An analysis of unsurmountable antagonism to 5-hydroxytryptamine in the isolated perfused rat kidney: evidence for pseudoirreversible inhibition

  • D. A. Craig
  • A. G. Ornstein
  • D. E. Clarke
Part of the Developments in CardioCardiovascular Pharmacology of 5-Hydroxytryptamine book series (DICM, volume 106)


Many 5-hydroxytryptamine (5-HT) antagonists give rise to unsurmountable antagonism. Unlike competitive antagonism, unsurmountable antagonism is not limited to a single mechanism, and therefore its utility for receptor identification, characterization, and classification is at best limited. In general, however, the mechanistic bases of unsurmountable antagonism have not received rigorous attention. The objectives of this chapter are to document instances of unsurmountable antagonism, to discuss possible mechanisms involved, and to present data suggesting that pseudoirreversible antagonism best explains unsurmountable antagonism of 5-HT-induced vasoconstriction in the isolated perfused rat kidney. Finally, the utility of antagonist probes for receptor classification will be discussed.


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  1. 1.
    Gaddum JH, Hameed KA, Hathaway DE, Stephens FF (1955): Quantitative studies of antagonists for 5-hydroxytryptamine. Quart J Exp Physiol 40: 49–74.PubMedGoogle Scholar
  2. 2.
    Bradley PB, Engel G, Feniuk W, Fozard JR, Humphrey PPA, Middlemiss DN, Mylecharane EJ, Richardson BP, Saxena PR (1986): Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacol 25: 563–576.CrossRefGoogle Scholar
  3. 3.
    Wrigglesworth SJ (1983): Heterogeneity of 5-hydroxytryptamine receptors in the rat uterus and stomach strip. Br J Pharmacol 80: 691–697.PubMedCrossRefGoogle Scholar
  4. 4.
    Black JW, Brazenor RM, Gerskowitch VP, Leff P (1983): The problem of insurmountable antagonism in 5–hydroxytryptamine receptor classification. Br J Pharmacol 80: 607 P.Google Scholar
  5. 5.
    Feniuk W (1984): An analysis of 5-hydroxytryptamine receptors mediating contraction of isolated smooth muscle. Neuropharmacol 23: 1467–1472.CrossRefGoogle Scholar
  6. 6.
    Cohen M, Schenck KW, Colbert W, Wittenauer L (1985): Role of 5-HT2 receptors in serotonin-induced contractions of nonvascular smooth muscle. J Pharmacol Exp Ther 232: 770–774.PubMedGoogle Scholar
  7. 7.
    Brazenor RM, Angus J A (1981): Ergotamine contracts isolated canine coronary arteries by a serotonergic mechanism: No role for alpha adrenoceptors. J. Pharmacol. Exp. Ther 218: 530–536.PubMedGoogle Scholar
  8. 8.
    Brazenor RM, Angus JA (1982): Actions of serotonin antagonists on dog coronary artery. Eur J Pharmacol 81: 569–576.PubMedCrossRefGoogle Scholar
  9. 9.
    Kaumann AJ, This Book.Google Scholar
  10. 10.
    Leff P, Martin GR (1986): Peripheral 5-HT2-like receptors. Can they be classified with available antagonists? Br J Pharmacol 88: 585–593.PubMedCrossRefGoogle Scholar
  11. 11.
    Apperley E, Humphrey PPA, Levy GP (1976): Receptors for 5-hydroxytryptamine and noradrenaline in rabbit isolated ear artery and aorta. Br J Pharmacol 58: 211–221.PubMedCrossRefGoogle Scholar
  12. 12.
    Chang J-Y, Owman C (1987): Involvement of specific receptors and calcium mechanisms in serotonergic contractile response of isolated cerebral and peripheral arteries from rats. J Pharmacol Exp Ther 242: 629–636.PubMedGoogle Scholar
  13. 13.
    Taylor EW, Duckies SP, Nelson DL (1986): Dissociation constants of serotonin agonists in the canine basilar artery correlate to Kj values at the 5-HT1A binding site. J Pharmacol Exp Ther 236: 118–125.PubMedGoogle Scholar
  14. 14.
    Peroutka SJ (1984): Vascular serotonin receptors. Correlation with 5-HT, and 5-HT2 binding sites. Biochem Pharmacol 33: 2349–2353.PubMedCrossRefGoogle Scholar
  15. 15.
    Muller-Schweinitzer E, Engel G (1983): Evidence for mediation by 5-HT2 receptors of 5-hydroxytryptamine-induced contraction of canine basilar artery. Naunyn-Schmiede-berg’s Arch Pharmacol 324: 287–292.CrossRefGoogle Scholar
  16. 16.
    Charlton KG, Johnson TD, Clarke DE (1984): Vasoconstrictor and norepinephrine potentiating action of 5-hydroxykynuramine in the isolated perfused rat kidney: involvement of serotonin receptors and alpha1,-adrenoceptors. Naunyn-Schmiedeberg’s Arch Pharmacol 328: 154–159.CrossRefGoogle Scholar
  17. 17.
