Abstract
In freshly-dispersed cells from rat mesenteric artery, levcromakalim (1 and 10 μM) induced a non-inactivating potassium current (IKCO), an event which was associated with increased current noise. IKCO was fully inhibited in the presence of 10 μM glibenclamide. Stationary fluctuation analysis of the current noise associated with IKCO induced by levcromakalim at a holding potential of −10 mV indicated that the unitary conductance of the underlying K-channels was 10.2 pS at 0 mV under the quasi-physiological conditions of the experiment.
In isolated arterioles both levcromakalim (10 nM - 10 μM) and nifedipine (10 nM - 10 μM) each elicted full, concentration-dependent, parallel reductions of the increases in [Ca2+]i (assessed using fura-2) and tension induced by 10 μM noradrenaline. However, the effects of both drugs on KCl-induced increases in tension and in [Ca2+]i, did not follow a simple relationship. Levcromakalim relaxed KCl- and noradrenaline-induced sustained contractions with a similar potency. This was in contrast to nifedipine which was approximately 20 times more potent against KCl-induced contractions.
It is concluded that levcromakalim relaxes rat mesenteric arterioles primarily by the opening of a small conductance, glibenclamide-sensitive K-channel. An additional action of levcromakalim is suggested by its relative inability to suppress the increase in [Ca2+]i produced by 30 mM K+-PSS.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Beech DJ, Bolton TB (1989) Properties of the cromakalim-induced potassium conductance in smooth muscle cells isolated from the rabbit portal vein. Br J Pharmacol 98:851–864
Beech DJ, Zhang H, Nakao K, Bolton TB (1993) Single channel and whole-cell currents evoked by levcromakalim in smooth muscle cells from rabbit portal vein. Br J Pharmacol 110:583–590
Bray KM, Weston AH, Duty S, Newgreen DT, Longmore J, Edwards G, Brown TJ (1991) Differences between the effects of cromakalim and nifedipine on agonist-induced responses in rabbit aorta. Br J Pharmacol 102:337–344
Carl A, Brwen S, Gelband CH, Sanders KM, Hulme JR (1992) Cromakalim and leveromakalim activate Ca2+-dependent K+ channels in canine colon. Pflügers Arch 421:67–76
Chopra LC, Twort CHC, Ward JPT (1992) Direct action of BRL 38227 and glibenclamide on intracellular calcium stores in cultured airways smooth muscle of rabbit. Br J Pharmacol 105:259–260
Clapp LH, Gurney AM (1991) Outward currents in rabbit pulmonary artery cells dissociated with a new technique. Exp Physiol 76:677–693
Criddle DN, Greenwood IA, Weston AH (1992) Comparison of the effects of BRL 38227 and nifedipine on intracellular calcium levels in isolated mesenteric resistance vessels of the rat. J Physiol 452:129P
Edwards G, Ibbotson T, Weston AH (1993) Levcromakalim may induce a voltage-independent K-current in rat portal veins by modifying the gating properties of the delayed rectifier. Br J Pharmacol 110: 1037–1048
Escande D, Thuringer D, Leguern S, Cavero I (1988) The potassium channel opener cromakalim (BRL 34915) activates ATP-dependent K+ channels in isolated cardiac myocytes. Biochem Biophys Res Commun 154:620–625
Ganitkevich VYa, Isenberg G (1992) Contribution of Ca2+-induced Ca2+ release to the [Ca2+]; transients in myocytes from guinea-pig urinary bladder. J Physiol 458:119–137
Gelband CH, Lodge NJ, Van Breemen C (1989) A Ca2+-activated K+ channel from rabbit aorta: modulation by cromakalim. Eur J Pharmacol 167:201–210
Giligorski MS, Hruska KA, Loftus DJ, Elson EL (1986) Adrenergic stimulation and cytoplasmic free calcium concentration in cultured renal proximal tubular cells: Evidence for compartmentalization of Quin-2 and Fura-2. J Cell Physiol 128:466–474
Greenwood IA, Weston AH (1993) Effects of rubidium on responses to potassium channel openers in rat isolated aorta. Br J Pharmacol 109:925–932
Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391:85–100
Ibbotson T, Edwards G, Noack T, Weston AH (1993) Effects of P1060 and aprikalim on whole-cell currents in rat portal vein; inhibition by glibenclamide and phentolamine. Br J Pharmacol 108:991–998
Ito K, Ikemoto T, Takakura S (1991a) Involvement of Ca2+ influx-induced Ca2+ release in contractions of intact vascular smooth muscles. Am J Physiol 261:H1464–1470
Ito S, Kajikuri J, Itoh T, Kuriyama H (1991b) 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
