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 beta1-adrenoceptor antagonist atenolol was measured as an inhibitor of responses to isoprenaline in guinea-pig left atria. Measurements 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 beta1-adrenoceptors by these two methods gave divergent results. Specifically, it was found that the isoprenaline-induced increased rate of myocardial relaxation was resistant to receptor blockade. Thus, the rate-limiting step in the relaxation response was dissociated from receptor activation and therefore, could not be used for the measurement of receptor occupancy. 3. In contrast, the positive inotropic response was very responsive to receptor occupancy. However, when atenolol was used to block a steady-state isoprenaline response, there was a complicating depression of basal inotropy after receptor blockade that obfuscated measurement of receptor blockade. 4. In general, these data indicated that the blockade of a steady-state agonist response to measure the potency of an antagonist might in some cases yield erroneous results. These studies indicate some caution in the interpretation of blockade responses in pre-contracted or pre-stimulated pharmacological preparations.
Corsi
M
M
Pharmacology Department, Glaxo Wellcome S.p.A., Verona, Italy.
Kenakin
T
T
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D000465:Algorithms; D000818:Animals; D001262:Atenolol / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1; D001262:Atenolol; D007545:Isoproterenol