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Asymptomatic diastolic dysfunction can be the earliest manifestation of doxorubicin cardiotoxicity. Therefore, a search for therapeutic intervention that can interfere with early manifestations and possibly prevent later development of cardiotoxicity is warranted. Increased doxorubicin\u2010dependent ROS may explain, in part, Ca<jats:sup>2+<\/jats:sup> and Na<jats:sup>+<\/jats:sup> overload that contributes to diastolic dysfunction and development of heart failure. Therefore, we tested whether the administration of ranolazine, a selective blocker of late Na<jats:sup>+<\/jats:sup> current, immediately after completing doxorubicin therapy, could affect diastolic dysfunction and interfere with the progression of functional decline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Fischer 344 rats received a cumulative dose of doxorubicin of 15\u00a0mg\u00b7kg<jats:sup>\u22121<\/jats:sup> over a period of 2\u00a0weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80\u00a0mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, daily) for the following 4\u00a0weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>While diastolic and systolic function progressively deteriorated in doxorubicin\u2010treated animals, treatment with ranolazine relieved diastolic dysfunction and prevented worsening of systolic function, decreasing mortality. Ranolazine lowered myocardial NADPH oxidase 2 expression and oxidative\/nitrative stress. Expression of the Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> exchanger 1 and Na<jats:sub>v<\/jats:sub> 1.5 channels was reduced and of the sarcoplasmic\/endoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>\u2010ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin\u2010induced hyper\u2010phosphorylation and oxidation of Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010dependent protein kinase II, and decreased myocardial fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Ranolazine, by the increased Na<jats:sup>+<\/jats:sup> influx, induced by doxorubicin, altered cardiac Ca<jats:sup>2+<\/jats:sup> and Na<jats:sup>+<\/jats:sup> handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v174.21\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v174.21\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13791","type":"journal-article","created":{"date-parts":[[2017,3,20]],"date-time":"2017-03-20T22:12:41Z","timestamp":1490047961000},"page":"3696-3712","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Effects of ranolazine in a model of doxorubicin\u2010induced left ventricle diastolic dysfunction"],"prefix":"10.1111","volume":"174","author":[{"given":"Donato","family":"Cappetta","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, Division of Pharmacology University of Campania \u201cLuigi Vanvitelli\u201d  Naples 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