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. 1995 May;115(2):227–236. doi: 10.1111/j.1476-5381.1995.tb15868.x

Acute pro-inflammatory actions of endothelin-1 in the guinea-pig lung: involvement of ETA and ETB receptors.

J G Filep 1, A Fournier 1, E Földes-Filep 1
PMCID: PMC1908312  PMID: 7670725

Abstract

1. Although recent observations suggest that endothelin-1 (ET-1) may play a role in the pathogenesis of asthma, to date little is known about the effects of ET-1 on parameters other than bronchoconstriction. The objectives of the present experiments were to study whether intravenously administered ET-1 could exert pro-inflammatory actions in the guinea-pig lung and to assess the involvement of endothelin ETA and ETB receptors in these events by using the ETA receptor-selective antagonist, FR 139317, the novel ETA/ETB receptor antagonist, bosentan and the ETB receptor-selective agonist, IRL 1620. 2. Bolus i.v. injection of ET-1 (0.1-1 nmol kg-1) to anaesthetized guinea-pigs evoked dose-dependent increases in mean arterial blood pressure which lasted for 6-12 min. This was accompanied by a dose-dependent haemoconcentration (8-15% plasma volume losses) and increases (up to 546%) in albumin extravasation in the trachea, upper and lower bronchi, but not in the pulmonary parenchyma. Qualitatively similar changes were observed following i.v. injection of the ETB receptor agonist, IRL 1620 (0.3 and 1 nmol kg-1), although IRL 1620 appeared to be about 3 times less potent than ET-1. The ETA receptor-selective antagonist, FR 139317 (2.5 mg kg-1) inhibited the ET-1 (1 nmol kg-1)-induced pressor response, haemoconcentration and albumin extravasation by 75, 77 and 60-70%, respectively, whereas it did not attenuate IRL 1620 (1 nmol kg-1)-induced changes. The ETA/ETB receptor antagonist, bosentan (10 mg kg-1) almost completely inhibited the pressor, haemoconcentration and permeability effects of both ET-1 and IRL 1620. 3. ET-1, but not IRL 1620 (0.1-1 nmol kg-1), produced a dose-dependent neutropenia with relative lymphocytosis and monocytosis, but did not induce influx of neutrophil granulocytes into pulmonary tissues or the bronchoalveolar space. ET-1 (1 nmol kg-1)-induced neutropenia was prevented by pretreatment of the animals with FR 139317 (2.5 mg kg-1), bosentan (10 mg kg-1) or adrenaline (90 nmol kg-1), indicating that ET-1 caused intravascular sequestration of neutrophil granulocytes. 4. ET-1 or IRL 1620 (10(-10)-10(-6) M) alone did not activate alveolar macrophages in vitro, whereas at a concentration of 10(-8) M, ET-1, but not IRL 1620, markedly potentiated superoxide production in response to f-Met-Leu-Phe (10(-9)-10(-7) M) and platelet-activating factor (PAF, 10(-9)-10(-7) M), but not to phorbol 12-myristate 13-acetate (10(-9) M).(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

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  1. ATHENS J. W., HAAB O. P., RAAB S. O., MAUER A. M., ASHENBRUCKER H., CARTWRIGHT G. E., WINTROBE M. M. Leukokinetic studies. IV. The total blood, circulating and marginal granulocyte pools and the granulocyte turnover rate in normal subjects. J Clin Invest. 1961 Jun;40:989–995. doi: 10.1172/JCI104338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Abraham W. M., Ahmed A., Cortes A., Spinella M. J., Malik A. B., Andersen T. T. A specific endothelin-1 antagonist blocks inhaled endothelin-1-induced bronchoconstriction in sheep. J Appl Physiol (1985) 1993 May;74(5):2537–2542. doi: 10.1152/jappl.1993.74.5.2537. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Aramori I., Nirei H., Shoubo M., Sogabe K., Nakamura K., Kojo H., Notsu Y., Ono T., Nakanishi S. Subtype selectivity of a novel endothelin antagonist, FR139317, for the two endothelin receptors in transfected Chinese hamster ovary cells. Mol Pharmacol. 1993 Feb;43(2):127–131. [PubMed] [Google Scholar]
