Role of PGE(2) in protease-activated receptor-1, -2 and -4 mediated relaxation in the mouse isolated trachea.
1. The potential mediator role of the prostanoid PGE(2) in airway smooth muscle relaxations induced by peptidic and proteolytic activators of PAR-1, PAR-2, PAR-3 and PAR-4 was investigated in carbachol-precontracted mouse isolated tracheal segments. 2. The tethered ligand domain sequences of murine PAR-1 (SFFLRN-NH(2)), PAR-2 (SLIGRL-NH(2)) and PAR-4 (GYPGKF-NH(2)), but not PAR-3 (SFNGGP-NH(2)), induced smooth muscle relaxation that was abolished by the non-selective cyclo-oxygenase (COX) inhibitor, indomethacin. The relative order for mean peak relaxation was SLIGRL-NH(2)>GYPGKF-NH(2) approximately amp; SFFLRN-NH(2)>SFNGGP-NH(2). 3. SFFLRN-NH(2), SLIGRL-NH(2) and GYPGKF-NH(2), but not SFNGGP-NH(2), induced significant PGE(2) release that was abolished by indomethacin. Like that for relaxation, the relative order for mean PGE(2) release was SLIGRL-NH(2)>GYPGKF-NH(2)>SFFLRN-NH(2)>SFNGGP-NH(2). 4. In dose-response studies, SLIGRL-NH(2) induced concentration-dependent increases in PGE(2) release (EC(50)=20.4 microM) and smooth muscle relaxation (EC(50)=15.8 microM). 5. The selective COX-2 inhibitor, nimesulide, but not the COX-1 inhibitor valeryl salicylate, significantly attenuated SLIGRL-NH(2)-induced smooth muscle relaxation and PGE(2) release. 6. Exogenously applied PGE(2) induced potent smooth muscle relaxation (EC(50)=60.3 nM) that was inhibited by the mixed DP/EP(1)/EP(2) prostanoid receptor antagonist, AH6809. SLIGRL-NH(2)-induced relaxation was also significantly inhibited by AH6809. 7. In summary, the results of this study strongly suggest that PAR-mediated relaxation in murine tracheal smooth muscle is dependent on the generation of the spasmolytic prostanoid, PGE(2). PAR-stimulated PGE(2) release appears to be generated preferentially by COX-2 rather than COX-1, and induces relaxation via activation of the EP(2) receptor.
Lan
R S
RS
Department of Pharmacology, The University of Western Australia, Nedlands, Western Australia, 6907 Australia.
Knight
D A
DA
Stewart
G A
GA
Henry
P J
PJ
D000818:Animals; D029742:Caenorhabditis elegans Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology*; D004789:Enzyme Activation; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008024:Ligands; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008808:Mice, Inbred CBA; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000378:metabolism / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000502:physiology*; D014357:Trypsin / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology; D044004:Xanthones
D029742:Caenorhabditis elegans Proteins; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008024:Ligands; D008565:Membrane Proteins; D011448:Prostaglandin Antagonists; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D014966:Xanthenes; D044004:Xanthones; C105295:protease-activated receptor 3; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D014357:Trypsin; D013917:Thrombin; C112908:protease-activated receptor 4; D015232:Dinoprostone; D007213:Indomethacin