Relationship between beta adrenoceptor occupancy and receptor down-regulation induced by beta antagonists with intrinsic sympathomimetic activity

The relationship between the Ki of the B2 adrenoceptor and EC50 values characterizing receptor down-regulation induced by isoproterenol and six beta antagonists classified as having weak to strong intrinsic sympathomimetic activity (ISA) was determined using L6 myoblasts. It was hypothesized that if receptor loss induced by beta antagonists with ISA was mediated through cAMP, EC50 = Ki. EC50/Ki ratios for (-)isoproterenol, (-) and (+) celiprolol were 0.006, 0.01 and 0.08, respectively (p < 0.05); ratios for (-)pindolol and dilevalol were 19 and 9.5, respectively (p < 0.05). EC50/Ki ratios for acebutalol and (-)alprenolol were not significantly different from 1.0. Isoproterenol and dilevalol maximally down-regulated receptor density 89 and 83%, respectively, followed by (+)celiprolol, 54%; (-)celiprolol, 53%; acebutalol, 41%; (-)pindolol, 36% and (-)alprenolol, 31%. Receptor loss was blocked in each case by ICI118,551 or sotalol. A sensitive radioimmunoassay failed to detect increased cAMP accumulation following pretreatment with concentrations of acebutalol, (-)alprenolol, celiprolol and (-)pindolol 100 times their respective Ki values. Isoproterenol and dilevalol stimulated cAMP accumulation 100- and 2-fold over basal, respectively. We conclude that receptor loss induced by beta antagonists with ISA is mediated through the beta 2 adrenoceptor and in at least some cases is cAMP-independent.