  5. Boichot E., Carre C., Lagente V., Pons F., Mencia-Huerta J. M., Braquet P. Endothelin-1 and bronchial hyperresponsiveness in the guinea pig. J Cardiovasc Pharmacol. 1991;17 (Suppl 7):S329–S331. doi: 10.1097/00005344-199100177-00094. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Clozel M., Breu V., Gray G. A., Kalina B., Löffler B. M., Burri K., Cassal J. M., Hirth G., Müller M., Neidhart W. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther. 1994 Jul;270(1):228–235. [PubMed] [Google Scholar]
  8. Ehrhart I. C., Hofman W. F. Pressure-dependent increase in lung vascular permeability to water but not protein. J Appl Physiol (1985) 1992 Jan;72(1):211–218. doi: 10.1152/jappl.1992.72.1.211. [DOI] [PubMed] [Google Scholar]
  9. Filep J. G. Endothelin peptides: biological actions and pathophysiological significance in the lung. Life Sci. 1993;52(2):119–133. doi: 10.1016/0024-3205(93)90131-l. [DOI] [PubMed] [Google Scholar]
  10. Filep J. G., Fournier A., Földes-Filep E. Endothelin-1-induced myocardial ischaemia and oedema in the rat: involvement of the ETA receptor, platelet-activating factor and thromboxane A2. Br J Pharmacol. 1994 Jul;112(3):963–971. doi: 10.1111/j.1476-5381.1994.tb13175.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Filep J. G., Földes-Filep E., Rousseau A., Fournier A., Sirois P., Yano M. Endothelin-1 enhances vascular permeability in the rat heart through the ETA receptor. Eur J Pharmacol. 1992 Aug 25;219(2):343–344. doi: 10.1016/0014-2999(92)90318-x. [DOI] [PubMed] [Google Scholar]
  12. Filep J. G., Sirois M. G., Rousseau A., Fournier A., Sirois P. Effects of endothelin-1 on vascular permeability in the conscious rat: interactions with platelet-activating factor. Br J Pharmacol. 1991 Dec;104(4):797–804. doi: 10.1111/j.1476-5381.1991.tb12509.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Földes-Filep E., Filep J. G., Sirois P. C-reactive protein inhibits intracellular calcium mobilization and superoxide production by guinea pig alveolar macrophages. J Leukoc Biol. 1992 Jan;51(1):13–18. doi: 10.1002/jlb.51.1.13. [DOI] [PubMed] [Google Scholar]
  14. Gamble J. R., Harlan J. M., Klebanoff S. J., Vadas M. A. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8667–8671. doi: 10.1073/pnas.82.24.8667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Grega G. J., Adamski S. W., Dobbins D. E. Physiological and pharmacological evidence for the regulation of permeability. Fed Proc. 1986 Feb;45(2):96–100. [PubMed] [Google Scholar]
  16. Haller H., Schaberg T., Lindschau C., Lode H., Distler A. Endothelin increases [Ca2+]i, protein phosphorylation, and O2-. production in human alveolar macrophages. Am J Physiol. 1991 Dec;261(6 Pt 1):L478–L484. doi: 10.1152/ajplung.1991.261.6.L478. [DOI] [PubMed] [Google Scholar]
  17. Hay D. W., Henry P. J., Goldie R. G. Endothelin and the respiratory system. Trends Pharmacol Sci. 1993 Jan;14(1):29–32. doi: 10.1016/0165-6147(93)90111-v. [DOI] [PubMed] [Google Scholar]
  18. Hay D. W., Luttmann M. A., Hubbard W. C., Undem B. J. Endothelin receptor subtypes in human and guinea-pig pulmonary tissues. Br J Pharmacol. 1993 Nov;110(3):1175–1183. doi: 10.1111/j.1476-5381.1993.tb13938.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Henry P. J. Endothelin-1 (ET-1)-induced contraction in rat isolated trachea: involvement of ETA and ETB receptors and multiple signal transduction systems. Br J Pharmacol. 1993 Sep;110(1):435–441. doi: 10.1111/j.1476-5381.1993.tb13829.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hogg J. C. Neutrophil kinetics and lung injury. Physiol Rev. 1987 Oct;67(4):1249–1295. doi: 10.1152/physrev.1987.67.4.1249. [DOI] [PubMed] [Google Scholar]
