Certain β-blockers can decrease β-adrenergic receptor number: II. Down-regulation of receptor number by alprenolol and propranolol in cultured lymphoma and muscle cells

Abstract

We have used two different cultured cell lines - S49 lymphoma cells and BC3H-1 muscle cells - to examine the regulation of β-adrenergic receptors by receptor antagonists. Rather than an increase ('up-regulation') of receptor number that such antagonists often produce, we found that certain β-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 β-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 α-adrenergic receptor in BC3H-1 cells, and lack of a decrease in beta-adrenergic receptor-independent (forskolin-stimulated) 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 β-blockers 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 α-subunit of G(s), the guanine nucleotide-binding regulatory protein, thus implying a requirement for receptor-α(s) interaction in eliciting β-receptor down-regulation. The ability of certain antagonists to promote a down-regulation of β-adrenergic receptors provides a mechanism that may contribute to the pharmacological activity of these agents.