{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:35:22Z","timestamp":1791362122144,"version":"4.3.1"},"reference-count":78,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Fundamemntal Clinical Pharma"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Metabolic syndrome (MetS) is a multifaceted disease associated with heart failure (HF), which affects the vascular system. The endothelin (ET) system is a key player in MetS and HF; therefore, targets for ET receptors are of therapeutic interest.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>This study sought to evaluate the effects of macitentan, a dual endothelin receptor antagonist (ERA), in a rat model of MetS\u2010induced heart failure with preserved ejection fraction (HFpEF).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed in 12\u2010week\u2010old Zucker <jats:italic>fa\/fa<\/jats:italic> rats the effects of macitentan (10\u00a0mg\/kg\/day as a food additive for short\u2010term\/7\u2010 or long\u2010term\/90\u2010day treatment) on right ventricular (RV) and left ventricular (LV) function\/remodelling (MRI), RV and LV haemodynamics (catheterization) and RV and LV coronary function (myograph).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After 7\u2010 and 90\u2010days, untreated Zucker <jats:italic>fa\/fa<\/jats:italic> rats presented isolated LV diastolic dysfunction (illustrated by elevated LV end\u2010diastolic pressure [EDP] and LV end\u2010diastolic pressure\u2010volume relationship [EDPVR] without changes in LV EDPVR). This was associated with increased collagen deposition and impaired endothelium\u2010dependent coronary artery relaxation. Macitentan 7\u2010 and 90\u2010day treatment significantly decreased blood pressure and prevented LV, RV and coronary dysfunctions and long\u2010term treatment reduced LV collagen density. Moreover, 7\u2010 and 90\u2010day macitentan treatment significantly reduced cardiac inflammation and reactive oxygen species (ROS) production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Dual ERA macitentan improved both LV and RV diastolic dysfunction. This was associated with improved coronary vasodilation, diminished cardiac oxidative stress and improved blood composition. These results suggest that antagonizing the ET system with macitentan is a promising approach to treat HFpEF and its complications.<\/jats:p><\/jats:sec>","DOI":"10.1111\/fcp.70006","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T18:35:46Z","timestamp":1744223746000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dual ET<sub>A<\/sub>\u2010ET<sub>B<\/sub> receptor antagonism improves metabolic syndrome\u2010induced heart failure with preserved ejection fraction"],"prefix":"10.1111","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8426-9589","authenticated-orcid":false,"given":"Francesca","family":"Lockwood","sequence":"first","affiliation":[{"name":"Univ Rouen Normandie, INSERM U1096, EnVI  Rouen France"},{"name":"Institute for Clinical Medicine, Medical Faculty University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Lachaux","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie, INSERM U1096, EnVI  Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najah","family":"Harouki","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie, INSERM U1096, EnVI  Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Souli\u00e9","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie, INSERM U1096, EnVI  Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel","family":"Nicol","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie, INSERM U1096, EnVI  Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvanie","family":"Renet","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie, INSERM U1096, EnVI  Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana\u00efs","family":"Dumesnil","sequence":"additional","affiliation":[{"name":"Univ Rouen Normandie, INSERM U1096, EnVI  Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Vercauteren","sequence":"additional","affiliation":[{"name":"Idorsia Pharmaceuticals Ltd.  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