Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts - Role of late sodium current and intracellular ion accumulation

2008 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts - Role of late sodium current and intracellular ion accumulation​
Sossalla, S. ; Wagner, S. ; Rasenack, E. C. L.; Ruff, H.; Weber, S. L.; Schoendube, F. A.   & Tirilomis, T.  et al.​ (2008) 
Journal of Molecular and Cellular Cardiology45(1) pp. 32​-43​.​ DOI: https://doi.org/10.1016/j.yjmcc.2008.03.006 

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Authors
Sossalla, Samuel ; Wagner, Stefan ; Rasenack, Eva C. L.; Ruff, Hanna; Weber, Sarah L.; Schoendube, Friedrich A. ; Tirilomis, Theodor ; Tenderich, Gero; Hasenfuß, Gerd ; Belardinelli, Luiz; Maier, Lars S. 
Abstract
The goal of this study was to test the hypothesis that the novel anti-ischemic drug ratiolazine, which is known to inhibit late I-Na, could reduce intracellular [Na+](i) and diastolic [Ca2+](i) overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased [Na+](i) and elevated diastolic [Ca2+](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 mu mol/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 similar to 30% without significantly affecting sarcoplasmic reticulum (SR) Ca2+ 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 [Ca2+](i). In the presence of ranolazine the increases in late I-Na, as well as [Na+](i) and diastolic [Ca2+](i) were significantly blunted at all stimulation rates without significantly decreasing Ca2+ transient amplitudes or SR Ca2+ 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 [Ca2+](i) caused by ATX-II, were significantly blunted by ranolazine. These results suggest that ratiolazine may be of therapeutic benefit in conditions of diastolic dysfunction due to elevated [Na+](i) and diastolic [Ca2+](i). (C) 2008 Elsevier Inc. All rights reserved.
Issue Date
2008
Publisher
Academic Press Ltd- Elsevier Science Ltd
Journal
Journal of Molecular and Cellular Cardiology 
ISSN
0022-2828
eISSN
1095-8584

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