Systemic administration of β 2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses

Abstract

1 β 2-Adrenoceptor agonists provide a potential therapy for muscle wasting and weakness, but their use may be limited by adverse effects on the heart, mediated in part, by β 1-adrenoceptor activation. 2 Two β 2-agonists, formoterol and salmeterol, are approved for treating asthma and have an extended duration of action and increased safety, associated with greater β 2-adrenoceptor selectivity. 3 The pharmacological profiles of formoterol and salmeterol and their effects on skeletal and cardiac muscle mass were investigated in 12-week-old, male F344 rats. Formoterol and salmeterol were each administered via daily i.p. injection at one of seven doses (ranging from 1 to 2000 μg kg -1 day -1), for 4 weeks. Rats were anaesthetised and the EDL and soleus muscles and the heart were excised and weighed. Dose-response curves were constructed based on skeletal and cardiac muscle hypertrophy. 4 Formoterol was more potent than salmeterol, with a significantly lower ED 50 in EDL muscles (1 and 130 μg kg -1 day -1, P <0.05), whereas salmeterol had greater intrinsic activity than formoterol in both EDL and soleus muscles (12% greater hypertrophy than formoterol). The drugs had similar potency and intrinsic activity in the heart, with a smaller leftward shift for formoterol than seen in skeletal muscle. A dose of 25 μg kg -1 day -1 of formoterol elicited greater EDL and soleus hypertrophy than salmeterol, but resulted in similar β-adrenoceptor downregulation. 5 These results show that doses as low as 1 μg kg -1 day -1 of formoterol can elicit significant muscle hypertrophy with minimal cardiac hypertrophy and provide important information regarding the potential therapeutic use of formoterol and salmeterol for muscle wasting. © 2006 Nature Publishing Group All rights reserved.