Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 Aug;118(8):1931–1938. doi: 10.1111/j.1476-5381.1996.tb15627.x

Investigation of the contributions of nitric oxide and prostaglandins to the actions of endothelins and sarafotoxin 6c in rat isolated perfused lungs.

H Lal 1, B Woodward 1, K I Williams 1
PMCID: PMC1909892  PMID: 8864526

Abstract

1. The aims of the study were to assess the contribution of prostaglandins and nitric oxide (NO) to the effects of endothelin (ETs) and sarafotoxin 6c (SX6c) in perfused rat lungs. This was carried out by using indomethacin, a cyclo-oxygenase inhibitor and NG-nitro-L-arginine (L-NOARG), a NO synthase inhibitor. Responses were studied under basal perfusion conditions and in other experiments after the elevation of vascular tone with the thromboxane-mimetic, U46619. The sub-types of ET receptors involved were characterized by use of ET receptor antagonists and cross-tachyphylaxis. 2. Pulmonary perfusion pressure (PPP), lung weight and pulmonary inflation pressure (PIP), were continuously recorded. Although L-NOARG (100 microM) did not alter basal parameters it markedly augmented the vasoconstriction and lung weight increases induced by ET-1 (50-400 pmol) or SX6C (25-200 pmol) while vasoconstrictor responses to phenylephrine were not affected by L-NOARG. 3. L-NOARG markedly potentiated the bronchoconstriction induced by ET-1 or SX6C whereas it had no effect on responses to carbachol. 4. When vascular tone was elevated, low doses (1.25-40 pmol) of ET-1, ET-3 and SX6C produced falls in PPP. The vasodilator potencies were SX6C > ET-1 = ET-3. The ETA receptor antagonist, BQ123, did not affect these depressor responses whereas the mixed ETA/ETB antagonist, bosentan, blocked them. 5. Indomethacin (10 microM) partially inhibited vasodilator response to ET-1, whereas it had no effect on SX6C-induced vasodilation. 6. L-NOARG plus indomethacin completely blocked ET-1 induced vasodilation, whereas responses to SX6C were blocked by L-NOARG alone. 7. Repeated injections of submaximal doses of ET-1 or SX6C caused tachyphylaxis to vasodilator responses. Subsequent injections of SX6C or ET-1 did not elicit depressor responses showing cross tachyphylaxis had occurred. 8. These findings indicate that under basal conditions the pulmonary vasoconstrictor, lung weight and bronchoconstrictor responses to ET-1 and SX6C are attenuated by evoked release of nitric oxide (NO). When vascular tone was elevated, lower doses of ETs and SX6C produced vasodilatation. These vasodilator responses are indirect, those to SX6C being mediated via NO production, whereas those to ET-1 involve both NO and prostanoid(s). Tachyphylaxis and ET antagonist experiments indicate that the same receptor subtype is involved in mediating the vasodilatation and that this is of the ETB type located on the endothelium. However the post-receptor vasodilator events triggered by ET-1 or SX6C appear to be different.

