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 mu mol 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 KOC-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.