Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 343, Issue 4, pp 377–383 | Cite as

Analysis of cromakalim-, pinacidil-, and nicorandil-induced relaxation of the 5-hydroxytryptamine precontracted rat isolated basilar artery

  • Ernst Ksoll
  • Andrew A. Parsons
  • Jan R. L. Mackert
  • Lothar Schilling
  • Michael Wahl


The effects of the K+ channel activators cromakalim, pinacidil, and nicorandil were investigated in endothelium intact, 5-hydroxytryptamine (5-HT) precontracted rat isolated basilar artery. Cromakalim, pinacidil, and nicorandil produced concentration-dependent relaxation of rat isolated basilar artery precontracted with 5-HT with a rank order of potency of cromakalim > pinacidil > nicorandil. All compounds produced full or nearly full relaxation. The calculated Hill coefficients for cromakalim-, pinacidil-, and nicorandil-induced relaxation of 5-HT-precontracted rat isolated basilar artery were 2.20 ± 0.36, 1.30 ± 0.07, and 1.00 ± 0.01, respectively. Under conditions of increased tone produced by 50 mmol/1 KCl (which inhibits cromakalim-induced relaxation) pinacidil and nicorandil produced marked reversal of spasm, with pinacidil being more potent than nicorandil. In arteries precontracted with 5-HT, preincubation with glibenclamide (0.1–1 μmol/1) produced concentration-related inhibition of relaxation with calculated mean pA2 values (and slopes of Schild regression) ± SEM of 6.84 ± 0.20 (1.1 ± 0.20) against cromakalim, 6.60 ± 0.14 (0.95 ± 0.23) against nicorandil,and6.57 ± 0.26(1.04 ± 0.18) against pinacidil. For cromakalim, pinacidil, and nicorandil the slopes of Schild regression were not significantly different from unity. Tolbutamide 10 μmol/l was without effect against the cromakalim-, pinacidil-, or nicorandil-induced relaxation. Tetraethylammonium (TEA; 1–10 mmol/l) produced noncompetitive inhibition of the cromakalim-induced relaxation, but appeared to produce competitive inhibition of the pinacidil- and nicorandil-induced relaxations. We conclude that cromakalim, pinacidil, and nicorandil produce relaxation of the 5-HT precontracted rat basilar artery by similar mechanisms to those identified in other peripheral vascular and visceral smooth muscle. Furthermore, pinacidil and nicorandil differ from cromakalim in possessing marked spasmolytic activity in 50 mmol/l KCl precontracted arteries.

