Involvement of bradykinin in endotoxin-induced vascular permeability increase in the skin of rats.

The aim of the present study was to investigate the role of bradykinin as well as that of platelet-activating factor in the endotoxin-induced acute vascular permeability increase in the dorsal skin of rats by use of kininogen-deficient and normal Brown-Norway rats. In the kininogen-deficient rats, the dose-dependent dye exudation induced by endotoxin was about one half of that in the normal rats at any doses of endotoxin tested (0.1-1.0 mg per site), whereas the dose-response curves obtained by bradykinin (1-100 nmol per site), platelet-activating factor (0.1-1 nmol per site) or histamine (50-500 nmol per site) were the same in both rats. This effect induced by endotoxin in the kininogen-deficient rats was not changed by pretreatment with a bradykinin B2 receptor antagonist, HOE140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin, 1 mg kg-1 i.v.), whereas the endotoxin-induced response in the normal rats was attenuated by the receptor antagonist. These responses in both kininogen-deficient and normal rats were significantly inhibited by a selective platelet-activating factor antagonist, TCV309 (3-bromo-5-[N-phenyl-N-[2-[[2-(1,2,3,4,-tetrahydro-2- isoquinolylcarbonyl-oxy)-ethyl]-carbamoyl]-ethyl]carbamoyl]-1-prop yl- pyridinium nitrate, 0.1 mg kg-1 i.v.). These results suggest that bradykinin could be one of the major mediators in the endotoxin-induced vascular permeability increase in rat skin in addition to platelet-activating factor.