Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 334, Issue 3, pp 261–266 | Cite as

Evidence for a receptor mediated action of norepinephrine distinct from alpha- and beta-adrenoceptors

  • R. A. Bond
  • K. G. Charlton
  • D. E. Clarke


The mode of action of (-) norepinephrine (NE) and UK-14,304-18 has been investigated using the chohnergically-evoked ‘twitch’ response of the electrically stimulated guinea-pig ileum. St 587 and benextramine were employed as antagonists. St 587 acted as a competitive antagonist toward UK-14,304-18, yielding an apparent pA2 value of 7.3. In contrast, St 587 failed to act competitively toward NE. Similarly, benextramine (1×10−5 mol/l) blocked the inhibitory responses to UK-14,304-18 but was considerably less active toward NE. Remaining responses to NE after benextramine were not antagonized by St 587, even at a concentration of 3×10−5 mol/l. It is postulated that NE acts to inhibit the ‘twitch’ response be evoking two different receptor-mediated events: 1. agonism at the alpha2-adrenoceptor and 2. agonism at a site which is distinct from the alpha- and beta-subtypes. In the concentrations studied, UK-14,304-18, St 587 and benextramine age postulated to lack affinity for the proposed site.

The effect of NE and UK-14,304-18 was also investigated on the contractile responses to exogenously applied histamine. These experiments were done in the presence of muscarinic cholinergic and adrenoceptor blockade. NE inhibited responses to histamine but UK-14,304-18 was inactive. Furthermore, the inhibitory action of NE was stereoselective with the (-) form being 25 times more potent than the (+) enantiomer. These findings suggest the presence of a receptor site for NE which is distinct from cholinergic mechanisms and established alpha and beta-adrenoceptors.

