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

被引：71

作者：

Cappetta, Donato ^{[1
]}

Esposito, Grazia ^{[1
]}

Coppini, Raffaele ^{[2
]}

Piegari, Elena ^{[1
]}

Russo, Rosa ^{[1
]}

Ciuffreda, Loreta Pia ^{[1
]}

Rivellino, Alessia ^{[1
]}

Santini, Lorenzo ^{[2
]}

Rafaniello, Concetta ^{[1
]}

Scavone, Cristina ^{[1
]}

Rossi, Francesco ^{[1
]}

Berrino, Liberato ^{[1
]}

Urbanek, Konrad ^{[1
]}

De Angelis, Antonella ^{[1
]}

机构：

[1] Univ Campania Vanvitelli, Div Pharmacol, Dept Expt Med, Via Costantinopoli 16, I-80138 Naples, Italy

[2] Univ Florence, Div Pharmacol, Dept Neurosci Drug Res & Childs Hlth NeuroFarBa, Florence, Italy

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2017年 / 174卷 / 21期

关键词：

LATE SODIUM CURRENT; CONCISE GUIDE; INDUCED CARDIOMYOPATHY; AMERICAN-SOCIETY; OXIDATIVE STRESS; NAD(P)H OXIDASE; CARDIO-ONCOLOGY; HEART-FAILURE; CARDIOTOXICITY; PHARMACOLOGY;

D O I：

10.1111/bph.13791

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 Na-v 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.

引用

页码：3696 / 3712

页数：17

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