Effects of ranolazine in a model of doxorubicin-induced left ventricle diastolic dysfunction

Abstract

Background and Purpose: Doxorubicin is a highly effective anticancer drug, but its clinical application is hampered by cardiotoxicity. 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-dependent ROS may explain, in part, Ca2+ and Na+ 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+ current, immediately after completing doxorubicin therapy, could affect diastolic dysfunction and interfere with the progression of functional decline. Experimental Approach: Fischer 344 rats received a cumulative dose of doxorubicin of 15 mg·kg−1 over a period of 2 weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80 mg·kg−1, daily) for the following 4 weeks. Key Results: While diastolic and systolic function progressively deteriorated in doxorubicin-treated 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+/Ca2+ exchanger 1 and Nav 1.5 channels was reduced and of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin-induced hyper-phosphorylation and oxidation of Ca2+/calmodulin-dependent protein kinase II, and decreased myocardial fibrosis. Conclusions and Implications: Ranolazine, by the increased Na+ influx, induced by doxorubicin, altered cardiac Ca2+ and Na+ handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy. Linked Articles: 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 http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.