title: Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity.
abstract: BACKGROUND
  Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (I(Na)), reducing the net cytosolic Ca(2+) efflux.
  
  
  OBJECTIVE
  Oxidative stress in the DOCA-salt model may increase late I(Na), resulting in diastolic dysfunction amenable to treatment with ranolazine.
  
  
  RESULTS
  Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E':sham, 31.9 ± 2.8, sham+ranolazine, 30.2 ± 1.9, DOCA-salt, 41.8 ± 2.6, and DOCA-salt+ranolazine, 31.9 ± 2.6; P=0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16 ± 0.01 versus sham+ranolazine, 0.18 ± 0.01 versus DOCA-salt, 0.23 ± 0.2 versus DOCA-salt+ranolazine, 0.17 ± 0.0 1 mm Hg/L; P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt, 0.18 ± 0.02, DOCA-salt+ranolazine, 0.13 ± 0.01, sham, 0.11 ± 0.01, sham+ranolazine, 0.09 ± 0.02 seconds; P=0.0004). Neither late I(Na) nor the Ca(2+) transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca(2+) with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca(2+) response and cross-bridge kinetics.
  
  
  CONCLUSIONS
  Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.
authors.affiliation: Section of Cardiology, University of Illinois at Chicago, 60612, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Lovelock
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Monasky
authors.forename: Euy-Myoung
authors.initials: EM
authors.lastname: Jeong
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Lardin
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Bindiya G
authors.initials: BG
authors.lastname: Patel
authors.forename: Domenico M
authors.initials: DM
authors.lastname: Taglieri
authors.forename: Lianzhi
authors.initials: L
authors.lastname: Gu
authors.forename: Praveen
authors.initials: P
authors.lastname: Kumar
authors.forename: Narayan
authors.initials: N
authors.lastname: Pokhrel
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Dan
authors.initials: D
authors.lastname: Sorescu
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000083:Acetanilides / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003900:Desoxycorticosterone / Q000633:toxicity; D003971:Diastole / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology; D054144:Heart Failure, Diastolic / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008901:Mineralocorticoids / Q000633:toxicity; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D009210:Myofibrils / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*; D000069458:Ranolazine; D012964:Sodium / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D008901:Mineralocorticoids; D010879:Piperazines; D003900:Desoxycorticosterone; D012964:Sodium; D000069458:Ranolazine; D002118:Calcium