Full text

PDF
1931

Selected References

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

  1. Barnes P. J. Endothelins and pulmonary diseases. J Appl Physiol (1985) 1994 Sep;77(3):1051–1059. doi: 10.1152/jappl.1994.77.3.1051. [DOI] [PubMed] [Google Scholar]
  2. Bonvallet S. T., Oka M., Yano M., Zamora M. R., McMurtry I. F., Stelzner T. J. BQ123, an ETA receptor antagonist, attenuates endothelin-1-induced vasoconstriction in rat pulmonary circulation. J Cardiovasc Pharmacol. 1993 Jul;22(1):39–43. doi: 10.1097/00005344-199307000-00007. [DOI] [PubMed] [Google Scholar]
  3. Coleman R. A., Humphrey P. P., Kennedy I., Levy G. P., Lumley P. Comparison of the actions of U-46619, a prostaglandin H2-analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations. Br J Pharmacol. 1981 Jul;73(3):773–778. doi: 10.1111/j.1476-5381.1981.tb16814.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Douglas S. A., Meek T. D., Ohlstein E. H. Novel receptor antagonists welcome a new era in endothelin biology. Trends Pharmacol Sci. 1994 Sep;15(9):313–316. doi: 10.1016/0165-6147(94)90019-1. [DOI] [PubMed] [Google Scholar]
  5. Eddahibi S., Raffestin B., Clozel M., Levame M., Adnot S. Protection from pulmonary hypertension with an orally active endothelin receptor antagonist in hypoxic rats. Am J Physiol. 1995 Feb;268(2 Pt 2):H828–H835. doi: 10.1152/ajpheart.1995.268.2.H828. [DOI] [PubMed] [Google Scholar]
  6. Eddahibi S., Springall D., Mannan M., Carville C., Chabrier P. E., Levame M., Raffestin B., Polak J., Adnot S. Dilator effect of endothelins in pulmonary circulation: changes associated with chronic hypoxia. Am J Physiol. 1993 Dec;265(6 Pt 1):L571–L580. doi: 10.1152/ajplung.1993.265.6.L571. [DOI] [PubMed] [Google Scholar]
  7. Eguchi S., Hirata Y., Imai T., Marumo F. Endothelin receptor subtypes are coupled to adenylate cyclase via different guanyl nucleotide-binding proteins in vasculature. Endocrinology. 1993 Feb;132(2):524–529. doi: 10.1210/endo.132.2.7678793. [DOI] [PubMed] [Google Scholar]
  8. Ekelund U., Adner M., Edvinsson L., Mellander S. Effects of selective ETB-receptor stimulation on arterial, venous and capillary functions in cat skeletal muscle. Br J Pharmacol. 1994 Jul;112(3):887–894. doi: 10.1111/j.1476-5381.1994.tb13163.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ercan Z. S., Kilinç M., Yazar O., Korkusuz P., Türker R. K. Endothelin-1-induced oedema in rat and guinea-pig isolated perfused lungs. Arch Int Pharmacodyn Ther. 1993 May-Jun;323:74–84. [PubMed] [Google Scholar]
  10. Filep J. G., Battistini B., Sirois P. Induction by endothelin-1 of epithelium-dependent relaxation of guinea-pig trachea in vitro: role for nitric oxide. Br J Pharmacol. 1993 Jul;109(3):637–644. doi: 10.1111/j.1476-5381.1993.tb13620.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Frew J. D., Paisley K., Martin W. Selective inhibition of basal but not agonist-stimulated activity of nitric oxide in rat aorta by NG-monomethyl-L-arginine. Br J Pharmacol. 1993 Nov;110(3):1003–1008. doi: 10.1111/j.1476-5381.1993.tb13913.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gao Y., Zhou H., Raj J. U. Endothelium-derived nitric oxide plays a larger role in pulmonary veins than in arteries of newborn lambs. Circ Res. 1995 Apr;76(4):559–565. doi: 10.1161/01.res.76.4.559. [DOI] [PubMed] [Google Scholar]
  13. Kitazono T., Heistad D. D., Faraci F. M. Dilatation of the basilar artery in response to selective activation of endothelin B receptors in vivo. J Pharmacol Exp Ther. 1995 Apr;273(1):1–6. [PubMed] [Google Scholar]
  14. Lal H., Woodward B., Williams K. I. Actions of endothelins and sarafotoxin 6c in the rat isolated perfused lung. Br J Pharmacol. 1995 Jun;115(4):653–659. doi: 10.1111/j.1476-5381.1995.tb14982.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lal H., Woodward B., Williams K. I. Differential effects of agents on bronchial and vascular tone and lung weight in the rat isolated perfused lung. Pulm Pharmacol. 1994 Aug;7(4):271–278. doi: 10.1006/pulp.1994.1031. [DOI] [PubMed] [Google Scholar]
