Characterization of adrenoceptor involvement in skeletal and cardiac myotoxicity Induced by sympathomimetic agents: toward a new bioassay for beta-blockers.
Excessive levels of catecholamines have long been known to be cardiotoxic, but less well known are their toxic effects on skeletal muscle. By using an antimyosin monoclonal antibody and quantitative methods to measure the extent of myocyte necrosis, and by employing modulators of adrenoceptors (ARs), including clenbuterol, bupranolol, propranolol, bisoprolol, atenolol, ICI-118551, phenoxybenzamine, prazosin, and yohimbine, the involvement of ARs in isoproterenol-induced myotoxicity was characterized. In the myocardium, the toxic effects were predominantly mediated via the beta(1)-ARs. In the soleus muscle, it was almost solely via the beta(2)-ARs. Myotoxicity was also observed in the myocardium when challenged with the beta(2)-AR agonist clenbuterol. This was found to be mediated via sympathetic presynaptic beta(2)-ARs, leading to enhanced release of norepinephrine. This effect was abolished by prior treatment with reserpine. The skeletal muscle was found to be more sensitive to the myotoxic effects than cardiac muscle at lower doses of beta-AR agonists. These experiments introduce a new way of assaying beta-AR antagonists by classifying them according to their ability to prevent catecholamine-induced myotoxicity. Further research along these lines may deepen understanding of which beta-blockers work best in heart failure therapy.
Tan
Lip-Bun
LB
Academic Unit of Molecular Vascular Medicine, University of Leeds, England.
Burniston
Jatin G
JG
Clark
William A
WA
Ng
YeeLan
Y
Goldspink
David F
DF
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001681:Biological Assay / Q000379:methods; D004305:Dose-Response Relationship, Drug; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D009336:Necrosis; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000502:physiology*; D013566:Sympathomimetics / Q000633:toxicity*
D000319:Adrenergic beta-Antagonists; D011941:Receptors, Adrenergic; D013566:Sympathomimetics