C. Cicala et al., Protease-activated receptor-2 involvement in hypotension in normal and endotoxemic rats in vivo, CIRCULATION, 99(19), 1999, pp. 2590-2597
Citations number
23
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background-The protease-activated receptor-2 (PAR-2) is expressed by vascul
ar endothelial cells and upregulated by lipopolysaccharide (LPS) in vitro.
PAR-2 is activated by a tethered ligand created after proteolytic cleavage
by trypsin or experimentally by a synthetic agonist peptide (PAR-2AP) corre
sponding to the new amino terminus of the tethered ligand.
Methods and Results-Intravenous administration of PAR-2AP (0.1, 0.3, and 1
mg/kg) to rats: caused a dose-dependent hypotension. A scrambled peptide wa
s without effect. A specific trypsin inhibitor, biotin-SGKR-chloromethylket
one, inhibited trypsin-induced hypotension but not that stimulated by PAR-2
AP. In animals treated with LPS 20 hours earlier, we found an increased sen
sitivity to trypsin and PAR-2AP in the hypotensive response. In particular,
PAR-2AP caused hypotension at a low concentration of 30 ng/kg. Moreover, P
AR-2 was immunolocalized to endothelial and smooth muscle cells in aorta an
d jugular vein in LPS-treated rats, and increased levels of PAR-2 mRNA were
shown by reverse transcription-polymerase chain reaction analysis.
Conclusions-Our findings suggest that PAR-2 is important in the regulation
of blood pressure in vivo. A functional upregulation of PAR-2 by LPS was de
monstrated by the activity of concentrations of PAR-2AP that were inactive
in normal animals. We conclude that PAR-2 may play an important role in the
hypotension associated with endotoxic shock and may represent a new therap
eutic target.