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(Circulation. 2003;107:954.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

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; 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.

Correspondence to Dr Jonathan Robin, Centre for Clinical Pharmacology, BHF Laboratories, University College London, The Rayne Building, 5 University St, London WC1E 6JJ, UK. 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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