title: Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts--role of late sodium current and intracellular ion accumulation.
abstract: The goal of this study was to test the hypothesis that the novel anti-ischemic drug ranolazine, which is known to inhibit late I(Na), could reduce intracellular [Na(+)](i) and diastolic [Ca(2+)](i) overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased [Na(+)](i) and elevated diastolic [Ca(2+)](i). Increased Na(+) influx through voltage-gated Na(+) channels (late I(Na)) has been suggested to contribute to elevated [Na(+)](i) in HF. In isometrically contracting ventricular muscle strips from end-stage failing human hearts, ranolazine (10 micromol/L) did not exert negative inotropic effects on twitch force amplitude. However, ranolazine significantly reduced frequency-dependent increase in diastolic tension (i.e., diastolic dysfunction) by approximately 30% without significantly affecting sarcoplasmic reticulum (SR) Ca(2+) loading. To investigate the mechanism of action of this beneficial effect of ranolazine on diastolic tension, Anemonia sulcata toxin II (ATX-II, 40 nmol/L) was used to increase intracellular Na(+) loading in ventricular rabbit myocytes. ATX-II caused a significant rise in [Na(+)](i) typically seen in heart failure via increased late I(Na). In parallel, ATX-II significantly increased diastolic [Ca(2+)](i). In the presence of ranolazine the increases in late I(Na), as well as [Na(+)](i) and diastolic [Ca(2+)](i) were significantly blunted at all stimulation rates without significantly decreasing Ca(2+) transient amplitudes or SR Ca(2+) content. In summary, ranolazine reduced the frequency-dependent increase in diastolic tension without having negative inotropic effects on contractility of muscles from end-stage failing human hearts. Moreover, in rabbit myocytes the increases in late I(Na), [Na(+)](i) and [Ca(2+)](i) caused by ATX-II, were significantly blunted by ranolazine. These results suggest that ranolazine may be of therapeutic benefit in conditions of diastolic dysfunction due to elevated [Na(+)](i) and diastolic [Ca(2+)](i).
authors.affiliation: Heart Center, Georg-August-University Göttingen, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Eva C L
authors.initials: EC
authors.lastname: Rasenack
authors.forename: Hanna
authors.initials: H
authors.lastname: Ruff
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Weber
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Schöndube
authors.forename: Theodor
authors.initials: T
authors.lastname: Tirilomis
authors.forename: Gero
authors.initials: G
authors.lastname: Tenderich
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
mesh_terms: D000083:Acetanilides / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D003064:Cnidarian Venoms / Q000494:pharmacology; D003971:Diastole / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D000069458:Ranolazine; D012964:Sodium / Q000378:metabolism*
chemical_list: D000083:Acetanilides; D002316:Cardiotonic Agents; D003064:Cnidarian Venoms; D004791:Enzyme Inhibitors; D010879:Piperazines; C028800:toxin II (Anemonia sulcata); D012964:Sodium; D000069458:Ranolazine; D002118:Calcium