Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the rat

1 The effects of the long lasting and potent PAF receptor antagonist UK7450 5 were assessed on the local and remote injuries following ischaemia and re perfusion (I/R) of the superior mesenteric artery (SMA) in rats. 2 In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and ne utrophil accumulation, there was significant tissue haemorrhage, blood neut ropenia, systemic hypotension and elevated local and systemic TNF-alpha lev els. 3 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. 4 Treatment with an optimal dose of UK74505 (1 mg kg(-1)) also reversed loc al and remote neutrophil accumulation, increases in vascular permeability a nd intestinal haemorrhage. UK74505 partially inhibited blood neutropenia an d reperfusion-induced hypotension. 5 Interestingly, both fucoidin and UK745 05 prevented the local, but not systemic, increases of TNF-alpha levels fol lowing severe I/R injury, demonstrating an important role of migrating cell s for the local production of TNF-alpha. However, the results do not suppor t a role for PAF as an intermediate molecule in the production of systemic TNF-alpha. 6 The beneficial effects of UK74505 and other PAF receptor antagonists in m odels 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.