Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1981 Jul;73(3):595–604. doi: 10.1111/j.1476-5381.1981.tb16793.x

Hypotensive and sedative effects of α-adrenoceptor agonists: relationship to α1- and α2 -adrenoceptor potency

DP Clough, R Hatton
PMCID: PMC2071702  PMID: 6113864

Abstract

1 The purpose of this study was to investigate whether the separation between the hypotensive and sedative effects of a new series of centrally acting antihypertensive drugs was due to differences between the relative pre-junctional (α2) and post-junctional (α1) adrenoceptor agonist properties of the compounds.

2 In anaesthetized rats the intravenous doses of clonidine, ICI 101187, ICI 106270, ICI 109683 and ICI 110802 required to lower blood pressure (BP) by 20 mm Hg were 1.2, 5.1, 5.5, 3.3 and 5.4 μg/kg respectively.

3 In a test for sedation, ICI 101187 had at least 10 times less sedative effect than clonidine, ICI 106270 and ICI 109683 had at least 30 times less sedative effect than clonidine while ICI 110802 was not active. In a locomotor activity test the intravenous dose of clonidine required to reduce activity by 50% was 15.3 μg/kg, for ICI 101187 it was 194, for ICI 106270 it was 238 and for 110802 it was 313 μg/kg.

4 In the pithed rat the ED50s of clonidine, ICI 101187, ICI 106270, ICI 109683 and ICI 110802 as α2-agonists were 19.4, 9.3, 63.2, 43.0 and 78.5 μg/kg respectively. The α1-adrenoceptor potencies were quite similar for the five drugs and varied between 3.2 μg/kg for ICI 110802 and 8.7 μ/kg for ICI 106720. Potency as α2-adrenoceptor agonists was also assessed in the mouse vas deferens. Clonidine and ICI 101187 were similar in potency with IC50s of 9.3 × 10-9m and 8.9 × 10-9m respectively. ICI 106270 and ICI 110802 were much weaker with IC50s of 4.9 × 10-8m and over 5.7 × 10-8m respectively.

5 Since all the compounds had similar potencies as α1-agonists, this could not explain their different sedative effects. The weakest compounds as sedatives were also weakest as α2-agonists, although ICI 101187 which was as potent as clonidine as an α2-agonist was still 10 times weaker as a sedative.

6 Hypotensive activity appears to be more closely related to α1- than to α2-potency.

7 Clonidine was more potent as both a sedative and a hypotensive agent than would be predicted from its activity at either the α1- or the α2-adrenoceptor.

