RT Journal Article
SR Electronic
T1 Differential Role of Cyclooxygenase 1 and 2 Isoforms in the Modulation of Colonic Neuromuscular Function in Experimental Inflammation
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 938
OP 945
DO 10.1124/jpet.105.098350
VO 317
IS 3
A1 Matteo Fornai
A1 Corrado Blandizzi
A1 Luca Antonioli
A1 Rocchina Colucci
A1 Nunzia Bernardini
A1 Cristina Segnani
A1 Fabrizio De Ponti
A1 Mario Del Tacca
YR 2006
UL http://jpet.aspetjournals.org/content/317/3/938.abstract
AB This study examines the role played by cyclooxygenase (COX) isoforms (COX-1 and -2) in the regulation of colonic neuromuscular function in normal rats and after induction of colitis by 2,4-dinitrobenzenesulfonic acid (DNBS). The expression of COX-1 and COX-2 in the colonic neuromuscular layer was assessed by reverse transcription-polymerase chain reaction and immunohistochemistry. The effects of COX inhibitors on in vitro motility were evaluated by studying electrically induced and carbachol-induced contractions of the longitudinal muscle. Both COX isoforms were constitutively expressed in normal colon; COX-2 was up-regulated in the presence of colitis. In normal and inflamed colon, both COX isoforms were mainly localized in neurons of myenteric ganglia. In the normal colon, indomethacin (COX-1/COX-2 inhibitor), SC-560 [5-(4-chloro-phenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole] (COX-1 inhibitor), or DFU [5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone] (COX-2 inhibitor) enhanced atropine-sensitive electrically evoked contractions. The most prominent effects were observed with indomethacin or SC-560 plus DFU. In the inflamed colon, SC-560 lost its effect, whereas indomethacin and DFU maintained their enhancing actions. These results were more evident after blockade of noncholinergic pathways. In rats with colitis, in vivo treatment with superoxide dismutase or S-methylisothiourea (inhibitor of inducible nitric-oxide synthase) restored the enhancing motor effect of SC-560. COX inhibitors had no effect on carbachol-induced contractions in normal or DNBS-treated rats. In conclusion, in the normal colon, both COX isoforms act at the neuronal level to modulate the contractile activity driven by excitatory cholinergic pathways. In the presence of inflammation, COX-1 activity is hampered by oxidative stress, and COX-2 seems to play a predominant role in maintaining an inhibitory control of colonic neuromuscular function. The American Society for Pharmacology and Experimental Therapeutics