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. 1996 Jul;118(6):1397–1402. doi: 10.1111/j.1476-5381.1996.tb15551.x

The induction of a biphasic bronchospasm by the ETB agonist, IRL 1620, due to thromboxane A2 generation and endothelin-1 release in guinea-pigs.

S Noguchi 1, Y Kashihara 1, C Bertrand 1
PMCID: PMC1909659  PMID: 8832063

Abstract

1. IRL 1620 (0.01-0.1 mg kg-1, i.v.), a selective endothelin B (ETB) receptor agonist, induced a dose-dependent biphasic increase in total lung resistance and a decrease in dynamic compliance in anaesthetized and artificially ventilated guinea-pigs. After intravenous injection of IRL 1620 (0.03 mg kg-1), the first phase was observed within 2 min whereas the second phase started between 5 and 10 min after injection and was long lasting. 2. In order to characterize which endothelin receptors are involved in both phases of bronchoconstriction, we studied the effect of ETA and ETB receptor antagonists (BQ 123 and BQ 788, respectively). BQ 788 (0.1-1 mg kg-1, i.v.) inhibited, in a dose-dependent manner, both phases of bronchoconstriction. BQ 123 (3 mg kg-1, i.v.) markedly inhibited (by 76%) the second phase of bronchoconstriction but had no effect on the early component of the response. 3. The effect of atropine, neurokinin-I (NK1) and neurokinin-2 (NK2) receptor antagonists (SR140333 and SR48968, respectively) were tested to investigate the possible involvement of cholinergic and sensory nerve activation, respectively, in the response to IRL 1620. Likewise, the role of arachidonic acid metabolites (leukotriene D4 antagonist, ONO-1078 and thromboxane A2 (TXA2) inhibitor, OKY-046) in this response was also investigated. OKY-046 (1 mg kg-1, i.v.) and atropine (1 mg kg-1, i.v.) partially inhibited the first phase (by 80% and 20%, respectively) without affecting the late phase of bronchoconstriction. Neither ONO-1078 (1 mg kg-1, i.v.) nor the combination of SR140333 (0.2 mg kg-1, i.v.) and SR 48968 (0.2 mg kg-1, i.v.) modified IRL 1620-induced bronchoconstriction. 4. A low dose of IRL 1620 (0.005 mg kg-1, i.v.) induced a monophasic bronchoconstriction. Pretreatment by phosphoramidon (100 mumol kg-1, i.v.) restored the second phase of bronchoconstriction. In this condition, BQ 123 (3 mg kg-1, i.v.) was able to inhibit partially the second phase of bronchoconstriction. 5. These results suggest that both phases of bronchoconstriction induced by IRL 1620 were mediated primarily by ETB receptor activation, the first phase being a consequence of TXA2 and acetylcholine release. The inhibition by an ETA receptor antagonist and the restoration by a neutral endopeptidase (NEP) inhibitor of the second phase of bronchoconstriction suggests that primary activation of ETB receptors leads to autocrine/paracrine endothelin-1 (ET-1) release that would subsequently cause profound bronchoconstriction through both ETA and ETB receptor activation.

