Quantitative relationship between beta-adrenergic receptor number and physiologic responses as studied with a long-lasting beta-adrenergic antagonist

The aminobenzyl analog of propranolol, 1- (p-amino-alpha,alpha-dimethylphenethylamino)-3-(1-naphthoxy)-2- propanol, was synthesized and found to be a potent beta-adrenergic blocking agent. The beta-adrenergic receptors of cultured rat C6 glioma cells (2B clone) as assessed by [(125)I]iodohydroxybenzylpindolol binding were decreased 50 and >95% after pretreatment with 8 nM and 1 muM aminobenzylpropranolol, respectively. Unlike propranolol, aminobenzylpropranolol displayed a prolonged blockade of receptors that was maintained during several hours of washing. [(125)I]Iodohydroxybenzylpindolol saturation binding experiments in cells exposed to aminobenzylpropranolol and subsequently washed indicated that the compound effectively diminished receptor number with no change in the affinity of the remaining receptors for iodohydroxybenzylpindolol. Aminobenzylpropranolol inhibited catecholamine-stimulated intracellular cyclic AMP accumulation; with increasing blockade, isoproterenol dose-response curves became progressively shifted to the right but the maximal response was unaltered. Aminobenzylpropranolol inhibited the beta-adrenergic contractile response in atria isolated from rats and guinea pigs. Treatment with 0.1 and 10 muM aminobe...Continue Reading