Impairment of PAR-2-mediated relaxation system in colonic smooth muscle after intestinal inflammation.
Protease-activated receptor (PAR)-2 plays important roles in intestinal inflammatory responses. Changes in PAR-2-mediated smooth muscle function may contribute pathophysiologically to the intestinal motility disorders often observed in inflammatory bowel disease (IBD). Stimulation of PAR-2 by trypsin-induced relaxation of carbachol- and KCl-induced contractions in normal rat colonic smooth muscle was completely resolved by tissue pretreatment with apamin, but not by pretreatment with l-NMMA or a cocktail of neuronal blockers (tetrodotoxin, hexamethonium and propranolol). In colon inflamed by dextran sodium sulphate (DSS), trypsin-induced inhibitory effects were significantly reduced. Relaxation induced by SLIGRL-NH(2), a selective PAR-2-activating peptide, was also reduced in DSS-treated rat colon. However, inhibitory effects of 1-ethylbenzimidazolin-2-one, an activator of small conductance Ca(2+)-activated K(+) channel, were unaffected. Expression of PAR-2 mRNA in colonic muscularis externa was significantly lower in DSS-treated rats than in control rats. These results suggest that the PAR-2 mediated relaxation system in colonic smooth muscle is suppressed in this experimental colitis rat model, and may contribute to motility disorders in IBD.
Sato
Koichi
K
Department of Veterinary Pharmacology, Faculty of Agriculture, University of Yamaguchi, 1677-1 Yoshida, Yamaguchi 753-8515, Japan. k-sato@yamaguchi-u.ac.jp
Ninomiya
Hiromichi
H
Ohkura
Shinsuke
S
Ozaki
Hiroshi
H
Nasu
Tetsuyuki
T
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D003092:Colitis / Q000235:genetics / Q000503:physiopathology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D016264:Dextran Sulfate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology*; D009842:Oligopeptides / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044464:Receptor, PAR-2 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000502:physiology; D014357:Trypsin / Q000494:pharmacology
D009842:Oligopeptides; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D051640:Small-Conductance Calcium-Activated Potassium Channels; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; D001030:Apamin; D011189:Potassium Chloride; D002217:Carbachol; D016264:Dextran Sulfate; D014357:Trypsin