Key words

Norepinephrine UK-14,304-18 St 587 Benextramine Adrenoceptors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arunlakshana AD, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58Google Scholar
  2. Belleau B, Benfey BG, Melchiorre C (1982) Presynaptic effect of clonidine antagonized by the tetramine disulphide, benextramine. Br J Pharmacol 75:617–621Google Scholar
  3. Bond RA, Clarke DE (1986) Failure of propranolol to competitively block inhibitory responses to 1-isoproterenol in the electrically stimulated guinea-pig ileum: further evidence for a novel adrenoceptor. Fed Proc 45:526Google Scholar
  4. Bond RA, Charlton KG, Clarke DE (1985) Inhibition of the cholinergic twitch response in guinea pig ileum: Evidence for a clonidine receptor distinct from α2 sites. Br J Pharmacol 84:14PGoogle Scholar
  5. Bond RA, Charlton KG, Clarke DE (1986) Responses to norepinephrine resistant to inhibition by alpha and beta adrenoceptor antagonists. J Pharmacol Exp Ther 236:408–415Google Scholar
  6. Cambridge D (1981) UK-14,304-18, a potent and selective α2-agonist for the characterization of α-adrenoceptor subtypes. Eur J Pharmacol 72:413–415Google Scholar
  7. Clague RU, Eglen RM, Strachan AC, Whiting RL (1985) Action of agonists and antagonists at muscarinic receptors present on ileum and atria in vitro. Br J Pharmacol 86:163–170Google Scholar
  8. Drew GM (1978) Pharmacological characterization of the presynaptic α-adrenoceptors regulating cholinergic activity in the guineapig ileum. Br J Pharmacol 64:293–300Google Scholar
  9. de Jonge A, Timmermans PBMWM, Van Zwieten PA (1983) Quantitative aspects of alpha adrenergic effects induced by clonidine-like imidazolidines. III. Comparison of central and peripheral alpha-1 and alpha-2 adrenoceptors. J Pharmacol Exp Ther 226:563–571Google Scholar
  10. de Jonge A, Van Meel JCA, Timmermans PBMWM, Van Zwieten PA (1981) A lipophilic, selective α1-adrenoceptor agonist: 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587). Life Sci 28:2009–2016Google Scholar
  11. Hicks PE, Langer SZ, Macrae AD (1985) Differential blocking action of idazoxan against the inhibitory effects of 6-fluoronoradrenaline and clonidine in the rat vas deferens. Br J Pharmacol 86:141–150Google Scholar
  12. Hirst GDS, DeGleria S, van Helden DF (1985) Neuromuscular transmission in arterioles. Experientia 41:874–879Google Scholar
  13. Hirst GDS, Neild TO, Silverberg GD (1982) Noradrenaline receptors on the rat basilar artery. J Physiol (Lond) 328:351–360Google Scholar
  14. Kenakin TP (1984) The classification of drugs and drug receptors in isolated tissues. Pharmacol Rev 36:165–222Google Scholar
  15. Kenakin TP (1985) Schild regressions as indicators of non-equilibrium steady-states and heterogeneous receptor populations. Trends Pharmacol Sci 6:68–71Google Scholar
  16. Kobinger W, Pichler L (1982) Presynaptic activity of the imidazolidine derivative St 587, a highly selective α1-adrenoceptor agonist. Eur J Pharmacol 82:203–206Google Scholar
  17. Loftus DJ, Stolk JM, U'Pritchard DC (1984) Binding of the imidazoline UK-14,304-18, a putative full α2-adrenoceptor agonist, to rat cerebral cortex membranes. Life Sci 35:61–69Google Scholar
  18. Malta E, Raper C, Tawa PE (1981) Pre- and postjunctional effects of clonidine- and oxymetazoline-like compounds in guinea pig ileal preparations. Br J Pharmacol 73:355–362Google Scholar
  19. Melchiorre C (1981) Tetramine disulfides: A new tool in α-adrenergic pharmacology. Trends Pharmacol Sci 2:209–211Google Scholar
  20. Melchiorre C, Yong MS, Benfey BG, Belleau B (1978) Molecular properties of the adrenergic α receptor. 2. Optimum covalent inhibition by two different prototypes of polyamine disulfides. J Med Chem 21:1126–1132Google Scholar
  21. Mottram DR (1983a) Pre-junctional α2-adrenoceptor activity of B-HT920. J Pharm Pharmacol 35:652–655Google Scholar
  22. Mottram DR (1983b) Pharmacological evidence for high affinity and low affinity α2-adrenoceptor binding sites in rat vas deferens. Arch Int Pharmacol 264:28–39Google Scholar
  23. Mottram DR, Saggar P (1985) Cirazonne, an α2-adrenoceptor antagonist in guinea-pig ileum. Gen Pharmacol 16:367–370Google Scholar
  24. Mottram DR, Thakar Y (1984) The action and interaction of β-phenylethylamines and imidazolines on prejunctional α2-adrenoceptors of guinea-pig ileum in the presence of the noncompetitive antagonist benextramine. J Pharm Pharmacol 36:668–672Google Scholar
  25. Patil PN, Miller DD, Trendelenburg U (1975) Molecular geometry and adrenergic drug activity. Pharmacol Rev 26:323–392Google Scholar
  26. Pichler L, Kobinger W (1985) α2-Adrenoceptor blocking properties of the α1-selective agonist 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587). Arzneimittelforsch 35:201–205Google Scholar
  27. Schild HO (1973) Receptor classification with special reference to β-adrenergic receptors. In: Rang HP (ed) Drug receptors. University Park Press, Baltimore, pp 29–36Google Scholar
  28. Tayo FM (1979) Prejunctional inhibitory α-adrenoceptors and dopaminoceptors of the rat vas deferens and the guinea-pig ileum in vitro. Eur J Pharmacol 58:189–195Google Scholar
  29. Vizi ES, Ludvig N, Ronai AZ, Folly G (1983) Dissociation of presynaptic α2-adrenoceptora following prazosin administration: Presynaptic effect of prazosin. Eur J Pharmacol 95:287–290Google Scholar
  30. Wikberg JES (1978) Pharmacological classification of adrenergic α receptors in the guinea pig. Nature (Lond) 273:164–166Google Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • R. A. Bond
    • 1
  • K. G. Charlton
    • 1
  • D. E. Clarke
    • 1
  1. 1.Department of PharmacologyUniversity of Houston-University ParkHoustonUSA

Personalised recommendations