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.
Kawabata
A
A
Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan.
Kuroda
R
R
Nishikawa
H
H
Asai
T
T
Kataoka
K
K
Taneda
M
M
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006614:Hindlimb; D006632:Histamine / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis; D051381:Rats; D017208:Rats, Wistar; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000819:agonists / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D009569:Nitric Oxide; D012701:Serotonin; D003189:p-Methoxy-N-methylphenethylamine; D006632:Histamine; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester