Toxic cardiac effects of catecholamines: role of beta-adrenoceptor downregulation.
The aim of our study was to analyse the mechanisms underlying cardiac toxicity caused by beta-adrenoceptor stimulation and the relationships with their associated downregulation during heart failure. We used the experimental model of coronary artery ligation-induced myocardial infarction in male Wistar rats. In order to increase beta-adrenergic stimulation, rats were subjected to a 15-day chronic isoprenaline administration (30 microg/kg/h). Isoprenaline administration induced haemodynamic inotropic compensation, almost abolished in vitro inotropic response to isoprenaline on papillary muscle (P<0.005) but promoted fibrosis. Isoprenaline treatment markedly reduced the B(max) of beta(2)-adrenoceptors (by 53% in sham and 44% in infarcted rats) but not that of beta(1)-adrenoceptors. These results suggest that beta(1)-adrenoceptors rather than beta(2)-adrenoceptors underlie the deleterious effects of chronic beta-adrenergic stimulation on cardiac fibrosis and are in agreement with the demonstrated benefit induced in human heart failure by beta(1)-adrenoceptor antagonists.
Brouri
Fazia
F
Service de Pharmacologie, Hôpital de la Pitié-Salpêtrière, Paris, France.
Findji
Laurent
L
Mediani
Odile
O
Mougenot
Nathalie
N
Hanoun
Naima
N
Le Naour
Gilles
G
Hamon
Michel
M
Lechat
Philippe
P
D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000633:toxicity; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D015536:Down-Regulation; D005355:Fibrosis; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D011943:Receptors, Adrenergic, beta; C049763:CGP 20712A; D007545:Isoproterenol