The effect of amiodarone on the beta-adrenergic receptor is due to a downregulation of receptor protein and not to a receptor-ligand interaction.

Downregulation of beta adrenergic receptors (beta-AR) by amiodarone (Am) have been reported in several studies both in vivo and in vitro. The mechanism underlying the antiadrenergic effect of Am is, however, still unclear. The aim of this study was to characterize whether the antiadrenergic effect of amiodarone is due to binding to the beta-AR or to downregulation of the beta-AR receptor protein. All experiments were performed on confluent mouse AT-1 cardiomyocytes cultured for 6 days. In acute experiments, equilibrium binding with [3H]-CGP-12177 to beta-AR was not directly inhibited by Am and the equilibrium binding constant did not change during prolonged exposure up to 72 hours. After Am exposure for 48 hours beta-AR density was decreased by 26% (p<0.005). T3 partially prevented the downregulation elicited by Am (p<0.05). A Western blot analysis with beta1-AR antibodies revealed a decreased signal intensity in cells treated with Am for 48 h as compared to control (p<0.05). Isoproterenol-provoked cAMP response did not change after acute exposure to Am. After incubation for 48 hours with Am there was, however, a 20% decrease in cAMP response as compared to control (p<0.05). This study shows that the effect of Am on beta-AR is due to a downregulation of the beta-AR protein and not to a competitive or non-competitive receptor-ligand interaction. This indicates a new pharmacological mechanism for modulation of beta-AR, which probably is transcriptionally regulated.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Fysiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Physiology hsv//eng
Adenosine Triphosphate
metabolism
Adrenergic beta-Antagonists
pharmacology
toxicity
Amiodarone
pharmacology
toxicity
Animals
Binding Sites
drug effects
Blotting
Western
Down-Regulation
drug effects
Ligands
Mice
Myocardium
Propanolamines
metabolism
Receptors
Adrenergic
beta
metabolism
Signal Transduction
drug effects
Time Factors
Tritium
Tumor Cells
Cultured

Häggblad, J (author)
Blange, I (author)
Magnusson, Yvonne,1957Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xmagyv (author)
Sylvén, S (author)
Göteborgs universitetWallenberglaboratoriet (creator_code:org_t)

In:Biochemical and biophysical research communications: Elsevier BV255:2, s. 515-200006-291X

By the author/editor: Drvota, V; Häggblad, J; Blange, I; Magnusson, Yvonn ...; Sylvén, S

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Physiology

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