Full text

PDF
595

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Birch P., Clough D. P., Hatton R., Wheatley D. J. Hypotensive and sedative properties of alpha-adrenoceptor agonists: relation to pre- and post-synaptic stimulation [proceedings]. Br J Pharmacol. 1980 Jan;68(1):107P–108P. doi: 10.1111/j.1476-5381.1980.tb10705.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bolme P., Corrodi H., Fuxe K., Hökfelt T., Lidbrink P., Goldstein M. Possible involvement of central adrenaline neurons in vasomotor and respiratory control. Studies with clonidine and its interactions with piperoxane and yohimbine. Eur J Pharmacol. 1974 Sep;28(1):89–94. doi: 10.1016/0014-2999(74)90116-2. [DOI] [PubMed] [Google Scholar]
  3. Cambridge D., Davey M. J., Massingham R. Prazosin, a selective antagonist of post-synaptic alpha-adrenoceptors [proceedings]. Br J Pharmacol. 1977 Mar;59(3):514P–515P. [PMC free article] [PubMed] [Google Scholar]
  4. Cavero I., Roach A. G. The effects of prazosin on the clonidine induced hypotension and bradycardia in rats and sedation in chicks [proceedings]. Br J Pharmacol. 1978 Mar;62(3):468P–469P. [PMC free article] [PubMed] [Google Scholar]
  5. Clough D. P., Hatton R., Pettinger S. J., Samuels G. M., Shaw A. Substituted aryl-tetrahydro-pyrrolo imidazoles: a new class of centrally acting antihypertensives [proceedings]. Br J Pharmacol. 1978 Mar;62(3):385P–386P. [PMC free article] [PubMed] [Google Scholar]
  6. Delbarre B., Schmitt H. Sedative effects of alpha-sympathomimetic drugs and their antagonism by adrenergic and cholinergic blocking drugs. Eur J Pharmacol. 1971;13(3):356–363. doi: 10.1016/0014-2999(71)90226-3. [DOI] [PubMed] [Google Scholar]
  7. Drew G. M. Effects of alpha-adrenoceptor agonists and antagonists on pre- and postsynaptically located alpha-adrenoceptors. Eur J Pharmacol. 1976 Apr;36(2):313–320. doi: 10.1016/0014-2999(76)90084-4. [DOI] [PubMed] [Google Scholar]
  8. Drew G. M., Gower A. J., Marriott A. S. Alpha 2-adrenoceptors mediate clonidine-induced sedation in the rat. Br J Pharmacol. 1979 Sep;67(1):133–141. [PMC free article] [PubMed] [Google Scholar]
  9. Finch L. The cardiovascular effects of intraventricular clonidine and Bay 1470 in conscious hypertensive cats. Br J Pharmacol. 1974 Nov;52(3):333–338. [PMC free article] [PubMed] [Google Scholar]
  10. Gillespie J. S., Maclaren A., Pollock D. A method of stimulating different segments of the autonomic outflow from the spinal column to various organs in the pithed cat and rat. Br J Pharmacol. 1970 Oct;40(2):257–267. doi: 10.1111/j.1476-5381.1970.tb09919.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Haeusler G. Clonidine-induced inhibition of sympathetic nerve activity: no indication for a central presynaptic or an indirect sympathomimetic mode of action. Naunyn Schmiedebergs Arch Pharmacol. 1974;286(1):07–111. doi: 10.1007/BF00499107. [DOI] [PubMed] [Google Scholar]
  12. Holman R. B., Shillito E. E., Vogt M. Sleep produced by clonidine (2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride). Br J Pharmacol. 1971 Dec;43(4):685–695. doi: 10.1111/j.1476-5381.1971.tb07203.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hughes J., Kosterlitz H. W., Leslie F. M. Effect of morphine on adrenergic transmission in the mouse vas deferens. Assessment of agonist and antogonist potencies of narcotic analgesics. Br J Pharmacol. 1975 Mar;53(3):371–381. doi: 10.1111/j.1476-5381.1975.tb07373.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kobinger W., Pichler L. Evidence for direct alpha-adrenoceptor stimulation of effector neurons in cardiovascular centers by clonidine. Eur J Pharmacol. 1974 Jun;27(1):151–154. doi: 10.1016/0014-2999(74)90214-3. [DOI] [PubMed] [Google Scholar]
  15. Langer S. Z. Presynaptic regulation of catecholamine release. Biochem Pharmacol. 1974 Jul 1;23(13):1793–1800. doi: 10.1016/0006-2952(74)90187-7. [DOI] [PubMed] [Google Scholar]
  16. Schmitt H., Fenard S. Evidence for an alpha-sympathomimetic component in the effects of catapresan on vasomotor centres: antagonism by piperoxane. Eur J Pharmacol. 1971;14(1):98–100. doi: 10.1016/0014-2999(71)90130-0. [DOI] [PubMed] [Google Scholar]
  17. Starke K., Endo T. Presynaptic alpha-adrenoceptors. Gen Pharmacol. 1976 Oct;7(5):307–312. doi: 10.1016/0306-3623(76)90012-4. [DOI] [PubMed] [Google Scholar]
  18. Starke K., Endo T., Taube H. D. Pre- and postsynaptic components in effect of drugs with alpha adrenoceptor affinity. Nature. 1975 Apr 3;254(5499):440–441. doi: 10.1038/254440a0. [DOI] [PubMed] [Google Scholar]
  19. Turnbull M. J., Watkins J. W. Determination of halothane-induced sleeping time in the rat: effect of prior administration of centrally active drugs. Br J Pharmacol. 1976 Sep;58(1):27–35. doi: 10.1111/j.1476-5381.1976.tb07689.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES