SELECTIVE REGULATION OF BETA-1 AND BETA-2 ADRENERGIC-RECEPTORS BY ATYPICAL AGONISTS

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  • 1 December 1985
    • journal article
    • research article
    • Vol. 235  (3) , 657-664
Abstract
The interactions of the atypical agonists pindolol and celiprolol with beta adrenergic receptors were compared with those of the full agonist, isoproterenol. Studies were carried out using intact cells as well as membranes prepared from C6 glioma cells. Computer-assisted analysis of dose-response curves resulting from the inhibition of the binding of [125I]iodopindolol by the beta-1 and beta-2 selective compounds ICI 89,406 and ICI 118,551 revealed that approximately one-third of the beta adrenergic receptors on these cells were beta-1 receptors. Addition of GTP to the binding assay simplified the dose-response curve for inhibition of the binding of [125I]iodopindolol by isoproterenol and diminished the potency of the agonist. GTP had no effect on the binding of pindolol or celiprolol, suggesting that these drugs do not induce the formation of a ternary complex with the receptor and the guanine nucleotide-binding protein for stimulation of adenylate cyclase activity. When added to the growth medium of intact C6 cells, isoproterenol induced a 40-fold increase in cyclic AMP accumulation. Pindolol and celiprolol, however, caused no elevation of enzyme activity. Addition of isoproterenol to the growth medium of intact cells resulted in an 80% decrease in the density of both beta-1 and beta-2 adrenergic receptors within 8 hr. Growing cells in the presence of pindolol or celiprolol induced a 50% decrease in the density of beta-2 receptors, which was inhibited by beta adrenergic antagonists. Although pindolol has similar potencies for beta-1 and beta-2 receptors, and celiprolol is more potent at beta-1 receptors, both compounds appear to be more efficacious at beta-2 adrenergic receptors. Because pindolol and celiprolol do not cause changes in cyclic AMP levels, down-regulation of beta-2 receptors may occur without stimulation of adenylate cyclase activity or involvement of the guanine nucleotide-binding protein for stimulation of adenylate cyclase activity.

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