. Effects of chronic administration of clenbuterol on function and metabolism of adult rat cardiac muscle. Am J Physiol Heart Circ Physiol 288: H1468 -H1476, 2005. First published November 4, 2004 doi: 10.1152/ajpheart.00624.2004, a ␤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 2ϩ handling and substrate preference in cardiac muscle. Rats were treated with either 2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 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 2ϩ 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 2ϩ 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-␣. This study shows that chronic administration of Clen induces cellular hypertrophy and increases oxidative carbohydrate utilization together with an increase in sarcoplasmic reticulum Ca 2ϩ content, which results in increased amplitude of the Ca 2ϩ transients. These effects could be important when Clen is used in conjunction with left ventricular assist devices treatment.sarcoplasmic reticulum Ca 2ϩ content; tricarboxylic cycle; left ventricular assist devices LONG-TERM LEFT VENTRICULAR (LV) assist device (LVAD) support has been shown to improve survival and quality of life in patients with advanced heart failure and contraindications to cardiac transplantation (22). LVAD support is also routinely used as a bridge to transplantation in patients with end-stage heart failure. In a number of patients, with the use of this strategy in association with pharmacological therapy (combination therapy), a significant improvement in myocardial performance has been observed. In some cases the mechanical device could be explanted without resorting to heart transplantation ("bridge to recovery") (11-13, 27, 40).LVAD support results in profound and complex changes in the structure and function of the myocardium, which include "...

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