Clemo H F, Stambler B S, Baumgarten C M
Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
Circ Res. 1998 Jul 27;83(2):147-57. doi: 10.1161/01.res.83.2.147.
The hypothesis that cellular hypertrophy in congestive heart failure (CHF) modulates mechanosensitive (ie, swelling- or stretch-activated) 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 0.9x to 0.6x isosmotic solution (296 mOsm/L) was required to elicit an inwardly rectifying swelling-activated cation current (I(Cir,swell)) that reversed near -60 mV and was inhibited by 10 micromol/L Gd3+, a mechanosensitive channel blocker. Block of I(Cir,swell) by Gd3+ simultaneously reduced the volume of normal cells in hyposmotic solutions by up to approximately 10%, but Gd3+ had no effect on volume in isosmotic solution. In contrast, I(Cir,swell) was persistently activated under isosmotic conditions in CHF myocytes, and Gd3+ decreased cell volume by approximately 8%. Osmotic shrinkage in 1.1x to 1.5x isosmotic solution inhibited both I(Cir,swell) and Gd3+-induced cell shrinkage in CHF cells, whereas osmotic swelling only slightly increased I(Cir,swell). The K0.5 and Hill coefficient for Gd3+ block of I(Cir,swell) and Gd3+-induced cell shrinkage were estimated as approximately 2.0 micromol/L and approximately 1.9, respectively, for both normal and CHF cells. In both groups, the effects of Gd3+ on current and volume were blocked by replacing bath Na+ and K+ and were linearly related with varying Gd3+ concentration and the degree of cell swelling. CHF thus altered the set point for and caused persistent activation of I(Cir,swell). This current may contribute to dysrhythmias, hypertrophy, and altered contractile function in CHF and may be a novel target for therapy.
对充血性心力衰竭（CHF）中细胞肥大调节机械敏感（即肿胀或拉伸激活）通道这一假说进行了验证。采用数字视频显微镜和两性霉素穿孔膜片钳技术，测量从正常犬和快速心室起搏诱导的CHF犬分离出的心室肌细胞的细胞体积和离子电流。在正常心肌细胞中，需在0.9倍至0.6倍等渗溶液（296 mOsm/L）中进行渗透压肿胀，才能引发内向整流性肿胀激活阳离子电流（I(Cir,swell)），该电流在-60 mV附近反转，并被10 μmol/L Gd3+（一种机械敏感通道阻滞剂）抑制。Gd3+对I(Cir,swell)的阻断同时使低渗溶液中正常细胞的体积减少多达约10%，但Gd3+对等渗溶液中的细胞体积无影响。相比之下，在CHF心肌细胞的等渗条件下，I(Cir,swell)持续被激活，且Gd3+使细胞体积减少约8%。在1.1倍至1.5倍等渗溶液中的渗透压收缩抑制了CHF细胞中的I(Cir,swell)和Gd3+诱导的细胞收缩，而渗透压肿胀仅使I(Cir,swell)略有增加。对于正常细胞和CHF细胞，Gd3+阻断I(Cir,swell)和Gd3+诱导细胞收缩的半数抑制浓度（K0.5）和希尔系数分别估计约为2.0 μmol/L和约1.9。在两组中，通过更换浴液中的Na+和K+可阻断Gd3+对电流和体积的影响，且其与不同的Gd3+浓度和细胞肿胀程度呈线性相关。因此，CHF改变了I(Cir,swell)的设定点并导致其持续激活。该电流可能导致CHF中的心律失常、肥大和收缩功能改变，可能是一个新的治疗靶点。
