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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).

journal_name

J Mol Cell Cardiol

journal_title

Journal of molecular and cellular cardiology

authors

Sossalla S,Wagner S,Rasenack EC,Ruff H,Weber SL,Schöndube FA,Tirilomis T,Tenderich G,Hasenfuss G,Belardinelli L,Maier LS

doi

10.1016/j.yjmcc.2008.03.006

subject

Has Abstract

pub_date

2008-07-01 00:00:00

pages

32-43

issue

eissn

0022-2828

issn

1095-8584

pii

S0022-2828(08)00346-5

journal_volume

pub_type

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