Characterization of the endothelin receptor subtype mediating epithelium-derived relaxant nitric oxide release from guinea-pig trachea |
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Authors: | Costanza Emanueli Fabio Ricciardolo Luciana Vergnani Claude Bertrand Franco Ricci Nadia Manzoli Gert Folkerts Frans P Nijkamp Pierangelo Geppetti |
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Affiliation: | 1.Department of Experimental and Clinical Medicine, Pharmacology Section, University of Ferrara, Ferrara, Italy;2.Internal Medicine Section, University of Ferrara, Ferrara, Italy;3.Institute of Respiratory Diseases, University of Catania, Catania, Italy;4.Allergy and Inflammation Unit, Roche Bioscience, Palo Alto, California, U.S.A.;5.Department of Pharmacology, University of Utrecht, Utrecht, The Netherlands |
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Abstract: | - The endothelin (ET) receptor subtype that mediates niric oxide (NO)-dependent airway relaxation in tracheal tube preparations precontracted with carbachol and pretreated with indomethacin was investigated. The release of NO induced by ET from guinea-pig trachea using a recently developed porphyrinic microsensor was also measured.
- ET-1 (1 pM–100 nM) contracted tracheal tube preparations pretreated with the NO-synthase inhibitor, L-NMMA, and relaxed, in an epithelium-dependent manner, preparations pretreated with the inactive enantiomer D-NMMA. The effect of L-NMMA was reversed by L-Arg, but not by D-Arg.
- The selective ETB receptor agonists, IRL 1620 or sarafotoxin S6c, both (1 pM–100 nM) contracted tracheal tube preparations in a similar manner either after treatment with D-NMMA or with L-NMMA. In the presence of the ETA receptor antagonist, {"type":"entrez-nucleotide","attrs":{"text":"FR139317","term_id":"258103156","term_text":"FR139317"}}FR139317 (10 μM), ET-1 administration resulted in a contraction that was similar after either L-NMMA or D-NMMA. In the presence of the ETB receptor antagonist, BQ788 (1 μM), ET-1 relaxed and contracted tracheas pretreated with D-NMMA and L-NMMA, respectively.
- Exposure of tracheal segments to ET-1 (1–1000 nM) caused a concentration-dependent increase in NO release that was reduced by L-NMMA. IRL1620 (1 μM) did not cause any significant NO release. {"type":"entrez-nucleotide","attrs":{"text":"FR139317","term_id":"258103156","term_text":"FR139317"}}FR139317 (10 μM), but not, BQ788 (1 μM), inhibited the NO release induced by ET-1.
- These results demonstrate that in the isolated guinea-pig trachea activation of ETB receptors results in a contractile response, whereas activation of ETA receptors cause both a contraction, and an epithelium-dependent relaxation that is mediated by NO release.
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Keywords: | Endothelin ETA and ETB receptors nitric oxide trachea airway epithelium |
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