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. 1991 Oct;104(2):311–320. doi: 10.1111/j.1476-5381.1991.tb12428.x

Endothelium-dependent mesenteric vasorelaxant effects and systemic actions of endothelin (16-21) and other endothelin-related peptides in the rat.

S A Douglas 1, C R Hiley 1
PMCID: PMC1908533  PMID: 1797300

Abstract

1. The rat isolated superior mesenteric bed, perfused with Krebs-Henseleit solution containing 10 microM indomethacin and precontracted with 100 microM methoxamine, was used to study the vasorelaxation produced by some fragments of endothelin-1, by two alanyl-substituted analogues, and by human and porcine proendothelins. The systemic cardiovascular effects of some of these peptides were also studied in anaesthetized rats. 2. Endothelin (16-21) was an endothelium-dependent vasodilator about 10 times less potent than acetylcholine and its amide was about 500 times less potent than the free acid. Human proendothelin-1 and porcine proendothelin-1 also caused endothelium-dependent relaxations but neither [Ala3,11]endothelin-1 nor [Ala1,3,11,15]endothelin-1 produced significant reductions in the methoxamine-induced tone. Sodium nitroprusside was approximately 200 times less potent than acetylcholine in the presence of the endothelium and was the only vasorelaxant to be active after destruction of the endothelium by perfusion with 0.3% CHAPS; in the absence of the endothelium it was 3.7 times more potent as a vasodilator than in its presence. 3. Porcine proendothelin-1 had weak contractile activity in the isolated mesenteric bed but porcine endothelin (22-39), endothelin (16-21) and endothelin (16-21) amide did not have vasoconstrictor actions. 4. Endothelin-3, [Ala3,11]endothelin-1, [Ala1,3,11,15]endothelin-1 and endothelin (16-21) all had systemic blood pressure effects in the anaesthetized rat. Although endothelin (16-21) did not cause vasoconstriction in vitro, it increased mean arterial pressure in vivo but was at least 100 times less potent than endothelin-3. Despite causing no vasorelaxation in vitro, [Ala1,3,11,15]endothelin-1 and [Ala3,11]endothelin-1 induced short-lived systemic depressor responses which were followed by pressor responses. Endothelin-3 was more potent as a systemic depressor agent than as a pressor agonist and, as a vasodepressor agent, it was 3-4 times more potent than either of the alanyl-substituted analogues. Endothelin-3, [Ala3,11]endothelin-1 and [Ala1,3,11,15]endothelin-1 were equipotent vasopressor agents. Porcine endothelin (22-39) had no systemic blood pressure effects. 5. This study shows directly that the presence of both disulphide bonds is required in the endothelins for them to be able to cause endothelium-dependent relaxation in the mesenteric vascular bed and that this response is mediated by different receptors from those causing contraction of the vascular smooth muscle in the mesentery. Vasorelaxation caused by endothelin (16-21) and its amide suggests that there is a receptor on the endothelium similar to one reported in the guinea-pig trachea.(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

