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High doses of the 2 -adrenergic receptor (AR) agonist clenbuterol can induce necrotic myocyte death in the heart and slow-twitch skeletal muscle of the rat. However, it is not known whether this agent can also induce myocyte apoptosis and whether this would occur at a lower dose than previously reported for myocyte necrosis. Male Wistar rats were given single subcutaneous injections of clenbuterol. Immunohistochemistry was used to detect myocyte-specific apoptosis (detected on cryosections via a caspase 3 antibody and confirmed with annexin V, single-strand DNA labeling, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). Myocyte apoptosis was first detected at 2 h and peaked 4 h after clenbuterol administration. The lowest dose of clenbuterol to induce cardiomyocyte apoptosis was 1 µg/kg, with peak apoptosis (0.35 ± 0.05%; P < 0.05) occurring in response to 5 mg/kg. In the soleus, peak apoptosis (5.8 ± 2%; P < 0.05) was induced by the lower dose of 10 µg/kg. Cardiomyocyte apoptosis was detected throughout the ventricles, atria, and papillary muscles. However, this damage was most abundant in the left ventricular subendocardium at a point 1.6 mm, that is, approximately one-quarter of the way, from the apex toward the base. -AR antagonism (involving propranolol, bisoprolol, or ICI 118551) or reserpine was used to show that clenbuterol-induced myocardial apoptosis was mediated through neuromodulation of the sympathetic system and the cardiomyocyte 1 -AR, whereas in the soleus direct stimulation of the myocyte 2 -AR was involved. These data show that, when administered in vivo, 2 -AR stimulation by clenbuterol is detrimental to cardiac and skeletal muscles even at low doses, by inducing apoptosis through 1 - and 2 -AR, respectively. clenbuterol; caspase 3; skeletal muscle; myocardium; adrenergic receptor agonists/antagonists Address for reprint requests and other correspondence: J. G. Burniston, Research Institute for Sports and Exercise Sciences, Liverpool John Moores Univ., Webster St., Liverpool, L3 2ET, United Kingdom (E-mail: j.burniston@livjm.ac.uk )
Journal of Applied Physiology – The American Physiological Society
Published: Apr 1, 2005
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