Mechanisms of Downregulation of β-Adrenergic Receptors: Perspective on the Role of β-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 β-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 β-adrenergic receptor to adenylate cyclase. Studies of β-adrenergic receptors were carried out using three different experimental protocols(a) the interactions of the atypical agonists pindolol and celiprolol with β-adrenergic receptors from C6 glioma cells (40% β, 60% β2) were compared with those of the full agonist isoproterenol; (b) the ability of pindolol, celiprolol, and isoproterenol to induce downregulation and sequestration of β-adrenergic receptors in wild-type S49 lymphoma cells was compared with the responses observed with a mutant line of S49 cells (eye, 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 β-adrenergic receptors and isoproterenol-stimulated adenylate cyclase activity on circulating lymphocytes was investigated. The results of these studies suggest that downregulation of β-adrenergic receptors may occur by several different mechanisms(a) the studies with C6 cells suggest that downregulation of β-receptors may occur without stimulation of adenylate cyclase activity; (b) in S49 cells, downregulation can be induced by a mechanism that requires the interaction of β-adrenergic receptors with Gs but does not involve sequestration of receptors or the synthesis of cyclic AMP; and (c) exercise induces an increase in the density of β-adrenergic receptors on circulating lymphocytes in both normal subjects and patients with congestive heart failure, but only in normal subjects does an increase in isoproterenol-stimulated adenylate cyclase activity occur after maximal exercise; this suggests that desensitization occurs in patients with heart failure.