Comparative protection against rat intestinal reperfusion injury by a new inhibitor of sPLA2, COX-1 and COX-2 selective inhibitors, and an LTC4 receptor antagonist.
(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.
Arumugam
Thiruma V
TV
Department of Physiology and Pharmacology, School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia.
Arnold
Naomi
N
Proctor
Lavinia M
LM
Newman
Michelle
M
Reid
Robert C
RC
Hansford
Karl A
KA
Fairlie
David P
DP
Shiels
Ian A
IA
Taylor
Stephen M
SM
D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D054501:Group II Phospholipases A2; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018077:Receptors, Leukotriene / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; C083173:leukotriene C4 receptor; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D010741:Phospholipases A; D054501:Group II Phospholipases A2