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Selected References

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  1. Advenier C., Sarria B., Naline E., Puybasset L., Lagente V. Contractile activity of three endothelins (ET-1, ET-2 and ET-3) on the human isolated bronchus. Br J Pharmacol. 1990 May;100(1):168–172. doi: 10.1111/j.1476-5381.1990.tb12071.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Bird J. E., Waldron T. L. Endogenous synthesis of endothelin-1 may mediate a delayed pressor response after injection of endothelin-1 in rats. J Cardiovasc Pharmacol. 1995 Feb;25(2):307–313. doi: 10.1097/00005344-199502000-00017. [DOI] [PubMed] [Google Scholar]
  4. D'Orléans-Juste P., Claing A., Télémaque S., Maurice M. C., Yano M., Gratton J. P. Block of endothelin-1-induced release of thromboxane A2 from the guinea pig lung and nitric oxide from the rabbit kidney by a selective ETB receptor antagonist, BQ-788. Br J Pharmacol. 1994 Dec;113(4):1257–1262. doi: 10.1111/j.1476-5381.1994.tb17133.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ehrenreich H., Anderson R. W., Fox C. H., Rieckmann P., Hoffman G. S., Travis W. D., Coligan J. E., Kehrl J. H., Fauci A. S. Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med. 1990 Dec 1;172(6):1741–1748. doi: 10.1084/jem.172.6.1741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hay D. W., Hubbard W. C., Undem B. J. Relative contributions of direct and indirect mechanisms mediating endothelin-induced contraction of guinea-pig trachea. Br J Pharmacol. 1993 Nov;110(3):955–962. doi: 10.1111/j.1476-5381.1993.tb13906.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Henry P. J., Goldie R. G. Potentiation by endothelin-1 of cholinergic nerve-mediated contractions in mouse trachea via activation of ETB receptors. Br J Pharmacol. 1995 Feb;114(3):563–569. doi: 10.1111/j.1476-5381.1995.tb17176.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Henry P. J., Rigby P. J., Self G. J., Preuss J. M., Goldie R. G. Relationship between endothelin-1 binding site densities and constrictor activities in human and animal airway smooth muscle. Br J Pharmacol. 1990 Aug;100(4):786–792. doi: 10.1111/j.1476-5381.1990.tb14093.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Inui T., James A. F., Fujitani Y., Takimoto M., Okada T., Yamamura T., Urade Y. ETA and ETB receptors on single smooth muscle cells cooperate in mediating guinea pig tracheal contraction. Am J Physiol. 1994 Feb;266(2 Pt 1):L113–L124. doi: 10.1152/ajplung.1994.266.2.L113. [DOI] [PubMed] [Google Scholar]
  12. Jacoby D. B., Tamaoki J., Borson D. B., Nadel J. A. Influenza infection causes airway hyperresponsiveness by decreasing enkephalinase. J Appl Physiol (1985) 1988 Jun;64(6):2653–2658. doi: 10.1152/jappl.1988.64.6.2653. [DOI] [PubMed] [Google Scholar]
  13. Knott P. G., D'Aprile A. C., Henry P. J., Hay D. W., Goldie R. G. Receptors for endothelin-1 in asthmatic human peripheral lung. Br J Pharmacol. 1995 Jan;114(1):1–3. doi: 10.1111/j.1476-5381.1995.tb14895.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Nagase T., Fukuchi Y., Matsui H., Aoki T., Matsuse T., Orimo H. In vivo effects of endothelin A- and B-receptor antagonists in guinea pigs. Am J Physiol. 1995 May;268(5 Pt 1):L846–L850. doi: 10.1152/ajplung.1995.268.5.L846. [DOI] [PubMed] [Google Scholar]
  17. Ninomiya H., Yu X. Y., Hasegawa S., Spannhake E. W. Endothelin-1 induces stimulation of prostaglandin synthesis in cells obtained from canine airways by bronchoalveolar lavage. Prostaglandins. 1992 May;43(5):401–411. doi: 10.1016/0090-6980(92)90124-c. [DOI] [PubMed] [Google Scholar]
  18. Noguchi K., Noguchi Y., Hirose H., Nishikibe M., Ihara M., Ishikawa K., Yano M. Role of endothelin ETB receptors in bronchoconstrictor and vasoconstrictor responses in guinea-pigs. Eur J Pharmacol. 1993 Mar 16;233(1):47–51. doi: 10.1016/0014-2999(93)90347-k. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Ogawa Y., Nakao K., Arai H., Nakagawa O., Hosoda K., Suga S., Nakanishi S., Imura H. Molecular cloning of a non-isopeptide-selective human endothelin receptor. Biochem Biophys Res Commun. 1991 Jul 15;178(1):248–255. doi: 10.1016/0006-291x(91)91806-n. [DOI] [PubMed] [Google Scholar]
  21. Piedimonte G., Nadel J. A., Umeno E., McDonald D. M. Sendai virus infection potentiates neurogenic inflammation in the rat trachea. J Appl Physiol (1985) 1990 Feb;68(2):754–760. doi: 10.1152/jappl.1990.68.2.754. [DOI] [PubMed] [Google Scholar]
  22. Pons F., Loquet I., Touvay C., Roubert P., Chabrier P. E., Mencia-Huerta J. M., Braquet P. Comparison of the bronchopulmonary and pressor activities of endothelin isoforms ET-1, ET-2, and ET-3 and characterization of their binding sites in guinea pig lung. Am Rev Respir Dis. 1991 Feb;143(2):294–300. doi: 10.1164/ajrccm/143.2.294. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Rae G. A., Calixto J. B., D'Orléans-Juste P. Effects and mechanisms of action of endothelins on non-vascular smooth muscle of the respiratory, gastrointestinal and urogenital tracts. Regul Pept. 1995 Jan 5;55(1):1–46. doi: 10.1016/0167-0115(94)00098-i. [DOI] [PubMed] [Google Scholar]
  25. Redington A. E., Springall D. R., Ghatei M. A., Lau L. C., Bloom S. R., Holgate S. T., Polak J. M., Howarth P. H. Endothelin in bronchoalveolar lavage fluid and its relation to airflow obstruction in asthma. Am J Respir Crit Care Med. 1995 Apr;151(4):1034–1039. doi: 10.1164/ajrccm.151.4.7697227. [DOI] [PubMed] [Google Scholar]
  26. Rubanyi G. M., Polokoff M. A. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev. 1994 Sep;46(3):325–415. [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. 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]
  30. Takimoto M., Inui T., Okada T., Urade Y. Contraction of smooth muscle by activation of endothelin receptors on autonomic neurons. FEBS Lett. 1993 Jun 21;324(3):277–282. doi: 10.1016/0014-5793(93)80134-g. [DOI] [PubMed] [Google Scholar]
  31. Tschirhart E. J., Drijfhout J. W., Pelton J. T., Miller R. C., Jones C. R. Endothelins: functional and autoradiographic studies in guinea pig trachea. J Pharmacol Exp Ther. 1991 Jul 1;258(1):381–387. [PubMed] [Google Scholar]
  32. Vijayaraghavan J., Scicli A. G., Carretero O. A., Slaughter C., Moomaw C., Hersh L. B. The hydrolysis of endothelins by neutral endopeptidase 24.11 (enkephalinase). J Biol Chem. 1990 Aug 25;265(24):14150–14155. [PubMed] [Google Scholar]
  33. 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]

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