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

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. Intraperitoneal administration of the PAR‐2‐activating peptide SLIGRL‐NH 2 , but not the inactive control LSIGRL‐NH 2 , at 1–5 μmol kg −1 , in combination with the aminopeptidase inhibitor amastatin at 2.5 μmol 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 μmol kg −1 , in combination with amastatin, also promoted gastrointestinal transit. The Ca 2+ ‐activated, small conductance K + channel inhibitor apamin at 0.01 μmol kg −1 significantly potentiated the actions of SLIGRL‐NH 2 and TFLLR‐NH 2 at subeffective doses. The increased gastrointestinal transit exerted by either SLIGRL‐NH 2 at 5 μmol kg −1 or TFLLR‐NH 2 at 10 μmol kg −1 was completely abolished by the L‐type Ca 2+ channel inhibitor verapamil at 61.6 μmol kg −1 . In contrast, the tyrosine kinase inhibitor genistein at 18.5 μmol kg −1 failed to modify the effects of the agonists for PAR‐2 or PAR‐1. 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 Ca 2+ 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.British Journal of Pharmacology (2001) 133 , 1213–1218; doi: 10.1038/sj.bjp.0704211