M. Corsi et T. Kenakin, The relative importance of the time-course of receptor occupancy and response decay on apparent antagonist potency in dynamic assays, J AUT PHARM, 20(4), 2000, pp. 221-227
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.