Mechanisms of downregulation of beta-adrenergic receptors: perspective on the role of beta-adrenergic receptors in congestive heart failure.
The impaired inotropic responsiveness of myocardial tissue to catecholamines in congestive heart failure has been ascribed to downregulation of beta-adrenergic receptors. It has been reported recently that resistance to catecholamines is related to a defect in the guanine nucleotide binding protein that couples the beta-adrenergic receptor to adenylate cyclase. Studies of beta-adrenergic receptors were carried out using three different experimental protocols: (a) the interactions of the atypical agonists pindolol and celiprolol with beta-adrenergic receptors from C6 glioma cells (40% beta 1, 60% beta 2) were compared with those of the full agonist isoproterenol; (b) the ability of pindolol, celiprolol, and isoproterenol to induce downregulation and sequestration of beta-adrenergic receptors in wild-type S49 lymphoma cells was compared with the responses observed with a mutant line of S49 cells (cyc-, which lack Gs activity); and (c) the differential response of patients with heart failure and age-matched control subjects to exercise-induced changes in the density of beta-adrenergic receptors and isoproterenol-stimulated adenylate cyclase activity on circulating lymphocytes was investigated.(ABSTRACT TRUNCATED AT 250 WORDS)
Frey
M J
MJ
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6048.
Molinoff
P B
PB
D015536:Down-Regulation / Q000187:drug effects*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*
D011943:Receptors, Adrenergic, beta