The mediators involved in endotoxin-induced vascular permeability increase in the rat skin and their interactions

The injection of lipopolysaccharide (LPS) from E. Coli into the dorsal skin of rats caused a dose-dependent increase in vascular permeability as measured by the extravasation over a 40-min period of intravenously injected dye. This increase caused by LPS was attenuated by pretreatment with the bradykinin (BK) receptor antagonist HOE140, the selective platelet-activating factor (PAF) antagonist TCV309, and by combined treatment with mepyramine and methysergide. Combined treatment with HOE140 and TCV309 resulted in further suppression than that achieved with a single treatment alone. By the simultaneous pretreatment with all antagonists, the response was almost totally abolished. On the other hand, indomethacin also inhibited the response induced by LPS, but not those induced by BR and PAF itself. A small dose of BK or histamine synergistically potentiated the effect of PAF when simultaneously injected. These results suggest that BK, PAF, histamine/serotonin and prostaglandins are involved in the LPS-induced increase in vascular permeability, where PAF, in addition to its direct action, potentiates the response to BK and histamine, and prostaglandins potentiate the actions of other mediators without its direct action.