Systemic administration of ß2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses.

James Ryall, Martin Sillence, Gordon Lynch

    Research output: Contribution to journalArticle

    70 Citations (Scopus)

    Abstract

    ß2-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 ß1-adrenoceptor activation. * Two ß2-agonists, formoterol and salmeterol, are approved for treating asthma and have an extended duration of action and increased safety, associated with greater ß2-adrenoceptor selectivity. * 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 'g 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. * Formoterol was more potent than salmeterol, with a significantly lower ED50 in EDL muscles (1 and 130 'g 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 'g kg'1 day'1 of formoterol elicited greater EDL and soleus hypertrophy than salmeterol, but resulted in similar ß-adrenoceptor downregulation. * These results show that doses as low as 1 'g 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.
    Original languageEnglish
    Pages (from-to)587-595
    Number of pages9
    JournalBritish Journal of Pharmacology
    Volume147
    Issue number6
    DOIs
    Publication statusPublished - 2006

    Fingerprint

    Adrenergic Receptors
    Hypertrophy
    Skeletal Muscle
    Cardiomegaly
    Muscles
    Myocardium
    Formoterol Fumarate
    Salmeterol Xinafoate
    Muscle Weakness
    Inbred F344 Rats
    Therapeutic Uses
    Down-Regulation
    Asthma
    Pharmacology
    Safety
    Injections
    Pharmaceutical Preparations

    Cite this

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    title = "Systemic administration of {\~A}Ÿ2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses.",
    abstract = "{\~A}Ÿ2-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 {\~A}Ÿ1-adrenoceptor activation. * Two {\~A}Ÿ2-agonists, formoterol and salmeterol, are approved for treating asthma and have an extended duration of action and increased safety, associated with greater {\~A}Ÿ2-adrenoceptor selectivity. * 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 'g 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. * Formoterol was more potent than salmeterol, with a significantly lower ED50 in EDL muscles (1 and 130 'g 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 'g kg'1 day'1 of formoterol elicited greater EDL and soleus hypertrophy than salmeterol, but resulted in similar {\~A}Ÿ-adrenoceptor downregulation. * These results show that doses as low as 1 'g 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.",
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    Systemic administration of ß2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses. / Ryall, James; Sillence, Martin; Lynch, Gordon.

    In: British Journal of Pharmacology, Vol. 147, No. 6, 2006, p. 587-595.

    Research output: Contribution to journalArticle

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    AU - Sillence, Martin

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    AB - ß2-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 ß1-adrenoceptor activation. * Two ß2-agonists, formoterol and salmeterol, are approved for treating asthma and have an extended duration of action and increased safety, associated with greater ß2-adrenoceptor selectivity. * 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 'g 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. * Formoterol was more potent than salmeterol, with a significantly lower ED50 in EDL muscles (1 and 130 'g 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 'g kg'1 day'1 of formoterol elicited greater EDL and soleus hypertrophy than salmeterol, but resulted in similar ß-adrenoceptor downregulation. * These results show that doses as low as 1 'g 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.

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