Key words

K+ channel openers Glibenclamide Cerebral arteries 5-Hydroxytryptamine 


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  1. Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58Google Scholar
  2. Bray KM, Newgreen DT, Small RC, Southerton JS, Taylor SG, Weir SW, Weston AH (1987) 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 91:421–429CrossRefGoogle Scholar
  3. Cavero I, Mondot S, Mestre M (1989) Vasorelaxant effects of cromakalim in rats are mediated by glibenclamide-sensitive potassium channels. J Pharmacol Exp Ther 248:1261–1268PubMedGoogle Scholar
  4. Chang J-Y, Hardebo JE, Owman CH (1988) Differential vasomotor action of noradrenaline, serotonin, and histamine in isolated basilar artery from rat and guinea-pig. Acta Physiol Scand 132:91–102CrossRefGoogle Scholar
  5. Cook NS (1988) The pharmacology of potassium channels and their therapeutic potential. Trends Pharmacol Sci 9:21–28CrossRefGoogle Scholar
  6. Doyle VM, Creba JA, Rueg UT, Hoyer D (1986) Serotonin increases the production of inositol phosphates and mobilizes calcium via the 5-HT2 receptor in A7r5 smooth muscle cells. Naunyn-Schmiedeberg's Arch Pharmacol 333:98–103CrossRefGoogle Scholar
  7. Dunne MJ, Yule DJ, Gallacher DV, Petersen OH (1989) Cromakalim (BRL 34915) and diazoxide activate ATP-regulated potassium channels in insulin-secreting cells. Pflügers Arch 414, Suppl 1:S154-S155CrossRefGoogle Scholar
  8. Dunne MJ, Aspinall RJ, Petersen OH (1990) The effects of cromakalim on ATP-sensitive potassium channels in insulin-secreting cells. Br J Pharmacol 99:169–175CrossRefGoogle Scholar
  9. Ek TP, Danthuluri NR, Brock TA, Deth RC (1990) Differences in SHR/WKY arterial contractions in bicarbonate and HEPES buffer. Faseb J 4:A857Google Scholar
  10. Eltze M (1989) Glibenclamide is a competitive antagonist of cromakalim, pinacidil and RP 49356 in guinea-pig pulmonary artery. Eur J Pharmacol 165:231–240CrossRefGoogle Scholar
  11. Endoh M, Taira N (1983) Relationship between relaxation and cyclic GMP formation caused by nicorandil in canine mesenteric artery. Naunyn-Schmiedeberg's Arch Pharmacol 322:319–321CrossRefGoogle Scholar
  12. Furukawa K, Itoh T, Kajiwara M, Kitamura K, Suzuki H, Ito Y, Kuriyama H (1981) Vasodilating actions of 2-nicotinamidoethyl nitrate on porcine and guinea-pig coronary arteries. J Pharmacol Exp Ther 218:248–259PubMedGoogle Scholar
  13. Hamel E, Robert J-P, Young AR, MacKenzie ET (1989) Pharmacological properties of the receptor(s) involved in the 5-hydroxytryptamine-induced contraction of the feline middle cerebral artery. J Pharmacol Exp Ther 249:879–889PubMedGoogle Scholar
  14. 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 88:103–111CrossRefGoogle Scholar
  15. Harder DR, Dernbach P, Waters A (1987) Possible cellular mechanism for cerebral vasospasm after experimental subarachnoid hemorrhage in the dog. J Clin Invest 80:875–880CrossRefGoogle Scholar
  16. Itoh T, Furukawa K, Kajiwara M, Kitamura K, Suzuki H, Ito Y, Kuriyama H (1981) Effects of 2-nicotinamidoethyl nitrate on smooth muscle cells and on adrenergic transmission in the guinea-pig and porcine mesenteric arteries. J Pharmacol Exp Ther 218:260–270PubMedGoogle Scholar
  17. Karashima T, Itoh T, Kuriyama H (1982) Effects of 2-nicotinamidoethyl nitrate on smooth muscle cells of the guinea-pig mesenteric and portal veins. J Pharmacol Exp Ther 221:472–480PubMedGoogle Scholar
  18. Kauffman RF, Schenck KW, Conery BG, Cohen ML (1986) Effects of pinacidil on serotonin-induced contractions and cyclic nucleotide levels in isolated rat aortae: comparison with nitroglycerin, minoxidil, and hydralazine. J Cardiovasc Pharmacol 8:1195–1200CrossRefGoogle Scholar
  19. Masuzawa K, Matsuda T, Asano M (1990) Evidence that pinacidil may promote the opening of ATP-sensitive K+ channels yet inhibit the opening of Ca2+-activated K+ channels in K+-contracted canine mesenteric artery. Br J Pharmacol 100:143–149CrossRefGoogle Scholar
  20. Mellemkjaer S, Nielsen-Kudsk JE, Nielsen CB, Siggaard C (1989) A comparison of the relaxant effects of pinacidil in guinea-pig trachea, aorta and pulmonary artery. Eur J Pharmacol 167:275–280CrossRefGoogle Scholar
  21. Mikkelsen E, Pedersen OL (1982) Comparison of the effects of a new vasodilator pinacidil and nifedipine on isolated blood vessels. Acta Pharmacol Toxicol 51:407–412CrossRefGoogle Scholar
