Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1988 Mar;93(3):541–552. doi: 10.1111/j.1476-5381.1988.tb10309.x

Studies on the anti-vasoconstrictor activity of BRL 34915 in spontaneously hypertensive rats; a comparison with nifedipine.

R E Buckingham 1
PMCID: PMC1853837  PMID: 3370388

Abstract

1. The blood pressure lowering and anti-vasoconstrictor effects of BRL 34915 and nifedipine were compared in female spontaneously hypertensive rats (SHR). 2. In conscious SHR, intravenous injection of BRL 34915 (0.1, 0.3 mg kg-1) produced rapid, dose-related falls in mean arterial pressure of greater than 3 h duration. Nifedipine, at the same intravenous dose levels, also evoked rapid anti-hypertensive effects, though these responses were of lesser magnitude and duration than those observed for BRL 34915. 3. In anaesthetized, ganglion-blocked SHR, BRL 34915 (0.1, 0.3 mg kg-1 i.v.) dose-dependently antagonized the pressor responses to incremental intravenous infusions of noradrenaline (3.8-28.5 ng min-1) or phenylephrine (120-907 ng min-1) but did not inhibit pressor responses to incremental infusions of methoxamine (0.47-3.63 micrograms min-1), angiotensin II (7.0-52.9 ng min-1) or vasopressin (0.27-2.0 mu min-1). 4. In anaesthetized, ganglion-blocked SHR, nifedipine (0.1, 0.3 mgkg-1 i.v.) antagonized the pressor responses to each of the infused vasoconstrictor agents, being most effective against responses to noradrenaline or angiotensin II. 5. In pithed SHR, both BRL 34915 and nifedipine (each at 0.3 mg kg-1 i.v.) reduced the basal blood pressure level and produced marked inhibition of frequency-dependent pressor responses evoked by electrical stimulation of the spinal cord sympathetic outflow (0.25-4.0 Hz). Restoration of the basal diastolic blood pressure to within the control range, using a continuous intravenous infusion of vasopressin (0.98 mu min-1), prevented the inhibitory effect of BRL 34915. In the case of nifedipine, however, even raising the basal blood pressure to a level exceeding that recorded in control rats (with vasopressin, 2.0 mu min-1), did not reverse the inhibitory effect of the drug on frequency-dependent pressor responses. 6. It is concluded that the anti-hypertensive properties of BRL 34915 in SHR are probably unrelated to an anti-vasoconstrictor action. In contrast, it is suggested that the broadly-based anti-vasoconstrictor properties of nifedipine may contribute substantially to the anti-hypertensive properties of this drug.

