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


METHODS
Fischer 344 rats received a cumulative dose of doxorubicin of 15 mg·kg-1over 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.


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 Nav1.5 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
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.


BACKGROUND
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.
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Donato
D
Cappetta
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Grazia
G
Esposito
Department of Neuroscience, Drug Research and Child's Health (NeuroFarBa), Division of Pharmacology, University of Florence, Florence, Italy.
Raffaele
R
Coppini
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Elena
E
Piegari
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Rosa
R
Russo
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Loreta Pia
LP
Ciuffreda
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Alessia
A
Rivellino
Department of Neuroscience, Drug Research and Child's Health (NeuroFarBa), Division of Pharmacology, University of Florence, Florence, Italy.
Lorenzo
L
Santini
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Concetta
C
Rafaniello
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Cristina
C
Scavone
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Francesco
F
Rossi
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Liberato
L
Berrino
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Konrad
K
Urbanek
Department of Experimental Medicine, Division of Pharmacology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Antonella
A
De Angelis
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D066126:Cardiotoxicity / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D000073039:Nitrosative Stress / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D000069458:Ranolazine / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000517:prevention & control*
D000903:Antibiotics, Antineoplastic; D026941:Sodium Channel Blockers; D004317:Doxorubicin; D012964:Sodium; D000069458:Ranolazine; D002118:Calcium