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

Authors


Department of Pathophysiology & Therapeutics, Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. E-mail: kawabata@phar.kindai.ac.jp

Abstract

  • 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-NH2, but not the inactive control LSIGRL-NH2, 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-NH2 and the specific PAR-1 agonist TFLLR-NH2, but not the inactive control FSLLR-NH2, at 2.5–10 μmol kg−1, in combination with amastatin, also promoted gastrointestinal transit.

  • The Ca2+-activated, small conductance K+ channel inhibitor apamin at 0.01 μmol kg−1 significantly potentiated the actions of SLIGRL-NH2 and TFLLR-NH2 at subeffective doses.

  • The increased gastrointestinal transit exerted by either SLIGRL-NH2 at 5 μmol kg−1 or TFLLR-NH2 at 10 μmol kg−1 was completely abolished by the L-type Ca2+ 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 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.

British Journal of Pharmacology (2001) 133, 1213–1218; doi:10.1038/sj.bjp.0704211

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