{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:27:15Z","timestamp":1780493235527,"version":"3.54.1"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,3,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              There is a paucity of data about the mechanisms by which sacubitril\/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril\/valsartan on vascular function and\n              <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n              bioavailability have not been investigated. We hypothesized that sacubitril\/valsartan therapy increases circulating\n              <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n              levels and improves vascular function in the setting of heart failure.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Male spontaneously hypertensive rats underwent myocardial ischemia\/reperfusion surgery to induce heart failure and were followed for up to 12\u00a0weeks with serial echocardiography. Rats received sacubitril\/valsartan (68\u00a0mg\/kg), valsartan (31\u00a0mg\/kg), or vehicle starting at 4\u00a0weeks after reperfusion. At 8 or 12\u00a0weeks of reperfusion, animals were euthanized and tissues were collected for ex\u00a0vivo analyses of\n              <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n              bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril\/valsartan compared with vehicle. Sacubitril\/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end\u2010diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril\/valsartan, with more sustained improvements afforded by sacubitril\/valsartan. Furthermore, myocardial\n              <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n              bioavailability was significantly enhanced in animals receiving sacubitril\/valsartan therapy.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Sacubitril\/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril\/valsartan\u2010mediated improvements in cardiac and vascular function are likely related to increases in\n              <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>\n              bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.117.008268","type":"journal-article","created":{"date-parts":[[2018,3,4]],"date-time":"2018-03-04T01:10:21Z","timestamp":1520125821000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Combined Angiotensin Receptor\u2013Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure"],"prefix":"10.1161","volume":"7","author":[{"given":"Rishi K.","family":"Trivedi","sequence":"first","affiliation":[{"name":"Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New 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