Comparative protection against rat intestinal reperfusion injury by a new inhibitor of sPLA 2 , COX‐1 and COX‐2 selective inhibitors, and an LTC 4 receptor antagonist

A new group IIa sPLA 2 inhibitor was compared with selective inhibitors of COX‐1, COX‐2 and an LTC 4 antagonist for effects on local and remote tissue injuries following ischaemia and reperfusion (I/R) of the small intestine in rats. In an acute model of ischaemia (30 min) and reperfusion (150 min) injury in the absence of inhibitors, there was significant intestinal haemorrhage, oedema and mucosal damage, neutropenia, elevated serum levels of aspartate aminotransferase (AST) and hypotension. Preischaemic treatment with the inhibitor of sPLA 2 (Group IIa), at 5 mg kg −1 i.v. or 10 mg kg −1 p.o. significantly inhibited I/R‐induced neutropenia, the elevation of serum levels of AST, intestinal oedema and hypotension. Pretreatment with the COX‐2 inhibitor celebrex (10 mg kg −1 i.v.) and the LTC 4 antagonist zafirlukast (1 mg kg −1 i.v.) also showed marked improvement with I/R‐induced AST, oedema and neutropenia. Hypotension was only reduced by the LTC 4 antagonist. The COX‐1 inhibitor flunixin (1 mg kg −1 i.v.) did not effect improvement in the markers of tissue injury. Histological examination of rat I/R injury showed that all of the drugs offered some protection to the mucosal layer damage compared to no drug treatment. Given i.v., the sPLA 2 inhibitor was more effective than either the COX‐1 or COX‐2 inhibitors in preventing rat I/R injury. These results indicate that a potent new inhibitor of sPLA 2 (group IIa) protects the rat small intestine from I/R injury after oral or intravenous administration. COX‐2 and LTC 4 inhibitors also showed some beneficial effects against intestinal I/R injury. Our study suggests that sPLA 2 (Group IIa) may have a pathogenic role in intestinal I/R in rats.British Journal of Pharmacology (2003) 140 , 71–80. doi: 10.1038/sj.bjp.0705402