title: Long-term administration of ranolazine attenuates diastolic dysfunction and adverse myocardial remodeling in a model of heart failure with preserved ejection fraction.
abstract: BACKGROUND
  To investigate the effects of chronic administration of ranolazine (RAN) on experimental model of heart failure with preserved ejection fraction.
  
  
  METHODS
  Seven-weeks old Dahl salt-sensitive rats were fed a high salt diet for 5weeks to induce hypertension. Afterwards, rats continued with a high salt diet and were administered either with vehicle or RAN (20mg/kg/die, ip) for the following 8weeks. Control rats were maintained on a low salt diet.
  
  
  RESULTS
  While systolic parameters were not altered, diastolic parameters were changed in high salt animals. Hemodynamic analysis showed a decreased dP/dt min, increased LVEDP, longer time constant and steeper slope of the end-diastolic pressure-volume relationship. Treatment with RAN attenuated these alterations and determined a reduction in mortality. Additionally, the magnitude of myocardial hypertrophy and activation of PI3K/Akt pathway were reduced. Alteration in diastolic compliance as a consequence of elevated myocardial stiffness was confirmed by an increase of collagen deposition and activation of pro-fibrotic TGF-β/SMAD3/CTGF signaling. These effects were counteracted by RAN. High salt rats had a decrease in SERCA2 and an increase in Na(+)/Ca(2+) exchanger (NCX). Treatment with RAN reduced NCX expression and determined an increment of SERCA2. Moreover, the levels of nitrotyrosine and oxidized dyhydroethidium were higher in high salt rats. RAN induced a decrement of oxidative stress, supporting the concept that reduction in ROS may mediate beneficial effects.
  
  
  CONCLUSIONS
  Our findings support the possibility that diastolic dysfunction can be attenuated by RAN, indicating its ability to affect active relaxation and passive diastolic compliance.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Angelis
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Cappetta
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Piegari
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rinaldi
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Loreta Pia
authors.initials: LP
authors.lastname: Ciuffreda
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Fiorella Angelica Valeria
authors.initials: FA
authors.lastname: Ferraiolo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Rivellino
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Russo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Donniacuo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy. Electronic address: konrad.urbanek@unina2.it.
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy.
authors.forename: Liberato
authors.initials: L
authors.lastname: Berrino
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000069458:Ranolazine / Q000008:administration & dosage*; D051381:Rats; D020303:Rats, Inbred Dahl; D015398:Signal Transduction / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects*; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D002317:Cardiovascular Agents; D000069458:Ranolazine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Dahl salt-sensitive rats; Diastolic dysfunction; Heart failure with preserved ejection fraction; Ranolazine