Role of PGE(2) in protease-activated receptor-1, -2 and -4 mediated relaxation in the mouse isolated trachea

Br J Pharmacol. 2001 Jan;132(1):93-100. doi: 10.1038/sj.bjp.0703776.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans Proteins*
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Dinoprostone / physiology*
  • Enzyme Activation
  • In Vitro Techniques
  • Indomethacin / pharmacology
  • Isoenzymes / metabolism
  • Ligands
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred CBA
  • Muscle Relaxation / drug effects
  • Muscle Relaxation / physiology
  • Muscle Tonus / drug effects
  • Muscle Tonus / physiology
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology*
  • Prostaglandin Antagonists / pharmacology
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Receptor, PAR-2
  • Receptors, Thrombin / metabolism
  • Receptors, Thrombin / physiology*
  • Thrombin / pharmacology
  • Trachea / drug effects
  • Trachea / physiology*
  • Trypsin / pharmacology
  • Xanthenes / pharmacology
  • Xanthones*

Substances

  • Caenorhabditis elegans Proteins
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Ligands
  • Membrane Proteins
  • Prostaglandin Antagonists
  • Receptor, PAR-2
  • Receptors, Thrombin
  • Xanthenes
  • Xanthones
  • protease-activated receptor 3
  • 6-isopropoxy-9-oxoxanthene-2-carboxylic acid
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Trypsin
  • Thrombin
  • protease-activated receptor 4
  • Dinoprostone
  • Indomethacin