| Title | Diastolic transient inward current in Long QT Syndrome type 3 is caused by Ca(2+) overload and inhibited by Ranolazine. | | Author(s) | Lindegger N, Hagen B, Marks AR, Lederer WJ, Kass RS | | Institution | Department of Pharmacology, Columbia University College of Physicians & Surgeons, 630 West 168(th)St., New York, NY, 10032, USA. | | Source | J Mol Cell Cardiol 2009 Apr 13. | | 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 DeltaKPQ 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 DeltaKPQ 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 DeltaKPQ(+/-) 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 DeltaKPQ(+/-) myocytes occurs under conditions of elevated SR Ca(2+) load. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19371746 |
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