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Am J Physiol Heart Circ Physiol (November 4, 2004). doi:10.1152/ajpheart.00624.2004
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Submitted on June 23, 2004
Accepted on October 31, 2004

Effects of Chronic Administration of Clenbuterol on Function and Metabolism of Adult Rat Cardiac Muscle

Gopal K Soppa1, Ryszard T Smolenski1, Najma Latif1, A H Yuen1, Aalya H Malik2, Joanna Karbowska3, Zdzislaw Kochan3, Cesare M Terracciano1*, and Magdi H Yacoub1

1 Harefield Heart Science Centre, Imperial College London, NHLI, Harefield, United Kingdom
2 Harefield Heart Science Centre, Imperial College London, NHLI, Harefield, United Kingdom; Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
3 Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland

* To whom correspondence should be addressed. E-mail: c.terracciano{at}imperial.ac.uk.

Clenbuterol, 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 (LVAD) 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 clenbuterol on myocardial cells have not been fully elucidated. In an attempt to clarify this issue we have examined the effects of chronic administration of clenbuterol on Ca2+ handling and substrate preference in cardiac muscle. Rats were treated with either 2mg/kg/day clenbuterol (Clen) or saline (Sal) for 4 weeks using osmotic minipumps. Ventricular myocytes were enzymatically dissociated. Cells were field-stimulated at 0.5 Hz, 1Hz and 2Hz and cytoplasmic Ca2+ transients monitored using the fluorescent indicator Indo-1-AM. Two-dimensional surface area and action potentials in current-clamp were also measured. We found that in the Clen group there was a significant hypertrophy at the organ and cellular level compared with Sal. In Clen myocytes the amplitude of the Indo-1 ratio transients was significantly increased. Sarcoplasmic reticulum (SR) Ca2+ 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 Krebs cycle flux was increased several times in the Clen group. This increase was associated with decreased expression of peroxisome proliferator activated receptor {alpha} (PPAR{alpha}). This study has shown that chronic administration of clenbuterol induces cellular hypertrophy and increases oxidative carbohydrate utilisation together with an increase in SR Ca2+ content, which results in increased amplitude of the Ca2+ transients. These effects could be important when clenbuterol is used in conjunction with LVAD treatment.




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