Mechanisms of Vascular Dysfunction in COPD and Effects of a Novel Soluble Epoxide Hydrolase Inhibitor in Smokers
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 hy...
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| Published in: | Chest Vol. 151; no. 3; pp. 555 - 563 |
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| Main Authors: | , , , , , , , , , |
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01.03.2017
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| ISSN: | 1931-3543 |
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| Abstract | 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.
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.
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).
GSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD.
ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov. |
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| AbstractList | BACKGROUNDSmoking 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.METHODSEndogenous 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.RESULTSCompared 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).CONCLUSIONSGSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD.TRIAL REGISTRYClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov. 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. 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. 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). GSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD. ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov. |
| Author | Yang, Lucy Gutterman, David D Mayer, Ruth J Tal-Singer, Ruth Lazaar, Aili L Wilkinson, Ian B Cheriyan, Joseph Griffin, Jules L Newby, David E Ament, Zsuzsanna |
| Author_xml | – sequence: 1 givenname: Lucy surname: Yang fullname: Yang, Lucy organization: Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Addenbrooke's Hospital, Cambridge, England – sequence: 2 givenname: Joseph surname: Cheriyan fullname: Cheriyan, Joseph email: jc403@medschl.cam.ac.uk organization: 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 – sequence: 3 givenname: David D surname: Gutterman fullname: Gutterman, David D organization: Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI – sequence: 4 givenname: Ruth J surname: Mayer fullname: Mayer, Ruth J organization: GSK R&D, King of Prussia, PA – sequence: 5 givenname: Zsuzsanna surname: Ament fullname: Ament, Zsuzsanna organization: MRC Human Nutrition Research, Elsie Widdowson Laboratory; and Department of Biochemistry, University of Cambridge, Cambridge, England – sequence: 6 givenname: Jules L surname: Griffin fullname: Griffin, Jules L organization: MRC Human Nutrition Research, Elsie Widdowson Laboratory; and Department of Biochemistry, University of Cambridge, Cambridge, England – sequence: 7 givenname: Aili L surname: Lazaar fullname: Lazaar, Aili L organization: GSK R&D, King of Prussia, PA – sequence: 8 givenname: David E surname: Newby fullname: Newby, David E organization: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland – sequence: 9 givenname: Ruth surname: Tal-Singer fullname: Tal-Singer, Ruth organization: GSK R&D, King of Prussia, PA – sequence: 10 givenname: Ian B surname: Wilkinson fullname: Wilkinson, Ian B organization: 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 |
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| Snippet | Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that... BACKGROUNDSmoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that... |
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| SubjectTerms | 8,11,14-Eicosatrienoic Acid - analogs & derivatives 8,11,14-Eicosatrienoic Acid - metabolism Adult Aged Blood Vessels - drug effects Blood Vessels - physiopathology Bradykinin - pharmacology Case-Control Studies Cyclohexylamines - pharmacology Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism Endothelium, Vascular - physiopathology Epoxide Hydrolases - antagonists & inhibitors Fluconazole - pharmacology Forearm - blood supply Humans In Vitro Techniques Male Middle Aged Overweight - metabolism Overweight - physiopathology Plethysmography Pulmonary Disease, Chronic Obstructive - metabolism Pulmonary Disease, Chronic Obstructive - physiopathology Smoking - metabolism Smoking - physiopathology Triazines - pharmacology Vasodilation - drug effects Vasodilator Agents - pharmacology |
| Title | Mechanisms of Vascular Dysfunction in COPD and Effects of a Novel Soluble Epoxide Hydrolase Inhibitor in Smokers |
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