The measurement of antagonist potency and the importance of selective inhibition of agonist uptake processes

TP Kenakin and D Beek

Schild regressions in isolated tissues are powerful tools for receptor classification only if they yield equillibrium dissociation constants of antagonists which can, in turn, occur only when measurements are made under equillbrium conditions. Regressions with slopes different from unity of nonlinear regressions indicate noncompliance to equillbrium. This paper describes a condition whereby Schild regressions apparently comply with criteria which signify equillbrium conditions but in fact are regressions obtained at nonequilibrium steady states yielding significant underestimations of the potency of the antagonist. Specifically, if agonist uptake processes in isolated tissues are inhibited by uptake inhibitors with receptor blocking properties, the experimental data and a theoretical model suggest that the resulting Schild regression will be linear, have a slope of unity and be shifted to the right of the true Schild regression, thereby significantly underestimating antagonist potency. Experiments with the effects of neuronal uptake inhibition (with desmethylimipramine and amitriptylene) on the phentolamine-inhibition of norepinephrine responses in rat anococcygeus muscle and the effects of metanephrine on the propranolol-inhibition of isoproterenol relaxation of guinea-pig trachea provided data to compare to a theoretical model. The data and the model help define the selectivity of the uptake inhibitor fo uptake over receptors needed to achieve steady states approaching true equilibrium, a condition required for satisfactory estimation of antagonist potency.

Volume 219, Issue 1, pp. 112-120, 10/01/1981
Copyright © 1981 by American Society for Pharmacology and Experimental Therapeutics

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