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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.

Type

Journal article

Journal

Circulation

Publication Date

25/02/2003

Volume

107

Pages

954 - 959

Keywords

Aspirin, Cyclooxygenase Inhibitors, Dose-Response Relationship, Drug, Enzyme Inhibitors, Female, Humans, Male, Nitric Oxide, Nitric Oxide Synthase, Oligopeptides, Prostaglandins, Receptor, PAR-2, Receptors, Thrombin, Vasodilation, omega-N-Methylarginine