(1) A new group IIa
sPLA2 inhibitor was compared with selective inhibitors of COX-1, COX-2 and an
LTC4 antagonist for effects on local and remote tissue
injuries following ischaemia and reperfusion (I/R) of the small intestine in rats. (2) 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. (3) Preischaemic treatment with the inhibitor of
sPLA2 (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. (4) Pretreatment with the
COX-2 inhibitor celebrex (10 mg kg-1 i.v.) and the
LTC4 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
LTC4 antagonist. The COX-1 inhibitor
flunixin (1 mg kg-1 i.v.) did not effect improvement in the markers of tissue injury. (5) 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
sPLA2 inhibitor was more effective than either the COX-1 or
COX-2 inhibitors in preventing rat I/R injury. (6) These results indicate that a potent new inhibitor of
sPLA2 (group IIa) protects the rat small intestine from I/R injury after oral or
intravenous administration. COX-2 and
LTC4 inhibitors also showed some beneficial effects against intestinal I/R injury. Our study suggests that
sPLA2 (Group IIa) may have a pathogenic role in intestinal I/R in rats.