Sarcoplasmic reticulum Ca2+ release causes myocyte depolarization -: Underlying mechanism and threshold for triggered action potentials
Sarcoplasmic reticulum Ca2+ release causes myocyte depolarization -: Underlying mechanism and threshold for triggered action potentials
复制标题
DOI：
10.1161/01.res.87.9.774
复制
发表时间：
2000-10-27
影响因子：
20.1
通讯作者：
Bers, DM
中科院分区：
文献类型：
--
作者：
Schlotthauer, K;Bers, DM
自发肌浆网 (SR) Ca2+ 释放通过 Ca2+ 诱导的瞬时内向电流 (I-ti) 引起延迟后除极 (DAD)。然而，没有关于以下方面的定量数据：(1) DAD 的 Ca2+ 依赖性，(2) 将细胞去极化至阈值并触发动作电位 (AP) 所需的 Ca2+，或 (3) Ca2+ 激活电流对 DAD 的相对贡献。为了解决这些问题，我们通过在加载 indo 1-AM 的兔心室肌细胞中快速应用咖啡因来诱发 SR Ca2+ 释放，并用全细胞电流钳测量咖啡因诱导的 DAD (cDAD)。肌细胞的SR Ca2+负荷随AP频率的不同而变化。每 88+/-8 nmol/L Delta [Ca2+](i)（简单指数），cDAD 幅度就会加倍，并且 424+/-58 nmol/L 的 Delta [Ca2+](i) 阈值足以触发 AP。对于相同的 Delta [Ca2+](i)，通过去除 [Na](o) 和 [Ca2+](o)（或使用 5 mmol/L Ni2+）阻断 Na+-Ca2+ 交换电流 (I-Na/Ca)，可将 cDAD 降低 >90%。相反，用50μmol/L尼氟酯阻断Ca2+激活的Cl-电流(I-Cl(Ca))并没有显着改变cDAD。我们得出结论，DAD 几乎完全是由于 I-Na/Ca，而不是 I-Cl(Ca) 或 Ca2+ 激活的非选择性阳离子电流。要触发 AP，需要 30 至 40 μmol/L 胞质 Ca2+ 或 424 nmol/L 的 [Ca2+](i) 瞬态。通过电流注入模拟不同时间进程的 I(ti)，结果表明更快的 I(ti) 需要更少的 AP 触发电荷。鉴于自发 SR Ca2+ 释放以波形式发生，其速度比 cDAD 或快速 I(ti)s 慢，AP 激活的真正 Delta [Ca2+](i) 阈值可能比正常肌细胞高大约 3 倍。这为正常心室肌细胞提供了对抗心律失常的安全裕度。
Spontaneous sarcoplasmic reticulum (SR) Ca2+ release causes delayed afterdepolarizations (DADs) via Ca2+-induced transient inward currents (I-ti). However, no quantitative data exists regarding (1) Ca2+ dependence of DADs, (2) Ca2+ required to depolarize the cell to threshold and trigger an action potential (AP), or (3) relative contributions of Ca2+-activated currents to DADs. To address these points, we evoked SR Ca2+ release by rapid application of caffeine in indo 1-AM-loaded rabbit ventricular myocytes and measured caffeine-induced DADs (cDADs) with whole-cell current clamp. The SR Ca2+ load of the myocyte was varied by different AP frequencies. The cDAD amplitude doubled for every 88+/-8 nmol/L of Delta [Ca2+](i) (simple exponential), and the Delta [Ca2+](i) threshold of 424+/-58 nmol/L was sufficient to trigger an AP. Blocking Na+-Ca2+ exchange current (I-Na/Ca) by removal of [Na](o) and [Ca2+](o) (or with 5 mmol/L Ni2+) reduced cDADs by >90%, for the same Delta [Ca2+](i). In contrast, blockade of Ca2+-activated Cl- current (I-Cl(Ca)) with 50 mu mol/L niflumate did not significantly alter cDADs. We conclude that DADs are almost entirely due to I-Na/Ca, not I-Cl(Ca) or Ca2+-activated nonselective cation current. To trigger an AP requires 30 to 40 mu mol/L cytosolic Ca2+ or a [Ca2+](i) transient of 424 nmol/L. Current injection, simulating I(ti)s with different time courses, revealed that faster I(ti)s require less charge for AP triggering. Given that spontaneous SR Ca2+ release occurs in waves, which are slower than cDADs or fast I(ti)s, the true Delta [Ca2+](i) threshold for AP activation may be approximate to3-fold higher in normal myocytes. This provides a safety margin against arrhythmia in normal ventricular myocytes.