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.
Jump to: Cite & Linked | Documents & Media | Details | Version history
Cite this publication
Sossalla, Samuel, Stefan Wagner, Eva C. L. Rasenack, Hanna Ruff, Sarah L. Weber, Friedrich A. Schoendube, Theodor Tirilomis et al. "Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts - Role of late sodium current and intracellular ion accumulation." Journal of Molecular and Cellular Cardiology 45, no. 1 (2008): 32-43. https://doi.org/10.1016/j.yjmcc.2008.03.006.
Documents & Media
Details
- 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