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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Inhibitors of Prostaglandin Transport and Metabolism Augment Protease-Activated Receptor-2-Mediated Increases in Prostaglandin E₂ Levels and Smooth Muscle Relaxation in Mouse Isolated Trachea

School of Medicine and Pharmacology (P.J.H., A.D., G.S., T.H., T.S.M.) and Centre for Medical Research (P.J.H.), University of Western Australia, Nedlands, Western Australia, Australia

Stimulants of protease-activated receptor-2 (PAR₂), such as Ser-Leu-Ile-Gly-Arg-Leu-NH₂ (SLIGRL), cause airway smooth muscle relaxation via the release of the bronchodilatory prostanoid prostaglandin E₂ (PGE₂). The principal aim of the current study was to determine whether compounds that inhibit PGE₂ reuptake by the prostaglandin transporter [bromocresol green and U46619 (9,11-dideoxy-9,11-methanoepoxy PGF2) and PGE₂ metabolism by 15-hydroxyprostaglandin dehydrogenase (thiazolidenedione compounds rosiglitazone and ciglitazone) significantly enhanced the capacity of SLIGRL to elevate PGE₂ levels and produce relaxation in isolated segments of upper and lower mouse trachea. SLIGRL produced concentration-dependent increases in PGE₂ levels and smooth muscle relaxation, although both effects were significantly greater in lower tracheal segments than in upper tracheal segments. SLIGRL-induced increases in PGE₂ levels were significantly enhanced in the presence of ciglitazone and rosiglitazone, and these effects were not inhibited by GW9662 (2-chloro-5-nitrobenzanilide), a peroxisome proliferator-activated receptor- antagonist. SLI-GRL-induced relaxation responses were also significantly enhanced by ciglitazone and rosiglitazone, whereas responses to isoprenaline, a PGE₂-independent smooth muscle relaxant, were unaltered. Ciglitazone and rosiglitazone alone produced concentration-dependent increases in PGE₂ levels and smooth muscle relaxation, and these responses were inhibited by indomethacin, a cyclooxygenase inhibitor. Bromocresol green, an inhibitor of prostaglandin transport, significantly enhanced SLIGRL-induced increases in PGE₂ levels and relaxation. Immunohistochemical staining for 15-hydroxyprostaglandin dehydrogenase was relatively intense over airway smooth muscle, as was staining for the prostaglandin transporter over both airway smooth muscle and epithelium. In summary, inhibitors of PGE₂ reuptake and metabolism significantly potentiate PAR₂-mediated increases in PGE₂ levels and smooth muscle relaxation in murine-isolated airways.

Address correspondence to: Dr. Peter J. Henry, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia. E-mail: phenry{at}receptor.pharm.uwa.edu.au

This article has been cited by other articles:

				S. M. Saleh, T. S. Mann, T. Peters, R. J. Betts, and P. J. Henry Influence of Dexamethasone on Protease-Activated Receptor 2-Mediated Responses in the Airways J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 622 - 630. [Abstract] [Full Text] [PDF]