  21. Holgate S. T., Wilson J. R., Howarth P. H. New insights into airway inflammation by endobronchial biopsy. Am Rev Respir Dis. 1992 Feb;145(2 Pt 2):S2–S6. doi: 10.1164/ajrccm/145.2_Pt_2.S2. [DOI] [PubMed] [Google Scholar]
  22. Hosoda K., Nakao K., Hiroshi-Arai, Suga S., Ogawa Y., Mukoyama M., Shirakami G., Saito Y., Nakanishi S., Imura H. Cloning and expression of human endothelin-1 receptor cDNA. FEBS Lett. 1991 Aug 5;287(1-2):23–26. doi: 10.1016/0014-5793(91)80007-p. [DOI] [PubMed] [Google Scholar]
  23. Ihara M., Noguchi K., Saeki T., Fukuroda T., Tsuchida S., Kimura S., Fukami T., Ishikawa K., Nishikibe M., Yano M. Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci. 1992;50(4):247–255. doi: 10.1016/0024-3205(92)90331-i. [DOI] [PubMed] [Google Scholar]
  24. Ishida K., Takeshige K., Minakami S. Endothelin-1 enhances superoxide generation of human neutrophils stimulated by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine. Biochem Biophys Res Commun. 1990 Dec 14;173(2):496–500. doi: 10.1016/s0006-291x(05)80061-0. [DOI] [PubMed] [Google Scholar]
  25. Joyce R. A., Boggs D. R., Hasiba U., Srodes C. H. Marginal neutrophil pool size in normal subjects and neutropenic patients as measured by epinephrine infusion. J Lab Clin Med. 1976 Oct;88(4):614–620. [PubMed] [Google Scholar]
  26. Konishi F., Kondo T., Inagami T. Phospholipase D in cultured rat vascular smooth muscle cells and its activation by phorbol ester. Biochem Biophys Res Commun. 1991 Sep 16;179(2):1070–1076. doi: 10.1016/0006-291x(91)91928-6. [DOI] [PubMed] [Google Scholar]
  27. Krawisz J. E., Sharon P., Stenson W. F. Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models. Gastroenterology. 1984 Dec;87(6):1344–1350. [PubMed] [Google Scholar]
  28. Laitinen L. A., Laitinen A., Haahtela T. Airway mucosal inflammation even in patients with newly diagnosed asthma. Am Rev Respir Dis. 1993 Mar;147(3):697–704. doi: 10.1164/ajrccm/147.3.697. [DOI] [PubMed] [Google Scholar]
  29. Lee T. H., Lane S. J. The role of macrophages in the mechanisms of airway inflammation in asthma. Am Rev Respir Dis. 1992 Feb;145(2 Pt 2):S27–S30. doi: 10.1164/ajrccm/145.2_Pt_2.S27. [DOI] [PubMed] [Google Scholar]
  30. Macquin-Mavier I., Levame M., Istin N., Harf A. Mechanisms of endothelin-mediated bronchoconstriction in the guinea pig. J Pharmacol Exp Ther. 1989 Aug;250(2):740–745. [PubMed] [Google Scholar]
  31. Mattoli S., Mezzetti M., Riva G., Allegra L., Fasoli A. Specific binding of endothelin on human bronchial smooth muscle cells in culture and secretion of endothelin-like material from bronchial epithelial cells. Am J Respir Cell Mol Biol. 1990 Aug;3(2):145–151. doi: 10.1165/ajrcmb/3.2.145. [DOI] [PubMed] [Google Scholar]
  32. Mattoli S., Soloperto M., Marini M., Fasoli A. Levels of endothelin in the bronchoalveolar lavage fluid of patients with symptomatic asthma and reversible airflow obstruction. J Allergy Clin Immunol. 1991 Sep;88(3 Pt 1):376–384. doi: 10.1016/0091-6749(91)90100-3. [DOI] [PubMed] [Google Scholar]
  33. McFadden E. R., Jr Microvasculature and airway responses. Am Rev Respir Dis. 1992 Feb;145(2 Pt 2):S42–S43. doi: 10.1164/ajrccm/145.2_Pt_2.S42. [DOI] [PubMed] [Google Scholar]
  34. Mullane K. M., Kraemer R., Smith B. Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium. J Pharmacol Methods. 1985 Nov;14(3):157–167. doi: 10.1016/0160-5402(85)90029-4. [DOI] [PubMed] [Google Scholar]
