Involvement of inflammatory cells on the dysmotility of gastrointestinal smooth muscles in experimental colitis model animals.

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The mechanism of gastro-intestinal dysmotility in the inflammatory bowel disease has not been cleared. In this study, we examined the mechanism involved in the inflamed distal colon isolated from dextran sodium sulphate-induced ulcerative colitis model mouse (DSS-treated mouse). Although substance P-induced contraction was not changed, carbachol-induced contraction was reduced in DSS-treated mouse colon. Pre-incubation with NO synthase inhibitor, L-NMMA, cyclooxygenase inhibitor, indomethacin, or ATP-sensitive K^+ channel inhibitor, glibenclamide, did not recovered the carbachol-induced contraction in DSS-treated moue colon. In semi-quantitative RT-PCR experiments and Western blotting analysis, muscarinic M_3 receptor expressions were not changed. The Ca^<2+>-sensitization of contractile elements induced by carbachol with GTP or GTP_YS was reduced in the β-escin permeabilized DSS-treated mouse colon. Although the expression of proteins, such as rhoA, ROCK1 or ROCK2, that are involved i … More n G-protein coupled signaling in smooth muscles, were not changed, the expression of CPI-17, the functional proteins involved in the smooth muscle Ca^<2+>-sensitization, was significantly decreased in DSS-treated mouse colon. These results suggest that the suppression of carbachol-induced contraction in colitis mouse is attributable at lease partially to the increased activity of myosin phosphatase following the down regulation of CPI-17.Protease activated receptor-2 (PAR-2) is highly expressed in gastrointestinal tract and is activated by proteases released form mast cell and trypsin in intestinal lumen. PAR-2-acitivation induces a relaxation of colonic smooth muscle which is important for the motility. In order to elucidate the relationship of dysmotility of colon in ulcerative colitis model rat and PAR-2, we used the dextran sodium sulphate-induced ulcerative colitis model rat (DSS rat). In the control rat colon, trypsin induced relaxation of carbachol (CCh) and high KCl-induced contraction, which is completely resolved by the pretreatment of apamin. In DSS rat colon, these inhibitory effects of trypsin on CCh and high KCl-induced contraction were significantly reduced. In DSS rat colon, the relaxation induced by SLIGRL-NH was also reduced, but the inhibitory effect of EBIO-1, SK_<Ca> activator, has not been changed. In RT-PCR experiments, the expression of PAR-2 mRNA of colonic smooth muscle decreased in DSS rat from control rat. These results suggest that suppression of PAR-2 activator-induced relaxation in colitis rat colon is attributable to the down regulation of PAR-2 mRNA expression level. It is shown that gastro-intestinal-dysmotility is at least partially due to the down regulation of PAR-2 in IBD. Less