  16. Le Monnier de Gouville A. C., Cavero I. Cross tachyphylaxis to endothelin isopeptide-induced hypotension: a phenomenon not seen with proendothelin. Br J Pharmacol. 1991 Sep;104(1):77–84. doi: 10.1111/j.1476-5381.1991.tb12388.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Le Monnier de Gouville A. C., Lippton H., Cohen G., Cavero I., Hyman A. Vasodilator activity of endothelin-1 and endothelin-3: rapid development of cross-tachyphylaxis and dependence on the rate of endothelin administration. J Pharmacol Exp Ther. 1990 Sep;254(3):1024–1028. [PubMed] [Google Scholar]
  18. Lippton H. L., Hauth T. A., Cohen G. A., Hyman A. L. Functional evidence for different endothelin receptors in the lung. J Appl Physiol (1985) 1993 Jul;75(1):38–48. doi: 10.1152/jappl.1993.75.1.38. [DOI] [PubMed] [Google Scholar]
  19. MacLean M. R., McCulloch K. M., Baird M. Endothelin ETA- and ETB-receptor-mediated vasoconstriction in rat pulmonary arteries and arterioles. J Cardiovasc Pharmacol. 1994 May;23(5):838–845. doi: 10.1097/00005344-199405000-00022. [DOI] [PubMed] [Google Scholar]
  20. Moore P. K., al-Swayeh O. A., Chong N. W., Evans R. A., Gibson A. L-NG-nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilatation in vitro. Br J Pharmacol. 1990 Feb;99(2):408–412. doi: 10.1111/j.1476-5381.1990.tb14717.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Namiki A., Hirata Y., Ishikawa M., Moroi M., Aikawa J., Machii K. Endothelin-1- and endothelin-3-induced vasorelaxation via common generation of endothelium-derived nitric oxide. Life Sci. 1992;50(10):677–682. doi: 10.1016/0024-3205(92)90470-a. [DOI] [PubMed] [Google Scholar]
  23. Pinheiro J. M., Malik A. B. Mechanisms of endothelin-1-induced pulmonary vasodilatation in neonatal pigs. J Physiol. 1993 Sep;469:739–752. doi: 10.1113/jphysiol.1993.sp019840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rodman D. M., Stelzner T. J., Zamora M. R., Bonvallet S. T., Oka M., Sato K., O'Brien R. F., McMurtry I. F. Endothelin-1 increases the pulmonary microvascular pressure and causes pulmonary edema in salt solution but not blood-perfused rat lungs. J Cardiovasc Pharmacol. 1992 Oct;20(4):658–663. doi: 10.1097/00005344-199210000-00021. [DOI] [PubMed] [Google Scholar]
  25. Sokolovsky M., Ambar I., Galron R. A novel subtype of endothelin receptors. J Biol Chem. 1992 Oct 15;267(29):20551–20554. [PubMed] [Google Scholar]
  26. Stewart D. J., Levy R. D., Cernacek P., Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med. 1991 Mar 15;114(6):464–469. doi: 10.7326/0003-4819-114-6-464. [DOI] [PubMed] [Google Scholar]
  27. Warner T. D., Mitchell J. A., de Nucci G., Vane J. R. Endothelin-1 and endothelin-3 release EDRF from isolated perfused arterial vessels of the rat and rabbit. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S85–S102. doi: 10.1097/00005344-198900135-00021. [DOI] [PubMed] [Google Scholar]
  28. Williams D. L., Jr, Jones K. L., Pettibone D. J., Lis E. V., Clineschmidt B. V. Sarafotoxin S6c: an agonist which distinguishes between endothelin receptor subtypes. Biochem Biophys Res Commun. 1991 Mar 15;175(2):556–561. doi: 10.1016/0006-291x(91)91601-8. [DOI] [PubMed] [Google Scholar]
  29. Xue C., Rengasamy A., Le Cras T. D., Koberna P. A., Dailey G. C., Johns R. A. Distribution of NOS in normoxic vs. hypoxic rat lung: upregulation of NOS by chronic hypoxia. Am J Physiol. 1994 Dec;267(6 Pt 1):L667–L678. doi: 10.1152/ajplung.1994.267.6.L667. [DOI] [PubMed] [Google Scholar]
  30. Zellers T. M., McCormick J., Wu Y. Interaction among ET-1, endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins. Am J Physiol. 1994 Jul;267(1 Pt 2):H139–H147. doi: 10.1152/ajpheart.1994.267.1.H139. [DOI] [PubMed] [Google Scholar]
  31. 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]

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

RESOURCES