Enhancement of vascular permeability by specific activation of protease-activated receptor-1 in rat hindpaw: a protective role of endogenous and exogenous nitric oxide.

1. To clarify the role of the first thrombin receptor/protease-activated receptor (PAR)-1 in an inflammatory process, we tested and characterized the effect of intraplantar (i.pl.) administration of the highly specific PAR-1 agonist TFLLR-NH2 in rat hindpaw. 2. TFLLR-NH2 administered i.pl. at 0.01-0.03 micromol per paw enhanced vascular permeability in the hindpaw and produced paw oedema in a dose-dependent manner. This effect was almost completely abolished by repeated pretreatment with compound 48/80 to deplete inflammatory mediators in mast cells. 3. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester or N-iminoethyl-L-ornithine, preadministered i.pl., stereospecifically potentiated the i.pl. TFLLR-NH2-induced permeability increase, while the NO donor sodium nitroprusside or NOC-18, given i.pl., suppressed the effect of TFLLR-NH2. 4. These findings demonstrate that specific activation of PAR-1 produces increased vascular permeability accompanied by oedema formation in the rat hindpaw, predominantly via mast cell degranulation, and that endogenous and exogenous NO plays a protective role in the PAR-1-mediated inflammatory event.