Swelling-activated chloride current is persistently activated in ventricular myocytes from dogs with tachycardia-induced congestive heart failure
Swelling-activated chloride current is persistently activated in ventricular myocytes from dogs with tachycardia-induced congestive heart failure
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DOI：
10.1161/01.res.84.2.157
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发表时间：
1999-02-05
影响因子：
20.1
通讯作者：
Baumgarten, CM
中科院分区：
文献类型：
--
作者：
Clemo, HF;Stambler, BS;Baumgarten, CM
充血性心力衰竭 (CHF) 中的细胞肥大调节机械敏感（即肿胀或拉伸激活）阴离子通道的假设得到了测试。使用数字视频显微镜和两性霉素穿孔贴片电压钳测量从正常狗和患有快速心室起搏诱发的 CHF 的狗中分离出的心室肌细胞的细胞体积和离子电流。在正常肌细胞中，需要在 0.9T 至 0.6T 溶液（T，相对渗透压；等渗溶液，296 mOsmol/L）中渗透膨胀才能引发 I-Cl,I-swell，这是一种向外整流的膨胀激活的 Cl- 电流，该电流在 -33 mV 附近反转，并被 1 mmol/L 9-蒽甲酸 (9AC)（一种阴离子通道）抑制。 拦截器。 9AC 阻断 I-Cl,I-swell 同时使低渗溶液中正常细胞的体积增加高达 7%，但 9AC 对等渗或高渗溶液中的体积没有影响。相比之下，CHF肌细胞在等渗条件下I-Cl,I-swell持续被激活，9AC使细胞体积增加9%，1.1T至1.5T溶液中渗透收缩抑制CHF细胞中I-Cl,I-swell和9AC诱导的细胞肿胀，而渗透膨胀仅轻微增加I-Cl,I-swell。 CHF 中完全激活的 9AC 敏感 I-Cl,I-swell 的电流密度比正常肌细胞高 40%。在两组中，9AC敏感电流和9AC诱导的细胞肿胀与渗透压和9AC浓度的变化成正比，并且通过用甲磺酸盐替代浴Cl-来阻断9AC对电流和体积的影响。因此，CHF 改变了 I-Cl、I-swell 的设定点和幅度，并导致其持续激活。我们之前在同一 CHF 模型中观察到机械敏感阳离子通道的类似调节。机械敏感的阴离子和阳离子通道可能导致 CHF 的电生理和收缩紊乱，并可能成为治疗的新靶点。
The hypothesis that cellular hypertrophy in congestive heart failure (CHF) modulates mechanosensitive (ie, swelling- or stretch-activated) anion channels was tested. Digital video microscopy and amphotericin-perforated-patch voltage clamp were used to measure cell volume and ion currents in ventricular myocytes isolated from normal dogs and dogs with rapid ventricular pacing-induced CHF. In normal myocytes, osmotic swelling in 0.9T to 0.6T solution (T, relative osmolarity; isosmotic solution, 296 mOsmol/L) was required to elicit I-Cl,I-swell, an outwardly rectifying swelling-activated Cl- current that reversed near -33 mV and was inhibited by 1 mmol/L 9-anthracene carboxylic acid (9AC), an anion channel blocker. Block of I-Cl,I-swell by 9AC simultaneously increased the volume of normal cells in hyposmotic solutions by up to 7%, but 9AC had no effect on volume in isosmotic or hyperosmotic solutions. In contrast, I-Cl,I-swell was persistently activated under isosmotic conditions in CHF myocytes, and 9AC increased cell volume by 9%, Osmotic shrinkage in 1.1T to 1.5T solution inhibited both I-Cl,I-swell and 9AC-induced cell swelling in CHF cells, whereas osmotic swelling only slightly increased I-Cl,I-swell. The current density for fully activated 9AC-sensitive I-Cl,I-swell was 40% greater in CHF than normal myocytes. In both groups, 9AC-sensitive current and 9AC-induced cell swelling were proportional with changes in osmolarity and 9AC concentration, and the effects of 9AC on current and volume were blocked by replacing bath Cl- with methanesulfonate. CHF thus altered the set point and magnitude of I-Cl,I-swell and resulted in its persistent activation. We previously observed analogous regulation of mechanosensitive cation channels in the same CHF model. Mechanosensitive anion and cation channels may contribute to the electrophysiological and contractile derangements in CHF and may be novel targets for therapy.