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The Endothelin Receptor Antagonist Macitentan Improves Isosorbide-5-Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) Induced Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation
Joint Authors
Oelze, Matthias
Daiber, Andreas
Münzel, Thomas
Steven, Sebastian
Hausding, Michael
Kröller-Schön, Swenja
Helmstädter, Johanna
Roohani, Siyer
Kashani, Fatemeh
Jansen, Thomas
Baum, Christine
Iglarz, Marc
Schulz, Eberhard
Source
Oxidative Medicine and Cellular Longevity
Issue
Vol. 2018, Issue 2018 (31 Dec. 2018), pp.1-17, 17 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2018-12-27
Country of Publication
Egypt
No. of Pages
17
Main Subjects
Abstract EN
Objective.
Organic nitrates such as isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) are used for the treatment of patients with chronic symptomatic stable coronary artery disease and chronic congestive heart failure.
Limiting side effects of these nitrovasodilators include nitrate tolerance and/or endothelial dysfunction mediated by oxidative stress.
Here, we tested the therapeutic effects of the dual endothelin (ET) receptor antagonist macitentan in ISMN- and ISDN-treated animals.
Methods and Results.
Organic nitrates (ISMN, ISDN, and nitroglycerin (GTN)) augmented the oxidative burst and interleukin-6 release in cultured macrophages, whereas macitentan decreased the oxidative burst in isolated human leukocytes.
Male C57BL/6j mice were treated with ISMN (75 mg/kg/d) or ISDN (25 mg/kg/d) via s.c.
infusion for 7 days and some mice in addition with 30 mg/kg/d of macitentan (gavage, once daily).
ISMN and ISDN in vivo therapy caused endothelial dysfunction but no nitrate (or cross-)tolerance to the organic nitrates, respectively.
ISMN/ISDN increased blood nitrosative stress, vascular/cardiac oxidative stress via NOX-2 (fluorescence and chemiluminescence methods), ET1 expression, ET receptor signaling, and markers of inflammation (protein and mRNA level).
ET receptor signaling blockade by macitentan normalized endothelial function, vascular/cardiac oxidative stress, and inflammatory phenotype in both nitrate therapy groups.
Conclusion.
ISMN/ISDN treatment caused activation of the NOX-2/ET receptor signaling axis leading to increased vascular oxidative stress and inflammation as well as endothelial dysfunction.
Our study demonstrates for the first time that blockade of ET receptor signaling by the dual endothelin receptor blocker macitentan improves adverse side effects of the organic nitrates ISMN and ISDN.
American Psychological Association (APA)
Steven, Sebastian& Oelze, Matthias& Hausding, Michael& Roohani, Siyer& Kashani, Fatemeh& Kröller-Schön, Swenja…[et al.]. 2018. The Endothelin Receptor Antagonist Macitentan Improves Isosorbide-5-Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) Induced Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation. Oxidative Medicine and Cellular Longevity،Vol. 2018, no. 2018, pp.1-17.
https://search.emarefa.net/detail/BIM-1212090
Modern Language Association (MLA)
Steven, Sebastian…[et al.]. The Endothelin Receptor Antagonist Macitentan Improves Isosorbide-5-Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) Induced Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation. Oxidative Medicine and Cellular Longevity No. 2018 (2018), pp.1-17.
https://search.emarefa.net/detail/BIM-1212090
American Medical Association (AMA)
Steven, Sebastian& Oelze, Matthias& Hausding, Michael& Roohani, Siyer& Kashani, Fatemeh& Kröller-Schön, Swenja…[et al.]. The Endothelin Receptor Antagonist Macitentan Improves Isosorbide-5-Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) Induced Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation. Oxidative Medicine and Cellular Longevity. 2018. Vol. 2018, no. 2018, pp.1-17.
https://search.emarefa.net/detail/BIM-1212090
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1212090