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  1. Arai H., Hori S., Aramori I., Ohkubo H., Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990 Dec 20;348(6303):730–732. doi: 10.1038/348730a0. [DOI] [PubMed] [Google Scholar]
  2. Cocks T. M., Faulkner N. L., Sudhir K., Angus J. Reactivity of endothelin-1 on human and canine large veins compared with large arteries in vitro. Eur J Pharmacol. 1989 Nov 14;171(1):17–24. doi: 10.1016/0014-2999(89)90425-1. [DOI] [PubMed] [Google Scholar]
  3. Douglas S. A., Hiley C. R. Endothelium-dependent vascular activities of endothelin-like peptides in the isolated superior mesenteric arterial bed of the rat. Br J Pharmacol. 1990 Sep;101(1):81–88. doi: 10.1111/j.1476-5381.1990.tb12093.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gardiner S. M., Compton A. M., Bennett T., Palmer R. M., Moncada S. NG-monomethyl-L-arginine does not inhibit the hindquarters vasodilator action of endothelin-1 in conscious rats. Eur J Pharmacol. 1989 Nov 21;171(2-3):237–240. doi: 10.1016/0014-2999(89)90113-1. [DOI] [PubMed] [Google Scholar]
  5. Gardiner S. M., Compton A. M., Bennett T. Regional haemodynamic effects of endothelin-1 and endothelin-3 in conscious Long Evans and Brattleboro rats. Br J Pharmacol. 1990 Jan;99(1):107–112. doi: 10.1111/j.1476-5381.1990.tb14662.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gardiner S. M., Compton A. M., Bennett T. Regional hemodynamic effects of endothelin-1 in conscious, unrestrained, Wistar rats. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S202–S204. doi: 10.1097/00005344-198900135-00057. [DOI] [PubMed] [Google Scholar]
  7. Gardiner S. M., Compton A. M., Bennett T. Regional hemodynamic effects of endothelin-2 and sarafotoxin-S6b in conscious rats. Am J Physiol. 1990 Apr;258(4 Pt 2):R912–R917. doi: 10.1152/ajpregu.1990.258.4.R912. [DOI] [PubMed] [Google Scholar]
  8. Gardiner S. M., Compton A. M., Kemp P. A., Bennett T. Cardiac output effects of endothelin-1, -2 and -3 and sarafotoxin S6b in conscious rats. J Auton Nerv Syst. 1990 Jun;30(2):143–147. doi: 10.1016/0165-1838(90)90138-9. [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. Hoffman A., Grossman E., Ohman K. P., Marks E., Keiser H. R. Endothelin induces an initial increase in cardiac output associated with selective vasodilation in rats. Life Sci. 1989;45(3):249–255. doi: 10.1016/0024-3205(89)90257-9. [DOI] [PubMed] [Google Scholar]
  12. Inoue A., Yanagisawa M., Kimura S., Kasuya Y., Miyauchi T., Goto K., Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2863–2867. doi: 10.1073/pnas.86.8.2863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jones C. R., Hiley C. R., Pelton J. T., Miller R. C. Autoradiographic localisation of endothelin binding sites in kidney. Eur J Pharmacol. 1989 Apr 25;163(2-3):379–382. doi: 10.1016/0014-2999(89)90211-2. [DOI] [PubMed] [Google Scholar]
  14. Kimura S., Kasuya Y., Sawamura T., Shinmi O., Sugita Y., Yanagisawa M., Goto K., Masaki T. Structure-activity relationships of endothelin: importance of the C-terminal moiety. Biochem Biophys Res Commun. 1988 Nov 15;156(3):1182–1186. doi: 10.1016/s0006-291x(88)80757-5. [DOI] [PubMed] [Google Scholar]
  15. Kloog Y., Ambar I., Sokolovsky M., Kochva E., Wollberg Z., Bdolah A. Sarafotoxin, a novel vasoconstrictor peptide: phosphoinositide hydrolysis in rat heart and brain. Science. 1988 Oct 14;242(4876):268–270. doi: 10.1126/science.2845579. [DOI] [PubMed] [Google Scholar]
  16. Le Monnier de Gouville A. C., Lippton H. L., Cavero I., Summer W. R., Hyman A. L. Endothelin--a new family of endothelium-derived peptides with widespread biological properties. Life Sci. 1989;45(17):1499–1513. doi: 10.1016/0024-3205(89)90415-3. [DOI] [PubMed] [Google Scholar]
  17. Lin H. Y., Kaji E. H., Winkel G. K., Ives H. E., Lodish H. F. Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3185–3189. doi: 10.1073/pnas.88.8.3185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lovenberg W., Miller R. C. Endothelin: a review of its effects and possible mechanisms of action. Neurochem Res. 1990 Apr;15(4):407–417. doi: 10.1007/BF00969926. [DOI] [PubMed] [Google Scholar]
