Disposition and activity of beta-adrenoceptor antagonists in the rat using an ex vivo receptor binding assay

The disposition and activity of some beta-adrenoceptor antagonists in the rats was determined using an ex vivo receptor binding assay. Rats were injected with different doses of beta-adrenoceptor antagonists and the extent of receptor occupation was assessed in various tissues under in vitro conditions. Rats treated with (-)-propranolol (0.1 mumol. kg-1) displayed peak plasma levels of biologically active drug assayed by radioreceptor assay 15 min after administration. On the other hand, the highest concentration of bioactive drug, assessed by ex vivo assays, was observed at 30 min in all tissues examined. Dose-response curves revealed that (-)-propranolol was about 100 fold more potent than (+)-propranolol in all tissues examined, and that there was a small (3 fold) degree of selectivity for both isomers towards lung and spleen over heart, cortex and cerebellum. The affinity of (-)-propranolol in heart and lung using the ex vivo binding assay was similar to the affinity of this agent to inhibit in vivo isoprenaline-stimulated cyclic AMP formation in these tissues. The beta 1-selective antagonist (+/-)-atenolol demonstrated selectivity towards those tissues that have been previously shown to possess a predominance of beta 1-adrenoceptors, though penetration to the central nervous system was substantially less than propranolol. The inherent advantages of this ex vivo assay are discussed.