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. 1994 Jun;112(2):477–486. doi: 10.1111/j.1476-5381.1994.tb13098.x

Effects of an ET1-receptor antagonist, FR139317, on regional haemodynamic responses to endothelin-1 and [Ala11,15]Ac-endothelin-1 (6-21) in conscious rats.

S M Gardiner 1, P A Kemp 1, J E March 1, T Bennett 1, A P Davenport 1, L Edvinsson 1
PMCID: PMC1910376  PMID: 8075866

Abstract

1. In conscious, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, we compared responses to the putative, selective ETB-receptor agonist, [Ala1,3,11,15]endothelin-1 (ET-1), obtained from two sources (Microchemical Laboratory, Cambridge (MLC) and Neosystem Laboratory, France (NLF)). [Ala1,3,11,15]ET-1 (0.15, 0.3, 1 and 10 nmol kg-1) from MCL caused dose-dependent pressor effects, accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances; there was an initial hyperaemic vasodilatation in the hindquarters which was not dose-dependent, and only with the highest dose was there a subsequent vasoconstriction. There was no significant initial depressor response to [Ala1,3,11,15]ET-1 from MLC at any dose. However, the peptide from NLF exerted dose-dependent depressor and hindquarters vasodilator actions, and subsequent pressor effects. The difference between the two peptide preparations remains unexplained, but it appears that the [Ala1,3,11,15]ET-1 from MLC may activate ETB-receptors mediating vasoconstriction, more effectively than those mediating vasodilatation. 2. We also assessed responses to the putative ETB-receptor agonist, [Ala11,15]Ac-ET-1 (6-21) (BQ-3020), and determined the effects of the selective ETA-receptor antagonist, FR139317, on responses to ET-1 and BQ-3020 at doses matched for their initial depressor and subsequent pressor effects (ET-1, 0.5 nmol kg-1, BQ-3020, 10 nmol kg-1), and also at doses that did not affect mean arterial blood pressure, but which were matched for their renal vasoconstrictor effects (ET-1, 7.5 pmol kg-1; BQ-3020, 0.15 nmol kg-1). 3. BQ-3020 (0.15, 0.3 and 1 nmol kg-1) had dose-dependent pressor effects accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances. BQ-3020 at a dose of 10 nmol kg-1 elicited an initial depressor response which coincided with an attenuated mesenteric vasoconstrictor effect, accompanying a marked hindquarters vasodilatation. Hence, it appears that BQ-3020 may activate both vasoconstrictor and vasodilator ETB-receptors. 4. FR139317 (0.5 mumol kg-1) caused attenuation of the pressor, and renal, mesenteric and hindquarters vasoconstrictor effects of ET-1 (0.5 nmol kg-1) and of BQ-3020 (10 nmol kg-1), but the reductions of the pressor and renal vasoconstrictor effects of ET-1 were greater than those of BQ-3020. However, in the presence of FR139317, significant pressor and renal, mesenteric and hindquarters vasoconstrictor responses to ET-1 and BQ-3020 still occurred, and the initial depressor and hindquarters vasodilator responses to both peptides were unchanged.(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

