In vivo evidence that protease-activated receptors 1 and 2 modulate gastrointestinal transit in the mouse

Br J Pharmacol. 2001 Aug;133(8):1213-8. doi: 10.1038/sj.bjp.0704211.


1. Protease-activated receptors (PARs) 1 and 2 modulate the gastric and intestinal smooth muscle motility in vitro. In the present study, we examined if activation of PAR-2 and PAR-1 could alter gastrointestinal transit in mice. 2. Intraperitoneal administration of the PAR-2-activating peptide SLIGRL-NH(2), but not the inactive control LSIGRL-NH(2), at 1 - 5 micromol kg(-1), in combination with the aminopeptidase inhibitor amastatin at 2.5 micromol kg(-1), facilitated gastrointestinal transit in a dose-dependent manner. The human PAR-1-derived peptide SFLLR-NH(2) and the specific PAR-1 agonist TFLLR-NH(2), but not the inactive control FSLLR-NH(2), at 2.5 - 10 micromol kg(-1), in combination with amastatin, also promoted gastrointestinal transit. 3. The Ca2+-activated, small conductance K+ channel inhibitor apamin at 0.01 micromol kg(-1) significantly potentiated the actions of SLIGRL-NH(2) and TFLLR-NH(2) at subeffective doses. 4. The increased gastrointestinal transit exerted by either SLIGRL-NH(2) at 5 micromol kg(-1) or TFLLR-NH(2) at 10 micromol kg(-1) was completely abolished by the L-type Ca2+ channel inhibitor verapamil at 61.6 micromol kg(-1). In contrast, the tyrosine kinase inhibitor genistein at 18.5 micromol kg(-1) failed to modify the effects of the agonists for PAR-2 or PAR-1. 5. These findings demonstrate that PAR-1 and PAR-2 modulate gastrointestinal transit in mice in vivo. Our data also suggest that the PAR-1-and PAR-2-mediated effects are modulated by apamin-sensitive K+ channels and are dependent on activation of L-type Ca2+ channels, but independent of tyrosine kinase. Our study thus provides novel evidence for the physiological and/or pathophysiological roles of PARs 1 and 2 in the digestive systems, most probably during inflammation.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Apamin / pharmacology
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / metabolism
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Gastrointestinal Motility* / drug effects
  • Genistein / pharmacology
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Mice
  • Oligopeptides / pharmacology
  • Peptides*
  • Potassium Channel Blockers
  • Potassium Channels / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Receptors, Thrombin / agonists
  • Receptors, Thrombin / metabolism*
  • Verapamil / pharmacology


  • Anti-Bacterial Agents
  • C186 65
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Oligopeptides
  • Peptides
  • Potassium Channel Blockers
  • Potassium Channels
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Receptors, Thrombin
  • seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide
  • Apamin
  • amastatin
  • Verapamil
  • Genistein
  • Protein-Tyrosine Kinases