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₂-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle

¹Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool ²Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds General Infirmary, Leeds, United Kingdom

Submitted 22 June 2004 ; accepted in final form 6 December 2004

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

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