Relationship Between β Adrenoceptor Occupancy and Receptor Down-Regulation Induced β Antagonists with Intrinsic Sympathomimetic Activity

Abstract

The relationship between the Ki of the β₂ adrenoceptor and EC50 values characterizing receptor down-regulation induced by isoproterenol and six β 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 β 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 & antagonists with ISA is mediated through the β₂ adrenoceptor and in at least some cases is cAMP-independent.