Full text

PDF
546

Selected References

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

  1. Borkowski K. R., Quinn P. Adrenaline and the development of spontaneous hypertension in rats. J Auton Pharmacol. 1985 Jun;5(2):89–100. doi: 10.1111/j.1474-8673.1985.tb00109.x. [DOI] [PubMed] [Google Scholar]
  2. Buckingham R. E., Clapham J. C., Hamilton T. C., Longman S. D., Norton J., Poyser R. H. BRL 34915, a novel antihypertensive agent: comparison of effects on blood pressure and other haemodynamic parameters with those of nifedipine in animal models. J Cardiovasc Pharmacol. 1986 Jul-Aug;8(4):798–804. doi: 10.1097/00005344-198709010-00022. [DOI] [PubMed] [Google Scholar]
  3. Buckingham R. E. Indwelling catheters for direct recording of arterial blood pressure and intravenous injection of drugs in the conscious rat. J Pharm Pharmacol. 1976 May;28(5):459–461. doi: 10.1111/j.2042-7158.1976.tb04660.x. [DOI] [PubMed] [Google Scholar]
  4. Clapham J. C. Interaction between nifedipine and postsynaptic alpha 1- and alpha 2-adrenoceptors following oral pretreatment of spontaneously hypertensive rats. J Cardiovasc Pharmacol. 1984 Jul-Aug;6(4):668–671. doi: 10.1097/00005344-198407000-00018. [DOI] [PubMed] [Google Scholar]
  5. Eikenburg D. C., Lokhandwala M. F. Calcium antagonists and sympathetic neuroeffector function. J Auton Pharmacol. 1986 Sep;6(3):237–255. doi: 10.1111/j.1474-8673.1986.tb00650.x. [DOI] [PubMed] [Google Scholar]
  6. Gerold M., Haeusler G. alpha 2-Adrenoceptors in rat resistance vessels. Naunyn Schmiedebergs Arch Pharmacol. 1983 Feb;322(1):29–33. doi: 10.1007/BF00649348. [DOI] [PubMed] [Google Scholar]
  7. Goldberg J. P., Schrier R. W. Effect of calcium membrane blockers on in vivo vasoconstrictor properties of norepinephrine, angiotensin II and vasopressin. Miner Electrolyte Metab. 1984;10(3):178–183. [PubMed] [Google Scholar]
  8. Hamilton T. C., Weir S. W., Weston A. H. Comparison of the effects of BRL 34915 and verapamil on electrical and mechanical activity in rat portal vein. Br J Pharmacol. 1986 May;88(1):103–111. doi: 10.1111/j.1476-5381.1986.tb09476.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Holck M. I., Jones C. H., Haeusler G. Differential interactions of clonidine and methoxamine with the postsynaptic alpha-adrenoceptor of rabbit main pulmonary artery. J Cardiovasc Pharmacol. 1983 Mar-Apr;5(2):240–248. doi: 10.1097/00005344-198303000-00013. [DOI] [PubMed] [Google Scholar]
  10. Holck M., Gerold M. Calcium entry blockers inhibit vasoconstrictor responses to sympathetic nerve stimulation mediated by alpha 1-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1985 Jul;330(1):22–32. doi: 10.1007/BF00586705. [DOI] [PubMed] [Google Scholar]
  11. Medgett I. C., Langer S. Z. Heterogeneity of smooth muscle alpha adrenoceptors in rat tail artery in vitro. J Pharmacol Exp Ther. 1984 Jun;229(3):823–830. [PubMed] [Google Scholar]
  12. Pedrinelli R., Tarazi R. C. Calcium entry blockade by nitrendipine and alpha adrenergic responsiveness in vivo: comparison with noncalcium entry blocker vasodilators in absence and presence of phenoxybenzamine pretreatment. J Pharmacol Exp Ther. 1985 Jun;233(3):636–642. [PubMed] [Google Scholar]
  13. Ruffolo R. R., Jr, Morgan E. L., Messick K. Possible relationship between receptor reserve and the differential antagonism of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses by calcium channel antagonists in the pithed rat. J Pharmacol Exp Ther. 1984 Sep;230(3):587–594. [PubMed] [Google Scholar]
  14. Timmermans P. B., Mathy M. J., Wilffert B., Kalkman H. O., Thoolen M. J., de Jonge A., van Meel J. C., van Zwieten P. A. Differential effect of calcium entry blockers on alpha 1-adrenoceptor-mediated vasoconstriction in vivo. Naunyn Schmiedebergs Arch Pharmacol. 1983 Dec;324(4):239–245. doi: 10.1007/BF00502618. [DOI] [PubMed] [Google Scholar]
  15. Timmermans P. B., Thoolen M. J., Mathy M. J., Wilffert B., De Jonge A., Van Zwieten P. A. Sgd 101/75 is distinguished from other selective alpha 1-adrenoceptor agonists by the inhibition of its pressor responses by calcium entry blockade and vasodilatation in pithed rats and cats. Eur J Pharmacol. 1983 Dec 23;96(3-4):187–192. doi: 10.1016/0014-2999(83)90307-2. [DOI] [PubMed] [Google Scholar]
  16. Timmermans P. B., Thoolen M. J., Mathy M. J., Wilffert B., de Jonge A., van Zwieten P. A. Effects of the irreversible alpha-adrenoceptor antagonists phenoxybenzamine and benextramine on the effectiveness of nifedipine in inhibiting alpha 1- and alpha 2-adrenoceptor mediated vasoconstriction in pithed rats. Naunyn Schmiedebergs Arch Pharmacol. 1985 Jun;329(4):404–413. doi: 10.1007/BF00496376. [DOI] [PubMed] [Google Scholar]
  17. Timmermans P. B., de Jonge A., van Meel J. C., Mathy M. J., van Zwieten P. A. Influence of nifedipine on functional responses in vivo initiated at alpha 2-adrenoceptors. J Cardiovasc Pharmacol. 1983 Jan-Feb;5(1):1–11. doi: 10.1097/00005344-198301000-00001. [DOI] [PubMed] [Google Scholar]
  18. Toda N., Okamura T., Nakajima M., Miyazaki M. Modification by yohimbine and prazosin of the mechanical response of isolated dog mesenteric, renal and coronary arteries to transmural stimulation and norepinephrine. Eur J Pharmacol. 1984 Feb 10;98(1):69–78. doi: 10.1016/0014-2999(84)90110-9. [DOI] [PubMed] [Google Scholar]
  19. Van Meel J. C., De Jonge A., Kalkman H. O., Wilffert B., Timmermans P. B., Van Zwieten P. A. Vascular smooth muscle contraction initiated by postsynaptic alpha 2-adrenoceptor activation is induced by an influx of extracellular calcium. Eur J Pharmacol. 1981 Jan 16;69(2):205–208. doi: 10.1016/0014-2999(81)90415-5. [DOI] [PubMed] [Google Scholar]
  20. Van Meel J. C., De Zoeten K., Timmermans P. B., Van Zwieten P. A. Impairment by nifedipine of vasopressor responses to stimulation of postsynaptic alpha 2-adrenoreceptors in ganglion--blocked rabbits. Further evidence for the selective inhibition of postsynaptic alpha 2-adrenoreceptor-induced pressor responses by calcium antagonists. J Auton Pharmacol. 1982 Mar;2(1):13–20. doi: 10.1111/j.1474-8673.1982.tb00465.x. [DOI] [PubMed] [Google Scholar]
  21. Van Meel J. C., de Jonge A., Kalkman H. O., Wilffert B., Timmermans P. B., van Zwieten P. A. Organic and inorganic calcium antagonists reduce vasoconstriction in vivo mediated by postsynaptic alpha 2-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1981 Jul;316(4):288–293. doi: 10.1007/BF00501359. [DOI] [PubMed] [Google Scholar]
  22. Weir S. W., Weston A. H. The effects of BRL 34915 and nicorandil on electrical and mechanical activity and on 86Rb efflux in rat blood vessels. Br J Pharmacol. 1986 May;88(1):121–128. doi: 10.1111/j.1476-5381.1986.tb09478.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wilffert B., Davidesko D., De Jonge A., Thoolen M. J., Timmermans P. B., Van Zwieten P. A. Interaction between the calcium entry blocker nifedipine with the alpha 1-adrenoreceptor-mediated increase in diastolic pressure elicited by catecholamines. J Auton Pharmacol. 1984 Jun;4(2):87–92. doi: 10.1111/j.1474-8673.1984.tb00085.x. [DOI] [PubMed] [Google Scholar]
  24. Yamaguchi I., Kopin I. J. Plasma catecholamine and blood pressure responses to sympathetic stimulation in pithed rats. Am J Physiol. 1979 Sep;237(3):H305–H310. doi: 10.1152/ajpheart.1979.237.3.H305. [DOI] [PubMed] [Google Scholar]

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

RESOURCES