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. 1986;21(Suppl 1):9S–17S. doi: 10.1111/j.1365-2125.1986.tb02848.x

The α1-adrenoceptor antagonist profile of doxazosin

Preclinical pharmacology

V A Alabaster, M J Davey
PMCID: PMC1400757  PMID: 2871857

Abstract

1 The antihypertensive efficacy of the new α1-adrenoceptor antagonist doxazosin is described, and its selectivity for α1-adrenoceptors is reported from both in vivo and in vitro studies.

2 Groups of beagle dogs with chronic perinephritic hypertension were given doxazosin orally, and systolic blood pressure was recorded indirectly from an exteriorized carotid loop. Dogs given doxazosin 0.5 mg kg-1 daily for 10 days showed consistent daily falls in systolic pressure in addition to a progressive reduction in daily pre-dose pressures. A clear indication of antihypertensive action in excess of 24 h post dose was evident. Heart rate changes were minimal.

3 In pentobarbitone anaesthetized dogs pretreated with desimipramine, doxazosin 10-500 μg kg-1 i.v. reduced responses of the nictitating membrane to electrical stimulation of the vagosympathetic-depressor nerve trunk (an α1-adrenoceptor response) but had no effect on the chronotropic response of the heart to electrical stimulation of the ansa subclavia. In contrast, the prejunctional α2-adrenoceptor antagonist activity of yohimbine 10-100 μg kg-1 i.v. was manifest as a marked dose-related increase in both the heart rate and nictitating membrane responses.

4 The lack of effect of doxazosin on postjunctional α2-adrenoceptors in vivo was demonstrated in the anaesthetized cat. Doxazosin at 50 and 100 μg kg-1 i.v. inhibited pressor responses to injected phenylephrine (an α1-adrenoceptor agonist) but had no effect on pressor responses to either α-methylnoradrenaline (an α2-adrenoceptor agonist) or angiotensin II.

5 Studies in isolated tissues, for example the rabbit pulmonary artery and the dog saphenous vein, have also shown the lack of activity of doxazosin at pre- and postjunctional α2-adrenoceptors.

6 The high degree of selectivity of doxazosin for α1-adrenoceptor sites was confirmed by ligand binding studies in rat brain membranes where the mean ± s.e. mean Ki values (n = 6) for displacement of [3H]-prazosin, [3H]-rauwolscine and [3H]-clonidine were 1.1 ± 0.1 nM, 449 ± 61 nM and > 10 μM, respectively.

7 Pharmacological studies indicate therefore that the antihypertensive activity of doxazosin is a consequence of selective inhibition of postjunctional α1-adrenoceptors.

Keywords: α1-adrenoceptor antagonists, antihypertensives, doxazosin, pre- and post-junctional α-adrenoceptors

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Selected References

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

  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alabaster V., Davey M. Precapillary vessels: effects of the sympathetic nervous system and of catecholamines. J Cardiovasc Pharmacol. 1984;6 (Suppl 2):S365–S376. [PubMed] [Google Scholar]
  3. Elliott H. L., Meredith P. A., Sumner D. J., McLean K., Reid J. L. A pharmacodynamic and pharmacokinetic assessment of a new alpha-adrenoceptor antagonist, doxazosin (UK33274) in normotensive subjects. Br J Clin Pharmacol. 1982 May;13(5):699–703. doi: 10.1111/j.1365-2125.1982.tb01439.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Frick M. H., Halttunen P., Himanen P., Huttunen M., Pörsti P., Pitkäjärvi T., Pöyhönen L., Pyykönen M. L., Reinikainen P., Salmela P. A long-term double-blind comparison of doxazosin and atenolol in patients with mild to moderate essential hypertension. Br J Clin Pharmacol. 1986;21 (Suppl 1):55S–62S. doi: 10.1111/j.1365-2125.1986.tb02854.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Greengrass P., Bremner R. Binding characteristics of 3H-prazosin to rat brain alpha-adrenergic receptors. Eur J Pharmacol. 1979 May 1;55(3):323–326. doi: 10.1016/0014-2999(79)90202-4. [DOI] [PubMed] [Google Scholar]
  6. Hoffman B. B., Michel T., Kilpatrick D. M., Lefkowitz R. J., Tolbert M. E., Gilman H., Fain J. N. Agonist versus antagonist binding to alpha-adrenergic receptors. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4569–4573. doi: 10.1073/pnas.77.8.4569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Perry B. D., U'Prichard D. C. [3H]rauwolscine (alpha-yohimbine): a specific antagonist radioligand for brain alpha 2-adrenergic receptors. Eur J Pharmacol. 1981 Dec 17;76(4):461–464. doi: 10.1016/0014-2999(81)90123-0. [DOI] [PubMed] [Google Scholar]
  8. Shepperson N. B., Langer S. Z. The effects of the 2-amino-tetrahydronaphthalene derivative M7, a selective alpha 2-adrenoceptor agonist in vitro. Naunyn Schmiedebergs Arch Pharmacol. 1981 Dec;318(1):10–13. doi: 10.1007/BF00503305. [DOI] [PubMed] [Google Scholar]
  9. Singleton W., Saxton C. A., Hernandez J., Prichard B. N. Postjunctional selectivity of alpha-blockade with prazosin, trimazosin, and UK-33,274 in man. J Cardiovasc Pharmacol. 1982;4 (Suppl 1):S145–S151. doi: 10.1097/00005344-198200041-00029. [DOI] [PubMed] [Google Scholar]
  10. Starke K., Endo T., Taube H. D. Relative pre- and postsynaptic potencies of alpha-adrenoceptor agonists in the rabbit pulmonary artery. Naunyn Schmiedebergs Arch Pharmacol. 1975;291(1):55–78. doi: 10.1007/BF00510821. [DOI] [PubMed] [Google Scholar]
  11. Su C., Bevan J. A. The release of H3-norepinephrine in arterial strips studied by the technique of superfusion and transmural stimulation. J Pharmacol Exp Ther. 1970 Mar;172(1):62–68. [PubMed] [Google Scholar]
  12. Timmermans P. B., Kwa H. Y., Ali F. K., van Zwieten P. A. Prazosin and its analogues UK-18,596 and UK-33,274: a comparative study on cardiovascular effects and alpha-adrenoceptor blocking activities. Arch Int Pharmacodyn Ther. 1980 Jun;245(2):218–235. [PubMed] [Google Scholar]
  13. Timmermans P. B., van Zwieten P. A. Mini-review. The postsynaptic alpha 2-adrenoreceptor. J Auton Pharmacol. 1981 Mar;1(2):171–183. doi: 10.1111/j.1474-8673.1981.tb00509.x. [DOI] [PubMed] [Google Scholar]
  14. U'Prichard D. C., Greenberg D. A., Snyder S. H. Binding characteristics of a radiolabeled agonist and antagonist at central nervous system alpha noradrenergic receptors. Mol Pharmacol. 1977 May;13(3):454–473. [PubMed] [Google Scholar]

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