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

• Published in: British journal of pharmacology 2001-08, Vol.133 (8), p.1213-1218
• Main Authors: Kawabata, Atsufumi, Kuroda, Ryotaro, Nagata, Nanae, Kawao, Naoyuki, Masuko, Takashi, Nishikawa, Hiroyuki, Kawai, Kenzo
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Anti-Bacterial Agents - pharmacology; Apamin - pharmacology; Biological and medical sciences; calcium channel; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - metabolism; Dose-Response Relationship, Drug; Drug Synergism; Fundamental and applied biological sciences. Psychology; gastrointestinal motility; Gastrointestinal Motility - drug effects; Genistein - pharmacology; intestinal transit; Intestine. Mesentery; Intestines - drug effects; Intestines - metabolism; Mice; Oligopeptides - pharmacology; Peptides; potassium channel; Potassium Channel Blockers; Potassium Channels - metabolism; Protease (proteinase)‐activated receptor (PAR); Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Receptor, PAR-1; Receptor, PAR-2; Receptors, Thrombin - agonists; Receptors, Thrombin - metabolism; Stomach; tyrosine kinase; Verapamil - pharmacology; Vertebrates: digestive system
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704211

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