Certain /J-Blockers Can Decrease /3-Adrenergic Receptor Number: II. Down-Regulation of Receptor Number by Alprenolol and Propranolol in Cultured Lymphoma and Muscle Cells

We have used two different cultured cell lines—S49 lymphoma cells and BC3H-1 muscle cells— to examine the regulation of /3-adrenergic receptors by receptor antagonists. Rather than an increase ("up-regulation") of receptor number that such antagonists often produce, we found that certain /3-blockers elicit a decrease ("down-regulation") of beta-adrenergic receptors. Alprenolol and propranolol, but not sotalol or ICI 118,551, at concentrations of 10-100 nM down-regulated /3-adrenergic receptors 20-70% following 16-20 hours of treatment of S49 or BC3H-1 cells. Several observations suggest that this phenomenon depends upon beta-receptor interaction, including stereoselectivity [(— )-enantiomers more potent than ( + )-enantiomers], blockade of the effect by ICI 118,551, absence of down-regulation of or-adrenergic receptors hi BC3H-1 cells, and hick of a decrease in beta-adrenergic receptor-Independent (forskoUnstimulated) cyclic AMP accumulation in S49 cells. The possibility of retained antagonist interfering with receptor measurement was precluded by the fact that the antagonist-Induced decrease in receptor number required several hours incubation and occurred without a prominent change in receptor affinity. The ability of the 0-bIockers to elicit down-regulation did not correlate with hydrophobicity of the drugs. Antagonist-induced down regulation of beta-adrenergic receptors did not occur in S49 lymphoma cells that lack the a-subunit of G,, the guanine nucleotide-binding regulatory protein, thus implying a requirement for receptor-a, interaction in eliciting /3-receptor down-regulation. The ability of certain antagonists to promote a down-regulation of /3-adrenergic receptors provides a mechanism that may contribute to the pharmacological activity of these agents. {Circulation Research 1988;63:279-285)