  19. MCGREGOR D. D. THE EFFECT OF SYMPATHETIC NERVE STIMULATION OF VASOCONSTRICTOR RESPONSES IN PERFUSED MESENTERIC BLOOD VESSELS OF THE RAT. J Physiol. 1965 Mar;177:21–30. doi: 10.1113/jphysiol.1965.sp007572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. MacLean M. R., Randall M. D., Hiley C. R. Effects of moderate hypoxia, hypercapnia and acidosis on haemodynamic changes induced by endothelin-1 in the pithed rat. Br J Pharmacol. 1989 Nov;98(3):1055–1065. doi: 10.1111/j.1476-5381.1989.tb14638.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Maggi C. A., Giuliani S., Patacchini R., Rovero P., Giachetti A., Meli A. The activity of peptides of the endothelin family in various mammalian smooth muscle preparations. Eur J Pharmacol. 1989 Dec 12;174(1):23–31. doi: 10.1016/0014-2999(89)90869-8. [DOI] [PubMed] [Google Scholar]
  22. Maggi C. A., Giuliani S., Patacchini R., Santicioli P., Rovero P., Giachetti A., Meli A. The C-terminal hexapeptide, endothelin-(16-21), discriminates between different endothelin receptors. Eur J Pharmacol. 1989 Jul 4;166(1):121–122. doi: 10.1016/0014-2999(89)90693-6. [DOI] [PubMed] [Google Scholar]
  23. Moncada S., Rees D. D., Schulz R., Palmer R. M. Development and mechanism of a specific supersensitivity to nitrovasodilators after inhibition of vascular nitric oxide synthesis in vivo. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2166–2170. doi: 10.1073/pnas.88.6.2166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nakajima K., Kubo S., Kumagaye S., Nishio H., Tsunemi M., Inui T., Kuroda H., Chino N., Watanabe T. X., Kimura T. Structure-activity relationship of endothelin: importance of charged groups. Biochem Biophys Res Commun. 1989 Aug 30;163(1):424–429. doi: 10.1016/0006-291x(89)92153-0. [DOI] [PubMed] [Google Scholar]
  25. Randall M. D., Douglas S. A., Hiley C. R. Vascular activities of endothelin-1 and some alanyl substituted analogues in resistance beds of the rat. Br J Pharmacol. 1989 Oct;98(2):685–699. doi: 10.1111/j.1476-5381.1989.tb12644.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sakurai T., Yanagisawa M., Takuwa Y., Miyazaki H., Kimura S., Goto K., Masaki T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. 1990 Dec 20;348(6303):732–735. doi: 10.1038/348732a0. [DOI] [PubMed] [Google Scholar]
  27. Vane J. Endothelins come home to roost. Nature. 1990 Dec 20;348(6303):673–673. doi: 10.1038/348673a0. [DOI] [PubMed] [Google Scholar]
  28. Warner T. D. Simultaneous perfusion of rat isolated superior mesenteric arterial and venous beds: comparison of their vasoconstrictor and vasodilator responses to agonists. Br J Pharmacol. 1990 Feb;99(2):427–433. doi: 10.1111/j.1476-5381.1990.tb14720.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Warner T. D., de Nucci G., Vane J. R. Rat endothelin is a vasodilator in the isolated perfused mesentery of the rat. Eur J Pharmacol. 1989 Jan 17;159(3):325–326. doi: 10.1016/0014-2999(89)90167-2. [DOI] [PubMed] [Google Scholar]
  30. Whittle B. J., Lopez-Belmonte J., Rees D. D. Modulation of the vasodepressor actions of acetylcholine, bradykinin, substance P and endothelin in the rat by a specific inhibitor of nitric oxide formation. Br J Pharmacol. 1989 Oct;98(2):646–652. doi: 10.1111/j.1476-5381.1989.tb12639.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wright C. E., Fozard J. R. Regional vasodilation is a prominent feature of the haemodynamic response to endothelin in anaesthetized, spontaneously hypertensive rats. Eur J Pharmacol. 1988 Oct 11;155(1-2):201–203. doi: 10.1016/0014-2999(88)90425-6. [DOI] [PubMed] [Google Scholar]
  32. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K., Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988 Mar 31;332(6163):411–415. doi: 10.1038/332411a0. [DOI] [PubMed] [Google Scholar]
  33. de Nucci G., Thomas R., D'Orleans-Juste P., Antunes E., Walder C., Warner T. D., Vane J. R. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9797–9800. doi: 10.1073/pnas.85.24.9797. [DOI] [PMC free article] [PubMed] [Google Scholar]

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