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

Citation
A. Kawabata et al., In vivo evidence that protease-activated receptors 1 and 2 modulate gastrointestinal transit in the mouse, BR J PHARM, 133(8), 2001, pp. 1213-1218
Citations number
40
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
0007-1188 → ACNP
Volume
133
Issue
8
Year of publication
2001
Pages
1213 - 1218
Database
ISI
SICI code
0007-1188(200108)133:8<1213:IVETPR>2.0.ZU;2-E
Abstract
1 Protease-activated receptors (PARs) 1 and 2 modulate the gastric and inte stinal smooth muscle motility in vitro. In the present study, we examined i f activation of PAR-2 and PAR-1 could alter gastrointestinal transit in mic e. 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 combina tion with the aminopeptidase inhibitor amastatin at 2.5 mu mol kg(-1), faci litated gastrointestinal transit in a dose-dependent manner. The human PAR- 1-derived peptide SFLLR-NH2 and the specific PAR-1 agonist TFLLR-NH2, but n ot 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 TFLL R-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 contr ast. the tyrosine kinase inhibitor genistein at 18.5 mu mol kg(-1) failed t o 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-me diated effects are modulated by apamin-sensitive K+ channels and are depend ent on activation of L-type Ca2+ channels, but independent of tyrosine kina se. Our study thus provides novel evidence for the physiological and/or pat hophysiological roles of PARs 1 and 2 in the digestive systems, most probab ly during inflammation.