Mechanisms of Vascular Dysfunction in COPD and Effects of a Novel Soluble Epoxide Hydrolase Inhibitor in Smokers. Chest 2017 Mar;151(3):555-563
Date
11/26/2016Pubmed ID
27884766Pubmed Central ID
PMC5332206DOI
10.1016/j.chest.2016.10.058Scopus ID
2-s2.0-85014572527 (requires institutional sign-in at Scopus site) 57 CitationsAbstract
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.
TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov.
Author List
Yang L, Cheriyan J, Gutterman DD, Mayer RJ, Ament Z, Griffin JL, Lazaar AL, Newby DE, Tal-Singer R, Wilkinson IBMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAdult
Aged
Blood Vessels
Bradykinin
Case-Control Studies
Cyclohexylamines
Endothelium, Vascular
Epoxide Hydrolases
Fluconazole
Forearm
Humans
In Vitro Techniques
Male
Middle Aged
Overweight
Plethysmography
Pulmonary Disease, Chronic Obstructive
Smoking
Triazines
Vasodilation
Vasodilator Agents