Platelet-activating factor receptor antagonist attenuates endotoxin-induced vascular hyporeactivity in the pithed rat

The role of platelet activating factor (PAF) and nitric oxide (NO) in the endotoxin-induced hyporeactivity to noradrenaline was studied in the pithed rat. Pressor dose-response curves to noradrenaline (0.01-10 microg/kg, i.v.) were made starting 1 h after the administration of endotoxin (0.5 mg/kg, i.v.) to the rats. Saline was administered to the control rats. The PAF receptor antagonist, TCV-309 (3-bromo-5-[N-phenyl-N-[2-[[2-(1,2,3,4-tetrahydro-2-isoquinolylcarbon yloxy)ethyl]carbamoyl]ethy]carbamoyl]-1-propylpyridinium nitrate, 100 microg/kg, i.v.), or the NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA, 30 mg/kg, i.v.), was administered to the endotoxin-treated rats 20 or 10 min before the noradrenaline challenge. L-NMMA reversed endotoxin-induced hyporeactivity completely. TCV-309 produced a significant, but partial attenuation of the hyporeactivity to noradrenaline (P < 0.01). There was still significant hyporeactivity when compared with the control rats (P < 0.01) and the L-NMMA-treated endotoxin-administered rats (P < 0.05). These data suggest that endogenous PAF contributes to the vascular hyporeactivity to noradrenaline induced by endotoxin and that NO plays a major role in the endotoxin-induced hyporeactivity.