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• W2034233911 endingPage "334" @default.
• W2034233911 startingPage "326" @default.
• W2034233911 abstract "Long QT syndrome variant 3 (LQT-3) is a channelopathy in which mutations in SCN5A, the gene coding for the primary heart Na(+) channel alpha subunit, disrupt inactivation to elevate the risk of mutation carriers for arrhythmias that are thought to be calcium (Ca(2+))-dependent. Spontaneous arrhythmogenic diastolic activity has been reported in myocytes isolated from mice harboring the well-characterized Delta KPQ LQT-3 mutation but the link to altered Ca(2+) cycling related to mutant Na(+) channel activity has not previously been demonstrated. Here we have investigated the relationship between elevated sarcoplasmic reticulum (SR) Ca(2+) load and induction of spontaneous diastolic inward current (I(TI)) in myocytes expressing Delta KPQ Na(+) channels, and tested the sensitivity of both to the antianginal compound ranolazine. We combined whole-cell patch clamp measurements, imaging of intracellular Ca(2+), and measurement of SR Ca(2+) content using a caffeine dump methodology. We compared the Ca(2+) content of Delta KPQ(+/-) myocytes displaying I(TI) to those without spontaneous diastolic activity and found that I(TI) induction correlates with higher sarcoplasmic reticulum (SR) Ca(2+). Both spontaneous diastolic I(TI) and underlying Ca(2+) waves are inhibited by ranolazine at concentrations that preferentially target I(NaL) during prolonged depolarization. Furthermore, ranolazine I(TI) inhibition is accompanied by a small but significant decrease in SR Ca(2+) content. Our results provide the first direct evidence that induction of diastolic transient inward current (I(TI)) in Delta KPQ(+/-) myocytes occurs under conditions of elevated SR Ca(2+) load." @default.
• W2034233911 created "2016-06-24" @default.
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• W2034233911 date "2009-08-01" @default.
• W2034233911 modified "2023-10-13" @default.
• W2034233911 title "Diastolic transient inward current in long QT syndrome type 3 is caused by Ca2+ overload and inhibited by ranolazine" @default.
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• W2034233911 doi "https://doi.org/10.1016/j.yjmcc.2009.04.003" @default.
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