Department of Medicine, Krannert Institute of Cardiology and Division of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Heart Rhythm. 2012 Jul;9(7):1125-32. doi: 10.1016/j.hrthm.2012.02.031. Epub 2012 Mar 1.
Na channel blockers are effective in suppressing delayed afterdepolarizations (DADs) in isolated Purkinje fibers. However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs.
To test the hypothesis that combined Na channel and type 2 ryanodine receptor channel blocker ((R)-propafenone) is more effective than a Na channel blocker (lidocaine) in suppressing SCaE and DADs in the intact rabbit ventricles.
We compared (R)-propafenone (3 μmol/L) with lidocaine (50 μmol/L) on SCaE and DADs by using epicardial optical mapping of intracellular calcium (Ca(i)) and membrane voltage in Langendorff-perfused rabbit hearts. SCaE and DADs were induced by rapid pacing trains and isoproterenol (0.3 μmol/L) infusion. One arbitrary unit is equivalent to the Ca transient amplitude of paced beats.
SCaEs were observed at the cessation of rapid pacing in all hearts at baseline. (R)-Propafenone nearly completely inhibited DADs and SCaE (0.04 arbitrary units [95% confidence interval 0.02-0.06] vs 0.23 arbitrary units [95% confidence interval 0.18-0.28] at baseline; n = 6 hearts; P <.001). Lidocaine also significantly reduced the SCaE but was significantly (P <.05) less effective than (R)-propafenone. Both drugs increased the rise time of action potential upstroke and reduced conduction velocity to a similar extent, suggesting a significant inhibition of I(Na).
Both Na channel blockers significantly reduced tachycardia-induced SCaEs in the rabbit ventricles, but (R)-propafenone was significantly more effective than lidocaine. These data suggest that type 2 ryanodine receptor inhibition potentiates the activity of Na channel blockers against SCaE and DADs in the intact hearts.
钠通道阻滞剂在抑制分离的浦肯野纤维中的延迟后去极化（DAD）方面非常有效。然而，在缺乏钙调蛋白的分离的小鼠心室肌细胞中，只有那些同时抑制 2 型ryanodine 受体通道的钠通道阻滞剂才对自发性钙升高（SCaE）和 DAD 有效。
测试假设，即联合钠通道和 2 型 ryanodine 受体通道阻滞剂（（R）-普罗帕酮）比钠通道阻滞剂（利多卡因）更有效地抑制完整兔心室中的 SCaE 和 DAD。
我们使用 Langendorff 灌注兔心的细胞内钙（Ca(i)）和膜电压的心外膜光学映射，比较（R）-普罗帕酮（3 μmol/L）与利多卡因（50 μmol/L）对 SCaE 和 DAD 的作用。通过快速起搏刺激和异丙肾上腺素（0.3 μmol/L）输注诱导 SCaE 和 DAD。一个任意单位等于起搏节拍的钙瞬变幅度。
在所有基线心脏的快速起搏刺激停止时，都观察到了 SCaE。（R）-普罗帕酮几乎完全抑制 DAD 和 SCaE（0.04 个任意单位[95%置信区间 0.02-0.06]与基线时的 0.23 个任意单位[95%置信区间 0.18-0.28]；n = 6 个心脏；P<.001）。利多卡因也显著降低了 SCaE，但与（R）-普罗帕酮相比显著（P<.05）效果较差。两种药物均显著增加动作电位上升的上升时间并以相似的程度降低传导速度，表明对 I(Na)有明显的抑制作用。
两种钠通道阻滞剂均显著降低了兔心室中的心动过速诱导的 SCaE，但（R）-普罗帕酮比利多卡因更有效。这些数据表明，2 型 ryanodine 受体抑制增强了钠通道阻滞剂对完整心脏中 SCaE 和 DAD 的作用。
