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

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-NH2, but not the inactive control LSIGRL-NH2, at 1-5 mu mol kg(-1), in combination with the aminopeptidase inhibitor amastatin at 2.5 mu mol kg(-1), facilitated gastrointestinal transit in a dose-dependent manner. The human PAR-1-derived peptide SFLLR-NH2 and the specific PAR-1 agonist TFLLR-NH2, but not the inactive control FSLLR-NH2, at 2.5 - 10 pmol kg(-1), in combination with amastatin, also promoted gastrointestinal transit. 3 The Ca2+-activated, small conductance K+ channel inhibitor apamin at 0.01 mu mol kg(-1) significantly potentiated the actions of SLIGRL-NH2 and TFLLR-NH2 at subeffective doses. 4 The increased gastrointestinal transit exerted by either SLIGRL-NH2 at 5 mu mol kg(-1) or TFLLR-NH2 at 10 mu mol kg(-1) was completely abolished by the L-type Ca2+ channel inhibitor verapamil at 61.6 mu mol kg(-1). In contrast. the tyrosine kinase inhibitor genistein at 18.5 mu mol kg(-1) failed to modify the effects of the agonists for PAR-2 or PAR-1. 5 These findings demonstrate that PAR-I 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.