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

Abstract

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-NH 2 , but not the inactive control LSIGRL-NH 2 , at 1±5 mmol kg 71 , in combination with the aminopeptidase inhibitor amastatin at 2.5 mmol kg 71 , facilitated gastrointestinal transit in a dose-dependent manner. The human PAR-1-derived peptide SFLLR-NH 2 and the speci®c PAR-1 agonist TFLLR-NH 2 , but not the inactive control FSLLR-NH 2 , at 2.5 ± 10 mmol kg 71 , in combination with amastatin, also promoted gastrointestinal transit. 3 The Ca 2+ -activated, small conductance K + channel inhibitor apamin at 0.01 mmol kg 71 signi®cantly potentiated the actions of SLIGRL-NH 2 and TFLLR-NH 2 at sube ective doses. 4 The increased gastrointestinal transit exerted by either SLIGRL-NH 2 at 5 mmol kg 71 or TFLLR-NH 2 at 10 mmol kg 71 was completely abolished by the L-type Ca 2+ channel inhibitor verapamil at 61.6 mmol kg 71 . In contrast, the tyrosine kinase inhibitor genistein at 18.5 mmol kg 71 failed to modify the e ects of the agonists for PAR-2 or PAR-1. 5 These ®ndings 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 e ects are modulated by apaminsensitive 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 in¯ammation.

PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat

“…Overall, contractile responses to PAR-2 activation were biphasic, with a transient relaxation followed by a contraction. In control conditions, the contractile phase predominated over the relaxation, in agreement with the PAR-2-mediated enhancement of intestinal motility observed under in vivo conditions (15). Similar PAR-2-induced biphasic responses were also observed when assessing hydroelectrolytic transport.…”

Involvement of nitric oxide and tachykinins in the effects induced by protease‐activated receptors in rat colon longitudinal muscle

“…A recent study in vivo has provided evidence for an increase of the mouse gastrointestinal transit in response to PAR-1 and PAR-2 activation (Kawabata et al, 2001). There is also in vitro evidence that PARs modulate smooth muscle mechanical activity and their activation can induce relaxant, contractile or biphasic responses (Al-Ani et al, 1995;Saifeddine et al, 1996;Corvera et al, 1997;Hollenberg et al, 1997;Kawabata et al, 1999;Cocks et al, 1999b;Mule`et al, 2002a).…”

Signal Transduction Pathways Involved in the Mechanical Responses to Protease-Activated Receptors in Rat Colon

“…PAR-2 appears to be involved in exocrine secretion (Nguyen et al, 1999;Kawabata et al, 2000c) and intestinal ion transport (Vergnolle et al, 1998). PAR-1 and PAR-2 modulate smooth muscle motility (Kawabata et al, 2001), and their activation can induce relaxant, contractile, or biphasic responses (Al-Ani et al, 1995;Saifeddine et al, 1996;Corvera et al, 1997;Hollenberg et al, 1997Hollenberg et al, , 1999Zheng et al, 1998;Cocks et al, 1999;Kawabata et al, 1999Kawabata et al, , 2000aTognetto et al, 2000;Mulè et al, 2002).…”