1 The present study examined the mechanical e ects of agonist enzymes and receptor-activating peptides for protease-activated receptor (PAR)-1 and PAR-2 on longitudinal and circular muscle of rat isolated colonic segments in the attempt to clarify the PAR functional role in intestinal motility. 2 The responses to PAR-1 and PAR-2 activation were examined in vitro by recording simultaneously the changes of endoluminal pressure (index of circular muscle activity) and of isometric tension (index of longitudinal muscle activity). 3 Both PAR-1 agonists, thrombin (0.1 nM ± 3 mM) and SFLLRN-NH 2 (1 nM ± 3 mM), and PAR-2 agonists, trypsin (0.1 nM ± 10 mM) and SLIGRL-NH 2 (1 nM ± 10 mM), induced di erent e ects in the two muscular layers: a reduction of the spontaneous contractions in the circular muscle and a contractile e ect or biphasic, relaxation followed by contraction, depending on the concentration, in the longitudinal muscle. 4 The inhibitory e ects were greatly reduced or abolished by apamin (0.1 mM) indicating that they mainly occur via activation of Ca 2+ -dependent small conductance, K + -channels. 5 The responses to PAR-1 and PAR-2 were una ected by tetrodotoxin (1 mM) or indomethacin (1 mM) suggesting that are independent by products of cyclooxygenase or by neural action potentials. 6 These ®ndings indicate that both PAR-1 and PAR-2 are functionally expressed in rat colon. PARs mediate changes of the mechanical activity of longitudinal and circular muscle which might explain the alterations of colonic motility observed during in¯ammatory conditions.
Recording simultaneously in vitro the changes of endoluminal pressure (index of circular muscle activity) and isometric tension (index of longitudinal muscle activity), we examined the mechanisms responsible for the apamin-sensitive relaxant and contractile responses induced by protease-activated receptor (PAR)-1 and PAR-2 activating peptides, SFLLRN-NH 2 and SLIGRL-NH 2 , respectively, in rat colon. In the circular muscle, the inhibitory effects of SFLLRN-NH 2 and SLIGRL-NH 2 were significantly reduced by ryanodine, an inhibitor of Ca 2ϩ release from the sarcoplasmic reticulum, but unaffected by 1-, a protein kinase C (PKC) inhibitor, or genistein, a tyrosine kinase inhibitor. In the longitudinal muscle, the contractile responses to SFLLRN-NH 2 and SLIGRL-NH 2 were significantly reduced by nifedipine, an L-type calcium channel blocker, ryanodine, GF109203X, genistein, and abolished by U73122. The effects of genistein were additive with GF109203X but not with nifedipine. In the longitudinal muscle, the relaxant responses to the highest concentrations of SFLLRN-NH 2 and SLIGRL-NH 2 were abolished by nifedipine, reduced by genistein, and unaffected by ryanodine or GF109203X. In conclusion, influx of extracellular Ca 2ϩ through L-type voltage-dependent channels or release of Ca 2ϩ from intracellular stores are determining for the opening of the apamin-sensitive K ϩ channels responsible for longitudinal muscle relaxation or circular muscle inhibitory response, respectively, in rat colon. The longitudinal muscle contraction is mediated by activation of PLC; PKC and tyrosine kinase are involved in the cascade process, playing a parallel role. Indeed, tyrosine kinase and L-type Ca 2ϩ channels would act sequentially.
1 The aim of the present study was to verify a possible involvement of nitric oxide (NO) and of tachykinins in the contractile and relaxant effects caused by the activation of protease-activated receptor (PAR)-1 and PAR-2 in the longitudinal muscle of rat colon. 2 Mechanical responses to the PAR-1 activating peptides, SFLLRN-NH 2 (10 nM -10 mM) and TFLLR-NH 2 (10 nM -10 mM), and to the PAR-2-activating peptide, SLIGRL-NH 2 (10 nM -10 mM), were examined in vitro in the absence and in the presence of different antagonists. The contractile responses to PAR-1 and PAR-2 activation were concentration-dependently attenuated by SR140333 (0.1 -1 mM), NK 1 receptor antagonist, or by SR48968 (0.1 -1 mM), NK 2 receptor antagonist. The combined pretreatment with SR140333 (1 mM) and SR48968 (1 mM) produced additive suppressive effects on the contractile responses to PAR activation. Pretreatment of the preparation with capsaicin (10 mM) markedly reduced the contractions evoked by SFLLRN-NH 2 , TFLLR-NH 2 and SLIGRL-NH 2 , while o-conotoxin GVIA (0.2 mM) had no effect. 5 The present results suggest that in rat colonic longitudinal muscle, PAR-1 and PAR-2 activation can evoke (i) relaxation through the production of NO or (ii) contraction through the release of tachykinins, likely, from sensory nerves. These actions may contribute to motility disturbances during intestinal trauma and inflammation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.