ca2+-free medium: evidence for interference with receptor-mediated Ca2+ mobilization. Eur J Pharmacol 200:239–249
Quast U, Cook NS (1989) In vitro and in vivo comparison of two K+ channel openers, diazoxide and cromakalim, and their inhibition by glibenclamide. J Pharmacol Exp Ther 250:261–271
Schultz JE, Klumpp S, Benz R, Schurhoff-Goeters WJCh, Schmid A (1992) Regulation of adenylyl cyclase from Paramecium by an intrinsic potassium conductance. Science 255:600–603
Standen NB, Quayle JM, Davies NW, Brayden JE, Huang Y, Nelson MT (1989) Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 245:177–180
Winquist RJ, Heaney LA, Wallace AA, Baskin EP, Stein RB, Garcia ML, Kaczorowski GJ (1989) Glyburide blocks the relaxation response to BRL 34915 (cromakalim), minoxidil sulfate and diazoxide in vascular smooth muscle. J Pharmacol Exp Ther 248:149–156
Yamagishi T, Yanagisawa T, Taira N (1992a) Activation of phospholipase C by the agonist U46619 is inhibited by cromakalim-induced hyperpolarization in porcine coronary artery. Biochem Biophys Res Commun 187:1517–1522
Yamagishi T, Yanagisawa T, Taira N (1992b) K+ channel openers, cromakalim and Ki4032, inhibit agonist-induced Ca2+ release in canine coronary artery. Naunyn Schmiedebergs Arch Pharmacol 346:691–700
Yanagisawa T, Kawada M, Taira N (1989) Nitroglycerin relaxes canine coronary arterial smooth muscle without reducing intracellular Ca2+ concentrations measured with fura-2. Br J Pharmacol 98:469–482
Yanagisawa T, Teshigawara T, Taira N (1990) Cytoplasmic calcium and the relaxation of canine coronary arterial smooth muscle produced by cromakalim, pinacidil and nicorandil. Br J Pharmacol 101:157–165
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Okada, Y., Yanagisawa, T. & Taira, N. BRL 38227 (levcromakalim)-induced hyperpolarization reduces the sensitivity to Ca2+ of contractile elements in canine coronary artery. Naunyn-Schmiedeberg's Arch Pharmacol 347, 438–444 (1993). https://doi.org/10.1007/BF00165396
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DOI: https://doi.org/10.1007/BF00165396