Itoh T, Seki N, Suzuki S, Ito S, Kajikuri J, Kuriyama H (1992) Membrane hyperpolarization inhibits agonist-induced synthesis of inositol 1,4,5-trisphosphate in rabbit mesenteric artery. J Physiol 45:307–328
Jensen PE, Mulvaney MJ, Aalkjaer C, Nilsson H, Yamaguchi H (1993) Free cytosolic Ca2+ measured with Ca2+-selective electrodes and fura-2 in rat resistance arteries. Am J Physiol 265:H741-H746
Kajioka S, Oike M, Kitamura K (1990) Nicorandil opens a calcium-dependent potassium channel in smooth muscle cells of the rat portal vein. J Pharmacol Exp Ther 254:905–913
Kajioka S, Nakashima M, Kitamura K, Kuriyama H (1991) Mechanism of vasodilatation induced by potassium channel activations. Clinical Sciences 81:129–139
Karaki H (1989) Ca2+ localization and sensitivity in vascular smooth muscle. Trends Pharmacol Sci 10:320–325
Klöckner U, Isenberg G (1985) Action potentials and net membrane currents of isolated smooth muscle cells (urinary bladder of the guinea-pig). Pflügers Arch 405:329–339
Klöckner U, Trieschmann U, Isenberg G (1989) Pharmacological modulation of calcium and potassium channels in isolated vascular smooth muscle cells. Arzneimittel-Forsch 39:20–126
Neher E, Stevens CF (1977) Conductance fluctuations and ionic pores in membranes. Annu Rev Biophys Bioeng 6:345–381
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 Th, Deitmer P, Edwards G, Weston AH (1992a) Characterization of potassium currents modulated by BRL 38227 in rat portal vein. Br J Pharmacol 106:717–724
Noack Th, Edwards G, Deitmer P, Weston AH (1992b) Potassium channel modulation in rat portal vein by ATP depletion; a comparison with the effects of levcromakalim (BRL 38227). Br J Pharmacol 107:945–955
Noack Th, Deitmer P, Lammel E (1992c) Characterization of membrane currents in single smooth muscle cells from the guinea-pig gastric antrum. J Physiol 451:387–418
Okabe K, Kajioka S, Nakao K, Kitamura K, Kuriyama H, Weston AH (1990) Actions of cromakalim on ionic currents recorded from single smooth muscle cells of the rat portal vein. J Pharmacol Exp Ther 252:832–839
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 (1993) BRL 38227 (levcromakalim)-induced hyperpolarization reduces the sensitivity to Ca2+ of contractile elements in canine coronary artery. Naunyn Schmiedebergs Arch Pharmacol 347:438–444
Pfründer D, Kreye VAW (1992) Tedisamil inhibits the delayed rectifier K+ current in single smooth muscle cells of the guinea-pig portal vein. Pflügers Arch 421:22–25
Quast U (1993) Do the K+ channel openers relax smooth muscle by opening K+ channels? Trends Pharmacol Sci 14:332–337
Roe MW, Lemasters JJ, Herman B (1990) Assessment of Fura-2 for measurements of cytosolic free calcium. Cell Calcium 11:63–73
Russell SN, Smirnov SV, Aaronson PI (1992) Effects of BRL 38227 on potassium currents in smooth muscle cells isolated from rabbit portal vein and human mesenteric artery. Br J Pharmacol 105:549–556
Sanguinetti MC, Scott AL, Zingaro GJ, Siegl PKS (1988) BRL 34915 (cromakalim) activates ATP-sensitive K+ current in cardiac muscle. Proc Natl Acad Sci (USA) 85:8360–8364
Sato K, Ozaki H, Karaki H (1988) Changes in cytosolic calcium level in vascular smooth muscle strip measured simultaneously with contraction using fluorescent calcium indicator fura-2. J Pharmacol Exp Ther 246:294–300
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
Steinberg SF, Bilezikian JP, Al-Awqati Q (1987) Fura-2 fluorescence is localized to mitochondria in endothelial cells. Am J Physiol 253:C744-C747
Wickenden AD, Grimwood S, Grant TL, Todd MH (1991) Comparison of the effects of the K+-channel openers cromakalim and minoxidil sulphate on vascular smooth muscle. Br J Pharmacol 103: 1148–1152
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 sulphate and diazoxide in vascular smooth muscle. J Pharmacol Exp Ther 248:149–156
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
Author information
Authors and Affiliations
Additional information
Correspondence to: A. H. Weston at the above address
Rights and permissions
About this article
Cite this article
Criddle, D.N., Greenwood, I.A. & Weston, A.H. Levcromakalim-induced modulation of membrane potassium currents, intracellular calcium and mechanical activity in rat mesenteric artery. Naunyn-Schmiedeberg’s Arch Pharmacol 349, 422–430 (1994). https://doi.org/10.1007/BF00170890
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF00170890