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2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle
1 Research Institute for Sports and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
2 Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds, United Kingdom
* To whom correspondence should be addressed. E-mail: j.burniston{at}livjm.ac.uk.
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 if 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 using a caspase 3 antibody and confirmed using annexin V, single-strand DNA labelling and TUNEL).
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-1, with peak apoptosis (0.35 ± 0.005 %; P<0.05) occurring in response to 5 mg kg-1. In the soleus, peak apoptosis (5.8 ± 2 %; P<0.05) was induced by the lower dose of 10 µg kg-1. Cardiomyocyte apoptosis occurred 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 towards the base. -AR antagonism (involving propranolol, bisoprolol or ICI 118,551) 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.
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