Original article Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts — Role of late sodium current and intracellular ion accumulation Samuel Sossalla a , Stefan Wagner a , Eva C.L. Rasenack a , Hanna Ruff a , Sarah L. Weber a , Friedrich A. Schöndube a , Theodor Tirilomis a , Gero Tenderich b , Gerd Hasenfuss a , Luiz Belardinelli c , Lars S. Maier a, ⁎ a Heart Center, Georg-August-University Göttingen, Germany b Department of Cardiovascular Surgery, Heart and Diabetes Center Bad Oeynhausen, Germany c CV Therapeutics, Palo Alto, CA, USA Received 17 December 2007; received in revised form 22 February 2008; accepted 4 March 2008 Available online 14 March 2008 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 μmol/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 ~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 . © 2008 Elsevier Inc. All rights reserved. Keywords: Diastolic dysfunction; Heart failure; Na channel inhibition; Diastolic Ca concentration; Intracellular Na concentration; Late Na current; SR Ca content; Stimulation frequency 1. Introduction Heart failure is associated with imbalances of cellular Ca 2+ and Na + homeostasis. An increase in intracellular Na + ([Na + ] i ) can lead to cytosolic Ca 2+ ([Ca 2+ ] i ) overload followed by left ventricular (LV) dysfunction [1]. Diastolic dysfunction, which can be caused by elevated diastolic [Ca 2+ ] i , becomes manifested when ventricular relaxation is significantly impaired, leading to decreases in filling and stroke volume. Heart failure is typically associated with a reduced re-uptake of cytosolic Ca 2+ by the SR due to a decrease in SR Ca 2+ -ATPase (SERCA) expression and activity thus contributing to elevated diastolic [Ca 2+ ] i and diastolic dysfunction especially when Ca 2+ extrusion through the Na + /Ca 2+ exchanger (NCX) is concomitantly reduced [1]. In contrast, when NCX is markedly up-regulated (in the presence Available online at www.sciencedirect.com Journal of Molecular and Cellular Cardiology 45 (2008) 32 – 43 www.elsevier.com/locate/yjmcc ⁎ Corresponding author. Department Cardiology and Pneumology/Heart Center, Georg-August-University Göttingen, Robert-Koch-Street 40, 37075 Göttingen, Germany. Tel.: +49 551 399481; fax: +49 551 398941. E-mail address: lmaier@med.uni-goettingen.de (L.S. Maier). 0022-2828/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yjmcc.2008.03.006