title: Mechanisms of Vascular Dysfunction in COPD and Effects of a Novel Soluble Epoxide Hydrolase Inhibitor in Smokers.
abstract: BACKGROUND
  Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD and that a novel soluble epoxide hydrolase inhibitor, GSK2256294, attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo.
  
  
  METHODS
  Endogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilation in human resistance arteries were assessed in vitro and in vivo in a phase I clinical trial in healthy overweight smokers.
  
  
  RESULTS
  Compared with control groups, there was reduced vasodilation with bradykinin (P = .005), a blunted effect of fluconazole on bradykinin-induced vasodilation (P = .03), and a trend toward reduced basal EET/dihydroxyepoxyeicosatrienoic acid ratio in patients with COPD (P = .08). A similar pattern was observed in overweight smokers. In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilation compared with vehicle (90% ± 4.2% vs 72.6% ± 6.2% maximal dilatation) and shifted the bradykinin half-maximal effective concentration (EC50) (-8.33 ± 0.172 logM vs -8.10 ± 0.118 logM; P = .001 for EC50). In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338% ± 46% before a dose to 566% ± 110% after a single dose (P = .02) and to 503% ± 123% after a chronic dose (P = .003).
  
  
  CONCLUSIONS
  GSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD.
  
  
  BACKGROUND
  ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov.
authors.affiliation: Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Addenbrooke's Hospital, Cambridge, England.
authors.forename: Lucy
authors.initials: L
authors.lastname: Yang
authors.affiliation: Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Addenbrooke's Hospital, Cambridge, England; Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Clinical Unit Cambridge, GSK R&D, Cambridge, England. Electronic address: jc403@medschl.cam.ac.uk.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cheriyan
authors.affiliation: Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
authors.affiliation: GSK R&D, King of Prussia, PA.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Mayer
authors.affiliation: MRC Human Nutrition Research, Elsie Widdowson Laboratory; and Department of Biochemistry, University of Cambridge, Cambridge, England.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Ament
authors.affiliation: MRC Human Nutrition Research, Elsie Widdowson Laboratory; and Department of Biochemistry, University of Cambridge, Cambridge, England.
authors.forename: Jules L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: GSK R&D, King of Prussia, PA.
authors.forename: Aili L
authors.initials: AL
authors.lastname: Lazaar
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland.
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
authors.affiliation: GSK R&D, King of Prussia, PA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Addenbrooke's Hospital, Cambridge, England; Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England.
authors.forename: Ian B
authors.initials: IB
authors.lastname: Wilkinson
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000328:Adult; D000368:Aged; D001808:Blood Vessels / Q000187:drug effects* / Q000503:physiopathology; D001920:Bradykinin / Q000494:pharmacology; D016022:Case-Control Studies; D003514:Cyclohexylamines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D015725:Fluconazole / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D050177:Overweight / Q000378:metabolism / Q000503:physiopathology*; D010991:Plethysmography; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000503:physiopathology*; D012907:Smoking / Q000378:metabolism / Q000503:physiopathology*; D014227:Triazines / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D003514:Cyclohexylamines; C584201:N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide; D014227:Triazines; D014665:Vasodilator Agents; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D015725:Fluconazole; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D001920:Bradykinin
keywords: COPD; EETs; clinical trial; endothelial function; smokers; soluble epoxide hydrolase inhibitor