Linked Life Data

18439620

Source:http://linkedlifedata.com/resource/pubmed/id/18439620

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2008-6-27
pubmed:abstractText
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).
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1095-8584
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
32-43
pubmed:meshHeading
pubmed-meshheading:18439620-Acetanilides, pubmed-meshheading:18439620-Adult, pubmed-meshheading:18439620-Aged, pubmed-meshheading:18439620-Animals, pubmed-meshheading:18439620-Calcium, pubmed-meshheading:18439620-Cardiotonic Agents, pubmed-meshheading:18439620-Cnidarian Venoms, pubmed-meshheading:18439620-Diastole, pubmed-meshheading:18439620-Enzyme Inhibitors, pubmed-meshheading:18439620-Female, pubmed-meshheading:18439620-Heart Failure, pubmed-meshheading:18439620-Heart Ventricles, pubmed-meshheading:18439620-Humans, pubmed-meshheading:18439620-Ion Transport, pubmed-meshheading:18439620-Male, pubmed-meshheading:18439620-Middle Aged, pubmed-meshheading:18439620-Myocardial Contraction, pubmed-meshheading:18439620-Myocardium, pubmed-meshheading:18439620-Myocytes, Cardiac, pubmed-meshheading:18439620-Piperazines, pubmed-meshheading:18439620-Rabbits, pubmed-meshheading:18439620-Sodium
pubmed:year
2008
pubmed:articleTitle
Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts--role of late sodium current and intracellular ion accumulation.
pubmed:affiliation
Heart Center, Georg-August-University Göttingen, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't