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Organic nitrates such as isosorbide\u20105\u2010mononitrate (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\u2010 and ISDN\u2010treated animals. <jats:italic>Methods and Results<\/jats:italic>. Organic nitrates (ISMN, ISDN, and nitroglycerin (GTN)) augmented the oxidative burst and interleukin\u20106 release in cultured macrophages, whereas macitentan decreased the oxidative burst in isolated human leukocytes. Male C57BL\/6j mice were treated with ISMN (75\u2009mg\/kg\/d) or ISDN (25\u2009mg\/kg\/d) via s.c. infusion for 7 days and some mice in addition with 30\u2009mg\/kg\/d of macitentan (gavage, once daily). ISMN and ISDN <jats:italic>in vivo<\/jats:italic> therapy caused endothelial dysfunction but no nitrate (or cross\u2010)tolerance to the organic nitrates, respectively. ISMN\/ISDN increased blood nitrosative stress, vascular\/cardiac oxidative stress via NOX\u20102 (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. <jats:italic>Conclusion<\/jats:italic>. ISMN\/ISDN treatment caused activation of the NOX\u20102\/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.<\/jats:p>","DOI":"10.1155\/2018\/7845629","type":"journal-article","created":{"date-parts":[[2018,12,27]],"date-time":"2018-12-27T23:30:59Z","timestamp":1545953459000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The Endothelin Receptor Antagonist Macitentan Improves Isosorbide\u20105\u2010Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) Induced Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation"],"prefix":"10.1155","volume":"2018","author":[{"given":"Sebastian","family":"Steven","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Oelze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hausding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyer","family":"Roohani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Kashani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swenja","family":"Kr\u00f6ller-Sch\u00f6n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Helmst\u00e4dter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Baum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Iglarz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eberhard","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"M\u00fcnzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2769-0094","authenticated-orcid":false,"given":"Andreas","family":"Daiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12,27]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.981407"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/eht249"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.05.031"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00392-007-0588-7"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000184694.03262.6d"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000036743.07406.53"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(02)02532-9"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(01)01414-0"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200419267"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.122225199"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2013.09.005"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9295-4"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.245837"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(99)00612-2"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.2133\/dmpk.22.15"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-4165(01)00148-9"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.10.074"},{"key":"e_1_2_12_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehs100"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.11.5244"},{"key":"e_1_2_12_20_2","first-page":"578","article-title":"Endothelin receptor antagonism does not prevent the development of in vivo glyceryl trinitrate tolerance in the rat","volume":"295","author":"Ratz J. 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