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  1. Bigaud M., Pelton J. T. Discrimination between ETA- and ETB-receptor-mediated effects of endothelin-1 and [Ala1,3,11,15]endothelin-1 by BQ-123 in the anaesthetized rat. Br J Pharmacol. 1992 Dec;107(4):912–918. doi: 10.1111/j.1476-5381.1992.tb13385.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cardell L. O., Uddman R., Edvinsson L. A novel ETA-receptor antagonist, FR 139317, inhibits endothelin-induced contractions of guinea-pig pulmonary arteries, but not trachea. Br J Pharmacol. 1993 Feb;108(2):448–452. doi: 10.1111/j.1476-5381.1993.tb12824.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Clozel M., Gray G. A., Breu V., Löffler B. M., Osterwalder R. The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun. 1992 Jul 31;186(2):867–873. doi: 10.1016/0006-291x(92)90826-7. [DOI] [PubMed] [Google Scholar]
  4. Cristol J. P., Warner T. D., Thiemermann C., Vane J. R. Mediation via different receptors of the vasoconstrictor effects of endothelins and sarafotoxins in the systemic circulation and renal vasculature of the anaesthetized rat. Br J Pharmacol. 1993 Mar;108(3):776–779. doi: 10.1111/j.1476-5381.1993.tb12877.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Douglas S. A., Elliott J. D., Ohlstein E. H. Regional vasodilation to endothelin-1 is mediated by a non-ETA receptor subtype in the anaesthetized rat: effect of BQ-123 on systemic haemodynamic responses. Eur J Pharmacol. 1992 Oct 20;221(2-3):315–324. doi: 10.1016/0014-2999(92)90718-j. [DOI] [PubMed] [Google Scholar]
  6. Gardiner S. M., Compton A. M., Kemp P. A., Bennett T. The effects of phosphoramidon on the regional haemodynamic responses to human proendothelin [1-38] in conscious rats. Br J Pharmacol. 1991 Aug;103(4):2009–2015. doi: 10.1111/j.1476-5381.1991.tb12368.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gardiner S. M., Kemp P. A., Bennett T. Inhibition by phosphoramidon of the regional haemodynamic effects of proendothelin-2 and -3 in conscious rats. Br J Pharmacol. 1992 Oct;107(2):584–590. doi: 10.1111/j.1476-5381.1992.tb12787.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Haywood J. R., Shaffer R. A., Fastenow C., Fink G. D., Brody M. J. Regional blood flow measurement with pulsed Doppler flowmeter in conscious rat. Am J Physiol. 1981 Aug;241(2):H273–H278. doi: 10.1152/ajpheart.1981.241.2.H273. [DOI] [PubMed] [Google Scholar]
  9. Hiley C. R., Douglas S. A., Randall M. D. Pressor effects of endothelin-1 and some analogs in the perfused superior mesenteric arterial bed of the rat. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S197–S199. doi: 10.1097/00005344-198900135-00055. [DOI] [PubMed] [Google Scholar]
  10. Hiley C. R., Jones C. R., Pelton J. T., Miller R. C. Binding of [125I]-endothelin-1 to rat cerebellar homogenates and its interactions with some analogues. Br J Pharmacol. 1990 Oct;101(2):319–324. doi: 10.1111/j.1476-5381.1990.tb12708.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Masaki T., Yanagisawa M., Goto K. Physiology and pharmacology of endothelins. Med Res Rev. 1992 Jul;12(4):391–421. doi: 10.1002/med.2610120405. [DOI] [PubMed] [Google Scholar]
  12. McMurdo L., Corder R., Thiemermann C., Vane J. R. Incomplete inhibition of the pressor effects of endothelin-1 and related peptides in the anaesthetized rat with BQ-123 provides evidence for more than one vasoconstrictor receptor. Br J Pharmacol. 1993 Feb;108(2):557–561. doi: 10.1111/j.1476-5381.1993.tb12840.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Molenaar P., Kuc R. E., Davenport A. P. Characterization of two new ETB selective radioligands, [125I]-BQ3020 and [125I]-[Ala1,3,11,15]ET-1 in human heart. Br J Pharmacol. 1992 Nov;107(3):637–639. doi: 10.1111/j.1476-5381.1992.tb14498.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Moreland S., McMullen D. M., Delaney C. L., Lee V. G., Hunt J. T. Venous smooth muscle contains vasoconstrictor ETB-like receptors. Biochem Biophys Res Commun. 1992 Apr 15;184(1):100–106. doi: 10.1016/0006-291x(92)91163-k. [DOI] [PubMed] [Google Scholar]
  15. Pollock D. M., Opgenorth T. J. Evidence for endothelin-induced renal vasoconstriction independent of ETA receptor activation. Am J Physiol. 1993 Jan;264(1 Pt 2):R222–R226. doi: 10.1152/ajpregu.1993.264.1.R222. [DOI] [PubMed] [Google Scholar]
  16. Randall M. D. Vascular activities of the endothelins. Pharmacol Ther. 1991;50(1):73–93. doi: 10.1016/0163-7258(91)90073-u. [DOI] [PubMed] [Google Scholar]
  17. Saeki T., Ihara M., Fukuroda T., Yamagiwa M., Yano M. [Ala1,3,11,15]endothelin-1 analogs with ETB agonistic activity. Biochem Biophys Res Commun. 1991 Aug 30;179(1):286–292. doi: 10.1016/0006-291x(91)91367-l. [DOI] [PubMed] [Google Scholar]
  18. Sun X. Y., Hedner T., Feng Q., Edvinsson L. Inhibition of endothelin (ET-1) induced pressor responses by the endothelin (ETA) receptor antagonist FR139317 in the pithed rat. Blood Press. 1992 Aug;1(2):108–112. doi: 10.3109/08037059209077501. [DOI] [PubMed] [Google Scholar]

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