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Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 7845629, 17 pages
Research Article

The Endothelin Receptor Antagonist Macitentan Improves Isosorbide-5-Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) Induced Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation

1Center for Cardiology, Department of Cardiology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
2Center of Thrombosis and Hemostasis, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
3Actelion Pharmaceuticals Deutschland GmbH, Konrad-Goldmann-Straße 5b, 79100 Freiburg, Germany
4Pharmacology and Preclinical Development, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
5Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr. 1, 55131 Mainz, Germany

Correspondence should be addressed to Andreas Daiber; ed.zniam-inu@rebiad

Received 25 May 2018; Accepted 17 October 2018; Published 27 December 2018

Academic Editor: Olga Pechanova

Copyright © 2018 Sebastian Steven et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.