The cellular mechanism of action of cardiotonic steroids: A new hypothesis
The cellular mechanism of action of cardiotonic steroids: A new hypothesis
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DOI：
10.3109/10641969809053247
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发表时间：
1998-07-01
影响因子：
12.3
通讯作者：
Golovina, VA
中科院分区：
文献类型：
--
作者：
Blaustein, MP;Juhaszova, M;Golovina, VA
动脉平滑肌（ASM）收缩是由激动剂诱发的肌浆网（SR）的Ca 2+动员触发的。释放的Ca 2+的量，因此，收缩的幅度，直接取决于SR Ca 2+含量。强心类固醇（CTS）的Na+泵抑制间接增加SR的Ca 2+含量，从而增加收缩性。然而，这一系列事件并不能解释多个Naf泵a亚基亚型对Na+和CTS具有不同亲和力的原因，也不能解释低剂量CTS的强心和血管作用，因为CTS不会升高细胞溶质Na+或Ca 2+。我们发现，Na+泵高哇巴因亲和力（α 3）亚型和质膜（PM）Na/Ca交换器被限制在PM域，覆盖连接SR在ASM，而低哇巴因亲和力铝和PM钙泵均匀分布在PM。因此，低剂量的CTS，包括内源性哇巴因样化合物，影响胞质Na+和（间接）Ca 2+浓度仅在PM和连接SR（我们称之为“浆体”的功能单位）之间的细胞质裂缝。反过来，这调节连接SR和细胞反应性的Ca 2+含量。
Arterial smooth muscle (ASM) contraction is triggered by agonist-evoked Ca2+ mobilization from sarcoplasmic reticulum (SR). The amount of Ca2+ released, and thus, the magnitude of the contractions, depends directly on SR Ca2+ content. Na+ pump inhibition by cardiotonic steroids (CTS) indirectly increases the Ca2+ content of the SR and, thus, contractility. This sequence of events does not, however, account for the multiple Naf pump a subunit isoforms with different affinities for Na+ and for CTS, nor does it explain the cardiotonic and vasotonic effects of low doses of CTS that do not elevate cytosolic Na+ or Ca2+. We show that the Na+ pump high ouabain affinity (alpha 3) isoform and the plasmalemmal (PM) Na/Ca exchanger are confined to PM domains that overlie junctional SR in ASM, while low ouabain affinity al and the PM Ca2+ pump are uniformly distributed in the PM. Thus, low doses of CTS, including an endogenous ouabain-like compound, influence cytosolic Na+ and (indirectly) Ca2+ concentrations only in the cytoplasmic clefts between the PM and junctional SR (a functional unit we call the "plasmerosome"). In turn, this modulates the Ca2+ content of the junctional SR and cell responsiveness.