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. 1989 Oct;98(2):685–699. doi: 10.1111/j.1476-5381.1989.tb12644.x

Vascular activities of endothelin-1 and some alanyl substituted analogues in resistance beds of the rat.

M D Randall 1, S A Douglas 1, C R Hiley 1
PMCID: PMC1854732  PMID: 2684315

Abstract

1. The effects of endothelin-1 and of three analogues in which alanyl residues had been substituted in place of cysteinyl residues were studied in the rat, isolated, Krebs-Henseleit-perfused mesenteric bed and the in situ, blood-perfused, mesenteric and hindquarters circulations of the rat. The effects on the vascular responses to these peptides of removing the endothelium by detergent perfusion or of cyclo-oxygenase inhibition by indomethacin were also determined. 2. In all three preparations, endothelin-1 was a potent vasoconstrictor (ED50 values ranged from 40 to 400 pmol) although it was rather less potent in the hindquarters than in the mesentery. Also, the maximum response was very much smaller in the isolated mesentery (24.7 +/- 2.1 mmHg) than in the in situ mesentery (81.8 +/- 2.6 mmHg) or hindquarters (107 +/- 10 mmHg). 3. Removal of the endothelium by perfusion with detergent significantly enhanced the potency of endothelin as a vasoconstrictor in the in situ messentery, but reduced the maximum response obtained, whereas removal of the endothelium in vitro significantly increased the maximum response without changing the ED50. The presence or absence of indomethacin had no significant effects in the blood-perfused hindquarters preparation or the isolated mesentery but, after administration of 5 mg kg-1 indomethacin to the in situ mesenteric preparation, the maximal response to endothelin-1 was enhanced. 4. When the preparations were preconstricted with alpha 1-adrenoceptor agonists, endothelin-1 had modest vasodilator effects. These vasodilator effects were abolished when the endothelium was destroyed by detergent perfusion. 5. Both [Ala3,11]endothelin-1 and [Ala1,15]endothelin-1 were also vasoconstrictor agents in the mesenteric preparations but they were less potent than endothelin-1 itself; [Ala3,11]endothelin-1 was intermediate in potency between endothelin-1 and [Ala1,15]endothelin-1. In the in situ preparation these analogues gave similar maximal responses to the parent peptide but, in vitro, they gave maximal responses that were much greater than that of endothelin-1 and which were similar to those found with all 3 peptides in the in situ mesentery. Destruction of the endothelium in vitro had no effect on the responses to these 2 analogues and the log dose-response curve for [Ala1,15]endothelin-1 in the isolated mesentery was biphasic. 6. A third analogue possessing no disulphide bridges [( Ala1,3,11,15]endothelin-1) was a partial agonist in the in situ preparations but had no vasoconstrictor effect in the in vitro mesentery.(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

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  1. Aceves J., Mariscal S., Morrison K. E., Young J. M. The binding of doxepin to histamine H1-receptors in guinea-pig and rat brain. Br J Pharmacol. 1985 Feb;84(2):417–424. doi: 10.1111/j.1476-5381.1985.tb12925.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brain S. D., Tippins J. R., Williams T. J. Endothelin induces potent microvascular constriction. Br J Pharmacol. 1988 Dec;95(4):1005–1007. doi: 10.1111/j.1476-5381.1988.tb11731.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Hiley C. R., Nichols A. J., Wilson A. C. Effects of phenobarbitone and 6-methylprednisolone pretreatment on pressure/flow relations in the superior mesenteric and iliac arterial beds of the rat. J Pharm Pharmacol. 1985 Mar;37(3):164–169. doi: 10.1111/j.2042-7158.1985.tb05033.x. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Jackson E. K., Campbell W. B. The in situ blood perfused rat mesentery; a model for assessing modulation of adrenergic neurotransmission. Eur J Pharmacol. 1980 Aug 29;66(2-3):217–224. doi: 10.1016/0014-2999(80)90145-4. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Jones C. R., Hiley C. R., Pelton J. T., Mohr M. Autoradiographic visualization of the binding sites for [125I]endothelin in rat and human brain. Neurosci Lett. 1989 Feb 27;97(3):276–279. doi: 10.1016/0304-3940(89)90610-1. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Komuro I., Kurihara H., Sugiyama T., Yoshizumi M., Takaku F., Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett. 1988 Oct 10;238(2):249–252. doi: 10.1016/0014-5793(88)80489-7. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Neuser D., Steinke W., Theiss G., Stasch J. P. Autoradiographic localization of [125I]endothelin-1 and [125I]atrial natriuretic peptide in rat tissue: a comparative study. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S67–S74. doi: 10.1097/00005344-198900135-00016. [DOI] [PubMed] [Google Scholar]
  15. Pohl U., Busse R. Differential vascular sensitivity to luminally and adventitially applied endothelin-1. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S188–S190. doi: 10.1097/00005344-198900135-00052. [DOI] [PubMed] [Google Scholar]
  16. Rae G. A., Trybulec M., de Nucci G., Vane J. R. Endothelin-1 releases eicosanoids from rabbit isolated perfused kidney and spleen. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S89–S102. doi: 10.1097/00005344-198900135-00022. [DOI] [PubMed] [Google Scholar]
  17. Randall M. D., Hiley C. R. Detergent and methylene blue affect endothelium-dependent vasorelaxation and pressure/flow relations in rat blood perfused mesenteric arterial bed. Br J Pharmacol. 1988 Dec;95(4):1081–1088. doi: 10.1111/j.1476-5381.1988.tb11742.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Shiba R., Yanagisawa M., Miyauchi T., Ishii Y., Kimura S., Uchiyama Y., Masaki T., Goto K. Elimination of intravenously injected endothelin-1 from the circulation of the rat. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S98–S102. doi: 10.1097/00005344-198900135-00024. [DOI] [PubMed] [Google Scholar]
  19. Spokes R. A., Ghatei M. A., Bloom S. R. Studies with endothelin-3 and endothelin-1 on rat blood pressure and isolated tissues: evidence for multiple endothelin receptor subtypes. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S191–S192. doi: 10.1097/00005344-198900135-00053. [DOI] [PubMed] [Google Scholar]
  20. Takagi M., Matsuoka H., Atarashi K., Yagi S. Endothelin: a new inhibitor of renin release. Biochem Biophys Res Commun. 1988 Dec 30;157(3):1164–1168. doi: 10.1016/s0006-291x(88)80996-3. [DOI] [PubMed] [Google Scholar]
  21. Thiemermann C., Lidbury P., Thomas R., Vane J. Endothelin inhibits ex vivo platelet aggregation in the rabbit. Eur J Pharmacol. 1988 Dec 6;158(1-2):181–182. doi: 10.1016/0014-2999(88)90273-7. [DOI] [PubMed] [Google Scholar]
  22. Walder C. E., Thomas G. R., Thiemermann C., Vane J. R. The hemodynamic effects of endothelin-1 in the pithed rat. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S93–S102. doi: 10.1097/00005344-198900135-00023. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Whittle B. J., Payne A. N., Esplugues J. V. Cardiopulmonary and gastric ulcerogenic actions of endothelin-1 in the guinea pig and rat. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S103–S123. doi: 10.1097/00005344-198900135-00026. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. 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]
  27. Yoshizawa T., Kimura S., Kanazawa I., Yanagisawa M., Masaki T. Endothelin-1 depolarizes a ventral root potential in the newborn rat spinal cord. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S216–S217. doi: 10.1097/00005344-198900135-00063. [DOI] [PubMed] [Google Scholar]
  28. 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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