Published Online
on February 10, 2003

A more recent version of this article appeared on February 25, 2003

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Submitted on June 21, 2002
Revised on November 5, 2002
Accepted on November 6, 2002

Protease-Activated Receptor 2-Mediated Vasodilatation in Humans In Vivo. Role of Nitric Oxide and Prostanoids

Jonathan Robin MRCP^*, Rajesh Kharbanda BSc, MRCP, Peter Mclean BSc, PhD, Richard Campbell BSc, and Patrick Vallance MD, FRCP

From the Centre for Clinical Pharmacology & Therapeutics (J.R., R.K., P.M., P.V.) and The Wolfson Institute for Biomedical Research (R.C.), University College London, London, UK.

^* To whom correspondence should be addressed. E-mail: j.robin{at}ucl.ac.uk.

Background--Systemic hypotension as a consequence of vascular dysfunction is a well-recognized and important feature of critical illness. Although serine protease activation has been implicated as a cause of vascular dysfunction in systemic inflammation, the mechanism is unknown. Recently, a class of receptors with an entirely novel mechanism of action, protease-activated receptors (PARs), has been identified that would explain the link between protease activation and systemic hypotension. Our aim was to test the hypothesis that in vivo activation of protease-activated receptor 2 (PAR-2) in humans would mediate vasodilatation.

Methods and Results--For these first-in-human studies, an activating peptide for the human PAR-2 receptor was synthesized and administered to healthy volunteers. Using both the dorsal hand vein technique and forearm plethysmography, we studied the effects of PAR-2 activation in human blood vessels and investigated the mechanism of vasodilation. Activation of PAR-2 receptors in vivo dilated human blood vessels in a dose-dependent manner, and the effects were reduced by inhibition of both nitric oxide and prostanoid synthesis

Conclusions--These findings demonstrate that serine protease activity can cause human vasodilation and provide a possible explanation of why serine protease activation in critical illness is associated with vascular dysfunction.

Key words: nitric oxide • prostaglandins • receptors • vasodilation

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