  35. Nagase T., Fukuchi Y., Jo C., Teramoto S., Uejima Y., Ishida K., Shimizu T., Orimo H. Endothelin-1 stimulates arachidonate 15-lipoxygenase activity and oxygen radical formation in the rat distal lung. Biochem Biophys Res Commun. 1990 Apr 30;168(2):485–489. doi: 10.1016/0006-291x(90)92347-3. [DOI] [PubMed] [Google Scholar]
  36. Nomura A., Uchida Y., Kameyana M., Saotome M., Oki K., Hasegawa S. Endothelin and bronchial asthma. Lancet. 1989 Sep 23;2(8665):747–748. doi: 10.1016/s0140-6736(89)90814-3. [DOI] [PubMed] [Google Scholar]
  37. O'Flaherty J. T., Jacobson D. P., Redman J. F. Bidirectional effects of protein kinase C activators. Studies with human neutrophils and platelet-activating factor. J Biol Chem. 1989 Apr 25;264(12):6836–6843. [PubMed] [Google Scholar]
  38. Pons F., Touvay C., Lagente V., Mencia-Huerta J. M., Braquet P. Comparison of the effects of intra-arterial and aerosol administration of endothelin-1 (ET-1) in the guinea-pig isolated lung. Br J Pharmacol. 1991 Apr;102(4):791–796. doi: 10.1111/j.1476-5381.1991.tb12253.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rogers D. F., Boschetto P., Barnes P. J. Plasma exudation. Correlation between Evans blue dye and radiolabeled albumin in guinea pig airways in vivo. J Pharmacol Methods. 1989 Jul;21(4):309–315. doi: 10.1016/0160-5402(89)90068-5. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Shirakami G., Nakao K., Saito Y., Magaribuchi T., Jougasaki M., Mukoyama M., Arai H., Hosoda K., Suga S., Ogawa Y. Acute pulmonary alveolar hypoxia increases lung and plasma endothelin-1 levels in conscious rats. Life Sci. 1991;48(10):969–976. doi: 10.1016/0024-3205(91)90362-f. [DOI] [PubMed] [Google Scholar]
  42. Sogabe K., Nirei H., Shoubo M., Nomoto A., Ao S., Notsu Y., Ono T. Pharmacological profile of FR139317, a novel, potent endothelin ETA receptor antagonist. J Pharmacol Exp Ther. 1993 Mar;264(3):1040–1046. [PubMed] [Google Scholar]
  43. Springall D. R., Howarth P. H., Counihan H., Djukanovic R., Holgate S. T., Polak J. M. Endothelin immunoreactivity of airway epithelium in asthmatic patients. Lancet. 1991 Mar 23;337(8743):697–701. doi: 10.1016/0140-6736(91)90279-x. [DOI] [PubMed] [Google Scholar]
  44. Takai M., Umemura I., Yamasaki K., Watakabe T., Fujitani Y., Oda K., Urade Y., Inui T., Yamamura T., Okada T. A potent and specific agonist, Suc-[Glu9,Ala11,15]-endothelin-1(8-21), IRL 1620, for the ETB receptor. Biochem Biophys Res Commun. 1992 Apr 30;184(2):953–959. doi: 10.1016/0006-291x(92)90683-c. [DOI] [PubMed] [Google Scholar]
  45. Tsien R. Y., Pozzan T., Rink T. J. Calcium homeostasis in intact lymphocytes: cytoplasmic free calcium monitored with a new, intracellularly trapped fluorescent indicator. J Cell Biol. 1982 Aug;94(2):325–334. doi: 10.1083/jcb.94.2.325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Vittori E., Marini M., Fasoli A., De Franchis R., Mattoli S. Increased expression of endothelin in bronchial epithelial cells of asthmatic patients and effect of corticosteroids. Am Rev Respir Dis. 1992 Nov;146(5 Pt 1):1320–1325. doi: 10.1164/ajrccm/146.5_Pt_1.1320. [DOI] [PubMed] [Google Scholar]
  47. 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]
  48. Yang Z. H., Bühler F. R., Diederich D., Lüscher T. F. Different effects of endothelin-1 on cAMP- and cGMP-mediated vascular relaxation in human arteries and veins: comparison with norepinephrine. J Cardiovasc Pharmacol. 1989;13 (Suppl 5):S129–S142. doi: 10.1097/00005344-198900135-00032. [DOI] [PubMed] [Google Scholar]

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