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

Abstract

1 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.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 sPLA 2 (Group IIa), at 5 mg kg À1 i.v. or 10 mg kg À1 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 À1 i.v.) and the LTC 4 antagonist zafirlukast (1 mg kg À1 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 À1 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 sPLA 2 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 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.

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

“…This dose was chosen because it was effective in the rat models described above (27)(28)(29). Olive oil-treated SHR and WKY rats served as vehicle controls.…”

“…27) prevents cardiovascular remodeling in young male SHR during the development of hypertension. KH064 is an orally active, competitive and reversible inhibitor with high potency (IC 50 29 nM) and selectivity (sPLA 2 -V: IC 50 Ͼ 5 M) for the human sPLA 2 -IIA enzyme (27,28). This inhibitor was effective at 5 mg/kg/day p.o.…”

“…This inhibitor was effective at 5 mg/kg/day p.o. as an anti-inflammatory drug in rat models of adjuvant-induced arthritis (27), intestinal ischemia-reperfusion injury (28), and inflammatory bowel disease (29). KH064 also reduces NOx production from the myocardium, myocardial damage, and cardiomyocyte death during cold ischemia associated with donor heart preservation, and sPLA 2 activation has been implicated in up-regulation of NO synthase-2 during cardiac ischemia (25).…”

Ketamine anesthesia reduces intestinal ischemia/reperfusion injury in rats

“…The small intestine is very sensitive to ischemic insult [5] . Reperfusion causes additional damage through the release of free radicals, pro-inflammatory cytokines, leukotrienes and other related products [6] . Intestinal Abstract AIM: To investigate the effects of ketamine anesthesia on the motility alterations and tissue injury caused by ischemia/reperfusion in rats.…”

“…The small intestine is very sensitive to ischemic insult [5] . Reperfusion causes additional damage through the release of free radicals, pro-inflammatory cytokines, leukotrienes and other related products [6] . Intestinal…”