The relative importance of the time-course of receptor occupancy and response decay on apparent antagonist potency in dynamic assays

1 The potency of the beta (1)-adrenoceptor antagonist atenolol was measured as an inhibitor of responses to isoprenaline in guinea-pig left atria. Mea surements were made in two ways, firstly, by pre-incubating the atria with a given concentration of atenolol followed by an isoprenaline dose-response curve and, secondly, by measuring the response to isoprenaline followed by addition of atenolol. 2 It was found that the estimation of atenolol potency as an antagonist of beta (1)-adrenoceptors by these two methods gave divergent results. Specifi cally, it was found that the isoprenaline-induced increased rate of myocard ial relaxation was resistant to receptor blockade. Thus, the rate-limiting step in the relaxation response was dissociated from receptor activation an d therefore, could not be used for the measurement of receptor occupancy. 3 In contrast, the positive inotropic response was very responsive to recep tor occupancy. However, when atenolol was used to block a steady-state isop renaline response, there was a complicating depression of basal inotropy af ter receptor blockade that obfuscated measurement of receptor blockade. 4 In general, these data indicated that the blockade of a steady-state agon ist response to measure the potency of an antagonist might in some cases yi eld erroneous results. These studies indicate some caution in the interpret ation of blockade responses in pre-contracted or prestimulated pharmacologi cal preparations.