    Bradley PB, Humphrey PPA, Williams RH (1983): Are vascular ‘D’ and ‘5-HT2’ receptors for 5-hydroxytryptamine the same? Br J Pharmacol 79: 295 P.Google Scholar
  18. 18.
    Apperley E, Feniuk W, Humphrey PPA, Levy GP (1980): Evidence for two types of excitatory receptor for 5-hydroxytryptamine on dog isolated vasculature. Br J Pharmacol 68: 215–224.PubMedCrossRefGoogle Scholar
  19. 19.
    Leff P, Martin CR, Morse JM (1987): Differential classification of vascular smooth muscle and endothelial cell 5-HT receptors by use of tryptamine analogues. Br J Pharmacol 91: 321–331.PubMedCrossRefGoogle Scholar
  20. 20.
    Stollak JS, Furchgott RF (1983): Use of selective antagonists for determining the types of receptors mediating the actions of 5-hydroxytryptamine and tryptamine in the isolated rabbit aorta. J Pharmacol Exp Ther 224: 215–221.PubMedGoogle Scholar
  21. 21.
    Foster C, Whalley ET (1982): Analysis of the human basilar arterial strip compared with rat aortic strip in vitro. Naunyn-Schmiedeberg’s Arch Pharmacol 319: 12–17.CrossRefGoogle Scholar
  22. 22.
    Ireland SJ, Tyers MB (1987): Pharmacological characterization of 5-hydroxytryptamine- induced depolarization of the isolated vagus nerve. Br J Pharmacol 90: 229–238.PubMedCrossRefGoogle Scholar
  23. 23.
    Round A, Wallis DF (1986): The depolarizing action of 5-hydroxytryptamine on rabbit vagal afferent and sympathetic neurones in vitro and its selective blockade by ICS 205–930. Br J Pharmacol 88: 485–494.PubMedCrossRefGoogle Scholar
  24. 24.
    Richardson BP, Engel G, Donatsch P, Stadler PA (1985): Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 316: 126–131.PubMedCrossRefGoogle Scholar
  25. 25.
    Doggrell SA (1987): Differential antagonism of initial fast and secondary slow contractile responses of the rat isolated aorta to 5-hydroxytryptamime by mianserin and ketanserin. J Auton Pharmacol 7: 157–164.PubMedCrossRefGoogle Scholar
  26. 26.
    Kaumann AJ, Frenken M (1985): A paradox: the 5-HT2-receptor antagonist ketanserin restores the 5-HT-induced contraction depressed by methysergide in large coronary arteries of calf. Allosteric regulation of 5-HT2 receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 328, 295–300.CrossRefGoogle Scholar
  27. 27.
    Frenken M, Kaumann AJ (1987): Interconversion into a low active state protects vascular 5-HT2 receptors against irreversible antagonism by phenoxybenzamine. Naunyn-Schmiedeberg’s Arch Pharmacol 335: 481–490.Google Scholar
  28. 28.
    Frenken M, Kaumann AJ (1988): Effects of tryptamine mediated through 2 states of the 5-HT2 receptor in calf coronary artery. Naunyn-Schmiedeberg’s Arch Pharmacol 337: 484–492.CrossRefGoogle Scholar
  29. 29.
    Kaumann AJ, Frenken M (1988): ICI 169,369 is both a competitive antagonist and an allo steric activator of the arterial 5-hydroxytryptamine2 receptor system. J Pharmacol Exp Ther 245: 1010–1015.PubMedGoogle Scholar
  30. 30.
    de Chaffoy de Courcelles D, Leysen J, Roevens P, Van Belle H (1986): The serotonin-S2 receptor: A receptor transducer coupling model to explain insurmountable antagonist effects. Drug Dev Res 8: 173–178.CrossRefGoogle Scholar
  31. 31.
    Bond RA, Ornstein AG, Clarke DE (1988): Unsurmountable antagonism to 5-HT results from pseudoirreversible inhibition rather than multiple receptors or allosteric receptor modulation. J Pharmacol Exp TherIn press.Google Scholar
  32. 32.
    Leff P, Martin GR (1988): The classification of 5-hydroxytryptamine receptors. Med Res Rev 8: 187–202.PubMedCrossRefGoogle Scholar
  33. 33.
    Hoyer D, Engel G, Kalkman HO (1985): Molecular pharmacology of 5-HT1, and 5-HT2 recognition sites in rat and pig membrances: Radioligand binding studies with [3H] 5-HT, [3H] 8-OH-DPAT, (—)-[125I] iodocyanopindolol, [3H] mesulergine and [3H] ketanserin. Eur J Pharmacol 118: 13–23.PubMedCrossRefGoogle Scholar
  34. 34.
    Leysen JE (1985): Serotonergic binding sites, pp. 43–62 in: Vanhoutte PM (ed) serotonin and the cardiovascular system. New York: Raven Press.Google Scholar
  35. 35.
    Arunlakshana O, Schild HO (1959): Some quantitative uses of drug antagonism. Br. J. Pharmacol 14: 48–58.Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1990

Authors and Affiliations

  • D. A. Craig
  • A. G. Ornstein
  • D. E. Clarke

There are no affiliations available

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