Characterization of the protease-activated receptor-1-mediated contraction and relaxation in the rat duodenal smooth muscle

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

“…In the rat duodenal smooth muscle, the PAR-1-induced effect depends on the activation of PLC and PKC (Kawabata et al, 1999;2000b); therefore, we verified the involvement of these enzymes in the signal transduction responsible for the PAR-1-and PAR-2-induced effects in rat colon. U73122 (0.5-1 M), a PLC inhibitor, significantly reduced the PAR-1-and PAR-2-induced contraction in a concentration-dependent manner (Fig.…”

“…In fact, the inhibitor of PLC, U73122, antagonized the contractile responses in a concentration-dependent manner to PAR-1 and PAR-2 agonists in the longitudinal muscle, up to blocking it, without affecting the inhibitory response in the circular muscle, indicating that the contraction is entirely dependent by activation of PLC. Partial involvement of PLC in the PAR-1-mediated rat duodenal muscle has been already reported (Kawabata et al, 2000b). Moreover, we tested the possible involvement of PKC and tyrosine kinase because it is well known that PLC produces diacylglycerol that in turn activates PKC and recent data indicate that tyrosine kinase is also involved in the signal transduction associated with rat intestinal contractions (Ohta et al, 2000) or relaxation (Takeuchi et al, 1999) through the modulation of L-type calcium channels or apamin-sensitive K ϩ channels, respectively.…”

“…The inhibitors/antagonists were the following: nifedipine, an L-type Ca 2ϩ channel inhibitor (1 M), ryanodine, an inhibitor of Ca 2ϩ -induced Ca 2ϩ release from the sarcoplasmic reticulum (10 M), U73122, a PLC inhibitor (0.5-5 M), GF109203X, a protein kinase C inhibitor (1 M), and genistein, a tyrosine kinase inhibitor (1-10 M). For the most of the drugs, the concentration used was known to be effective in our and other systems (Mulè and Serio, 1997;Cocks et al, 1999;Kawabata et al, 2000b). Some antagonists were coadministered to clarify if the effectors represent different steps of the same pathway.…”

“…Moreover, the signal transduction pathways triggered by PAR-1 and PAR-2 are complex and the "cascade" processes are not completely understood. In fact, although activation of L-type calcium channels, cyclooxygenase, protein kinase C, and tyrosine kinase for contractile effects (Hollenberg et al, 1992;Zheng et al, 1998;Kawabata et al, 1999;Kawabata et al, 2000b) and activation of apamin-sensitive K ϩ channels for relaxant effects (Cocks et al, 1999;Kawabata et al, 1999, 200b;Mulè et al, 2002) appear to be involved, the sequence of events leading to intestinal smooth muscle contraction or relaxation has not been yet clarified. Moreover, indomethacin-sensitive cyclooxygenase products might act in parallel to drive the effects.…”

Proinflammatory Cytokines Suppress the Expression Level of Protease-Activated Receptor-2 through the Induction of iNOS in Rat Colon

“…All of the identified members of the PAR family, PAR-1, -2, -3 and -4, are activated by endogenous proteinases. Among the PAR family, the function of PAR-2 has been widely studied, and this receptor is known to be involved in inflammation, allergies, haemorrhaging, exocrine activities and intestinal ion transport [12,20,25]. We have already reported that stimulation of PAR-2 with trypsin induces relaxation in rat colon by the activation of small conductance K + -channels, and we suggested that the PAR-2-mediated relaxation system in colonic smooth muscle is inhibited by the attenuation of PAR-2 mRNA expression in an experimental colitis rat model.…”