title: Protease-activated receptor 2-mediated vasodilatation in humans in vivo: role of nitric oxide and prostanoids.
abstract: 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.
  
  
  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.
authors.affiliation: Centre for Clinical Pharmacology & Therapeutics, University College London, London, UK. j.robin@ucl.ac.uk
authors.forename: Jonathan
authors.initials: J
authors.lastname: Robin
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kharbanda
authors.forename: Peter
authors.initials: P
authors.lastname: Mclean
authors.forename: Richard
authors.initials: R
authors.lastname: Campbell
authors.forename: Patrick
authors.initials: P
authors.lastname: Vallance
mesh_terms: D001241:Aspirin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology*; D011453:Prostaglandins / Q000502:physiology*; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D011453:Prostaglandins; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C109968:seryl-leucyl-isoleucyl--glycyl-lysyl-valine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001241:Aspirin