Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the rat
- 1 December 2000
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 131 (8), 1800-1808
- https://doi.org/10.1038/sj.bjp.0703756
Abstract
The effects of the long lasting and potent PAF receptor antagonist UK74505 were assessed on the local and remote injuries following ischaemia and reperfusion (I/R) of the superior mesenteric artery (SMA) in rats. In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and neutrophil accumulation, there was significant tissue haemorrhage, blood neutropenia, systemic hypotension and elevated local and systemic TNF-alpha levels. Post-ischaemic treatment with the selectin blocker fucoidin (10 mg kg(-1)) prevented neutrophil accumulation in tissue and, in consequence, all the local and systemic injuries following severe I/R. Treatment with an optimal dose of UK74505 (1 mg kg(-1)) also reversed local and remote neutrophil accumulation, increases in vascular permeability and intestinal haemorrhage. UK74505 partially inhibited blood neutropenia and reperfusion-induced hypotension. Interestingly, both fucoidin and UK74505 prevented the local, but not systemic, increases of TNF-alpha levels following severe I/R injury, demonstrating an important role of migrating cells for the local production of TNF-alpha. However, the results do not support a role for PAF as an intermediate molecule in the production of systemic TNF-alpha. The beneficial effects of UK74505 and other PAF receptor antagonists in models of I/R injury in animals and the safety of UK74505 use in man warrant further investigations of the use of this drug as preventive measure for I/R injury in humans.Keywords
This publication has 36 references indexed in Scilit:
- Platelet-activating factor mediates acid-induced lung injury in genetically engineered miceJCI Insight, 1999
- Two of the usual suspects, platelet-activating factor and its receptor, implicated in acute lung injuryJCI Insight, 1999
- Possible participation of intracellular platelet-activating factor in tumor necrosis factor-α production by rat peritoneal macrophagesEuropean Journal of Pharmacology, 1999
- β1 Integrins Are Critically Involved in Neutrophil Locomotion in Extravascular Tissue In VivoThe Journal of Experimental Medicine, 1998
- The effect of the selectin binding polysaccharide fucoidin on eosinophil recruitment in vivoBritish Journal of Pharmacology, 1997
- Modipafant, a new PAF antagonist: pharmacokinetics and disposition in rat, dog and manXenobiotica, 1996
- Therapeutic potential of inhibiting leukocyte rolling in ischemia/reperfusion.JCI Insight, 1995
- Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit. Evidence for a role for C5a and interleukin-8.JCI Insight, 1995
- The potential etiologic role of tumor necrosis factor in mediating multiple organ dysfunction in rats following intestinal ischemia-reperfusion injuryResuscitation, 1995
- TCV-309, a novel platelet activating factor antagonist, inhibits leukocyte accumulation and protects against splanchnic artery occlusion shockInflammation Research, 1994