  22. Nakajima S, Kurokawa K, Imamura N, Ueda M (1989) A study on the hypotensive mechanism of pinacidil: relationship between its vasodilating effect and intracellular Ca2+ levels. Jpn J Pharmacol 49:205–213CrossRefGoogle Scholar
  23. Nielsen ChK, Arrigoni-Martelli E (1981) Effect of anew vasodilator, pinacidil (P1134), on potassium, noradrenaline and serotonin induced contractions in rabbit vascular tissues. Acta Pharmacol Toxicol 49:427–431CrossRefGoogle Scholar
  24. Parsons AA, Whalley ET (1989a) Evidence for the presence of 5-HT1-like receptors in rabbit isolated basilar arteries. Eur J Pharmacol 174:189–196CrossRefGoogle Scholar
  25. Parsons AA, Whalley ET (1989b) Further characterization of the 5-HT1-like receptor present on human isolated basilar artery. In: Seylaz J, MacKenzie ET (eds) Neurotransmission and cerebrovascular function, vol 1. Elsevier, Amsterdam, pp 229–232Google Scholar
  26. Parsons AA, Whalley ET, Feniuk W, Connor HE, Humphrey PPA (1989) 5-HT1-like receptors mediate 5-hydroxytryptamine-induced contraction of human isolated basilar artery. Br J Pharmacol 96:434–449CrossRefGoogle Scholar
  27. Parsons AA, Ksoll E, Mackert JRL, Schilling L, Wahl M (1990) Comparison of cromakalim induced relaxation of pre-contracted rabbit, cat and rat isolated cerebral arteries. Naunyn-Schmiedeberg's Arch Pharmacol (in press)Google Scholar
  28. Parsons AA, Ksoll E, Mackert JRL, Schilling L, Wahl M (1991) Comparison of cromakalim induced relaxation of potassium pre-contracted rabbit, cat and rat isolated cerebral arteries. Naunyn-Schmiedeberg's Arch Pharmacol (in Press)Google Scholar
  29. 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 250:261–271PubMedGoogle Scholar
  30. Rang HP (1971) Drug receptor and their function. Nature 231:91–96CrossRefGoogle Scholar
  31. Schmid-Antomarchi H, deWeille JR, Fosset M, Lazdunski M (1987) The receptor for antidiabetic sulfonylureas controls the activity of the ATP-modulated K+ channel in insulin-secreting cells. J Biol Chem 262:15840–15844PubMedGoogle Scholar
  32. Southerton JS, Weston AH, Bray KM, Newgreen DT, Taylor SG (1988) The potassium channel opening action of pinacidil; studies using biochemical, ion flux and microelectrode techniques. Naunyn-Schmiedeberg's Arch Pharmacol 338:310–318CrossRefGoogle Scholar
  33. 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 245:177–180CrossRefGoogle Scholar
  34. Sumimoto K, Domae M, Yamanaka K, Nakao K, Hashimoto T, Kitamura K, Kuriyama H (1987) Actions of nicorandil on vascular smooth muscle. J Cardiovase Pharmacol 10 Suppl 8:S66-S75CrossRefGoogle Scholar
  35. Trube G, Rorsman P, Ohno-Shosaku T (1986) Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic a-cells. Pflügers Arch 407:493–499CrossRefGoogle Scholar
  36. Van Breemen C, Saida K (1989) Celluar mechanisms regulating [Ca2+]i smooth muscle. Annu Rev Physiol 51:315–329CrossRefGoogle Scholar
  37. Van Rossum JM (1963) Cumulative dose-response curves II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn 143:299–330Google Scholar
  38. Wahl M (1989) The effects of pinacidil and tolbutamide in feline pial arteries in situ. Pflügers Arch 415:250–252CrossRefGoogle Scholar
  39. Weir SW, Weston AH (1986a) Effect of apamin on responses to BRL 34915, nicorandil and other relaxants in the guinea-pig taenia caeci. Br J Pharmacol 88:113–120CrossRefGoogle Scholar
  40. Weir SW, Weston AH (1986b) The effects of BRL 34915 and nicorandil on electrical and mechanical activity and on 86Rb efflux in rat blood vessels. Br J Pharmacol 88:121–128CrossRefGoogle Scholar
  41. Wilson C, Coldwell MC, Howlett DR, Cooper SM, Hamilton TC (1988) Comparative effects of K+ channel blockade on the vasorelaxant activity of cromakalim, pinacidil and nicorandil. Eur J Pharmacol 152:331–339CrossRefGoogle Scholar
  42. 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 248:149–156PubMedGoogle Scholar
  43. Yanagisawa T, Hashimoto H, Taira N (1989) Interaction of potassium channel openers and blockers in canine atrial muscle. Br J Pharmacol 97:753–762CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Ernst Ksoll
    • 1
  • Andrew A. Parsons
    • 1
  • Jan R. L. Mackert
    • 1
  • Lothar Schilling
    • 1
  • Michael Wahl
    • 1
  1. 1.Physiologisches InstitutUniversität MünchenMünchen 2Germany

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