Soppa Gopal K R, Smolenski Ryszard T, Latif Najma, Yuen Ada H Y, Malik Aalya, Karbowska Joanna, Kochan Zdzislaw, Terracciano Cesare M N, Yacoub Magdi H
Imperial College London, National Heart and Lung Institute, Harefield Heart Science Centre, Harefield, Middlesex UB9 6JH, UK.
Am J Physiol Heart Circ Physiol. 2005 Mar;288(3):H1468-76. doi: 10.1152/ajpheart.00624.2004. Epub 2004 Nov 4.
Clenbuterol (Clen), a beta(2)-agonist, is known to produce skeletal and myocardial hypertrophy. This compound has recently been used in combination with left ventricular assist devices for the treatment of end-stage heart failure to reverse or prevent the adverse effects of unloading-induced myocardial atrophy. However, the mechanisms of action of Clen on myocardial cells have not been fully elucidated. In an attempt to clarify this issue, we examined the effects of chronic administration of Clen on Ca(2+) handling and substrate preference in cardiac muscle. Rats were treated with either 2 mg x kg(-1) x day(-1) Clen or saline (Sal) for 4 wk with the use of osmotic minipumps. Ventricular myocytes were enzymatically dissociated. Cells were field stimulated at 0.5, 1, and 2 Hz, and cytoplasmic Ca(2+) transients were monitored with the use of the fluorescent indicator indo-1 acetoxymethyl ester. Two-dimensional surface area and action potentials in current clamp were also measured. We found that in the Clen group there was significant hypertrophy at the organ and cellular levels compared with Sal. In Clen myocytes, the amplitude of the indo-1 ratio transients was significantly increased. Sarcoplasmic reticulum Ca(2+) content, estimated by rapid application of 20 mM caffeine, was significantly increased in the Clen group. The action potential was prolonged in the Clen group compared with Sal. Carbohydrate contribution to the tricarboxylic cycle (Krebs cycle) flux was increased several times in the Clen group. This increase was associated with decreased expression of peroxisome proliferator-activated receptor-alpha. This study shows that chronic administration of Clen induces cellular hypertrophy and increases oxidative carbohydrate utilization together with an increase in sarcoplasmic reticulum Ca(2+) content, which results in increased amplitude of the Ca(2+) transients. These effects could be important when Clen is used in conjunction with left ventricular assist devices treatment.
克仑特罗（Clen）是一种β₂肾上腺素能激动剂，已知可导致骨骼和心肌肥大。该化合物最近已与左心室辅助装置联合用于治疗终末期心力衰竭，以逆转或预防卸载诱导的心肌萎缩的不良反应。然而，Clen对心肌细胞的作用机制尚未完全阐明。为了阐明这个问题，我们研究了长期给予Clen对心肌中钙（Ca²⁺）处理和底物偏好的影响。使用渗透微型泵，将大鼠用2mg·kg⁻¹·天⁻¹的Clen或生理盐水（Sal）处理4周。通过酶解法分离心室肌细胞。以0.5、1和2Hz的频率对细胞进行场刺激，并使用荧光指示剂indo-1乙酰氧基甲酯监测细胞质Ca²⁺瞬变。还测量了二维表面积和电流钳中的动作电位。我们发现，与Sal组相比，Clen组在器官和细胞水平上有明显的肥大。在Clen处理的心肌细胞中，indo-1比率瞬变的幅度显著增加。通过快速施加20mM咖啡因估计的肌浆网Ca²⁺含量，在Clen组中显著增加。与Sal组相比，Clen组的动作电位延长。Clen组中碳水化合物对三羧酸循环（克雷布斯循环）通量的贡献增加了几倍。这种增加与过氧化物酶体增殖物激活受体-α的表达降低有关。本研究表明，长期给予Clen可诱导细胞肥大，并增加氧化碳水化合物的利用以及肌浆网Ca²⁺含量的增加，这导致Ca²⁺瞬变幅度增加。当Clen与左心室辅助装置治疗联合使用时，这些作用可能很重要。
