Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
J Am Coll Cardiol. 2010 Feb 23;55(8):801-9. doi: 10.1016/j.jacc.2009.10.033.
This study investigated whether ranolazine reduces dofetilide-induced torsades de pointes (TdP) in a model of long QT syndrome with down-regulated K(+) currents due to hypertrophic remodeling in the dog with chronic atrioventricular block (cAVB).
Ranolazine inhibits the late Na(+) current (I(NaL)) and is effective against arrhythmias in long QT3 syndromes despite its blocking properties of the rapid component of delayed rectifying potassium current.
Ranolazine was administered to cAVB dogs before or after TdP induction with dofetilide and electrophysiological parameters were determined including beat-to-beat variability of repolarization (BVR). In single ventricular myocytes, effects of ranolazine were studied on I(NaL), action potential duration, and dofetilide-induced BVR and early afterdepolarizations.
After dofetilide, ranolazine reduced the number of TdP episodes from 10 +/- 3 to 3 +/- 1 (p < 0.05) and partially reversed the increase of BVR with no abbreviation of the dofetilide-induced QT prolongation. Likewise, pre-treatment with ranolazine, or using lidocaine as a specific Na(+) channel blocker, attenuated TdP, but failed to prevent dofetilide-induced increases in QT, BVR, and ectopic activity. In cAVB myocytes, ranolazine suppressed dofetilide-induced early afterdepolarizations in 25% of cells at 5 micromol/l, in 75% at 10 micromol/l, and in 100% at 15 micromol/l. At 5 micromol/l, ranolazine blocked 26 +/- 3% of tetrodotoxin-sensitive I(NaL), and 49 +/- 3% at 15 micromol/l. Despite a 54% reduction of I(NaL) amplitude in cAVB compared with control cells, I(NaL) inhibition by 5 micromol/l tetrodotoxin equally shortened relative action potential duration and completely abolished dofetilide-induced early afterdepolarizations.
Despite down-regulation of I(NaL) in remodeled cAVB hearts, ranolazine is antiarrhythmic against drug-induced TdP. The antiarrhythmic effects are reflected in concomitant changes of BVR.
本研究旨在探讨雷诺嗪是否能降低因慢性房室传导阻滞（cAVB）犬肥厚重塑导致的 K+电流下调而引起的长 QT 综合征模型中多非利特诱发的尖端扭转型室性心动过速（TdP）。
雷诺嗪抑制晚期 Na+电流（I(NaL)），尽管其对快速延迟整流钾电流的阻断特性，但对长 QT3 综合征的心律失常仍有疗效。
在多非利特诱发 TdP 之前或之后，将雷诺嗪给予 cAVB 犬，并确定电生理参数，包括复极搏动间变异性（BVR）。在单个心室肌细胞中，研究了雷诺嗪对 I(NaL)、动作电位持续时间以及多非利特诱导的 BVR 和早期后除极的影响。
给予多非利特后，雷诺嗪将 TdP 发作次数从 10 +/- 3 减少至 3 +/- 1（p < 0.05），并部分逆转了 BVR 的增加，而没有缩短多非利特引起的 QT 延长。同样，雷诺嗪预处理或使用利多卡因作为特定的 Na+通道阻滞剂可减轻 TdP，但不能预防多非利特引起的 QT 延长、BVR 和异位活动增加。在 cAVB 心肌细胞中，雷诺嗪在 5μmol/l 时抑制 25%的细胞中多非利特诱导的早期后除极，在 10μmol/l 时抑制 75%的细胞，在 15μmol/l 时抑制 100%的细胞。在 5μmol/l 时，雷诺嗪阻断 26 +/- 3%的河豚毒素敏感的 I(NaL)，而在 15μmol/l 时阻断 49 +/- 3%。尽管与对照细胞相比，cAVB 中的 I(NaL)幅度降低了 54%，但 5μmol/l 的河豚毒素对 I(NaL)的抑制同样缩短了相对动作电位持续时间，并完全消除了多非利特诱导的早期后除极。
尽管在重塑的 cAVB 心脏中 I(NaL)下调，但雷诺嗪对药物诱导的 TdP 具有抗心律失常作用。抗心律失常作用反映在 BVR 的伴随变化中。
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