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(Circulation. 1999;99:2590-2597.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Protease-Activated Receptor-2 Involvement in Hypotension in Normal and Endotoxemic Rats In Vivo

Carla Cicala, PhD; Aldo Pinto, PhD; Mariarosaria Bucci, BSc; Raffaella Sorrentino, PhD; Brian Walker, PhD; Patrick Harriot, BSc; Alan Cruchley, PhD; Supriya Kapas, PhD; Gareth L. Howells, PhD; Giuseppe Cirino, PhD

From the Dipartimento di Farmacologia Sperimentale, Naples, Italy (C.C., M.B., R.S., G.C.); Dipartimento di Scienze Farmaceutiche, Penta (Sa), Italy (A.P.); the School of Biology and Biochemistry, Queen's University of Belfast, Medical Biology Centre, Belfast, UK (B.W., P.H.); and Clinical Sciences Research Centre, St Bartholomew's, and the Royal London School of Medicine and Dentistry, London, UK (A.C., S.K., G.L.H.).

Correspondence to Professor Giuseppe Cirino, PhD, Dipartimento di Farmacologia Sperimentale, Via Domenico Montesano 49, 80131 Naples, Italy. E-mail cirino{at}cds.unina.it

Background—The protease-activated receptor-2 (PAR-2) is expressed by vascular 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) corresponding 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 was without effect. A specific trypsin inhibitor, biotin–SGKR-chloromethylketone, inhibited trypsin-induced hypotension but not that stimulated by PAR-2AP. In animals treated with LPS 20 hours earlier, we found an increased sensitivity to trypsin and PAR-2AP in the hypotensive response. In particular, PAR-2AP caused hypotension at a low concentration of 30 ng/kg. Moreover, PAR-2 was immunolocalized to endothelial and smooth muscle cells in aorta and 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 demonstrated 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 therapeutic target.

Key Words: receptors • trypsin • endotoxemia • hypotension • shock

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