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.

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Medical Research Society 9Pdetermined from the Ni'+-sensitive current in response to a ramp protocol, with major interfering currents blocked and [Ca2+Ii buffered to =250 nM. Current density data were well fit by the model of NCX function of Weber el al (J Gen Physiol 2001; 117:119-131), which was used to determine VMax. Compared to sham-operated controls, in LVD cells the decay of the calcium transient was slowed (RC = 2.35M.17 vs 2.87M.21 s-', p=O.03), there was reduced NCX current density ( V h = 7.69a.57 vs 12.19M.56 A/F, p