An analysis of amplifying and potentiating interactions between agonists

Considerable attention has been given to interactions between different kinds of agonists mediating common pharmacologic effects, in particular those interactions that involve mutual amplification of effects. However, no satisfactory explanation has been given for this phenomenon. In this paper, a theoretical model for a two-receptor-one-transducer system is developed that can be used to establish conditions under which agonist-agonist interactions may exhibit amplification. It is predicted that threshold amplification results when the common transducer relation subserving each receptor is positively cooperative. When this relation is rectangular hyperbolic or negatively cooperative, less than additive affects are predicted in general. This model also predicts mutual potentiation between agonists in the positively cooperative case. In practice, amplification and potentiation between agonists may be related to and predicted from the shapes of concentration-effect curves for the individual agonists. The predictions of the model are tested experimentally by analyzing the interactions between histamine and 5-hydroxytryptamine in rabbit isolated aorta and between norepinephrine and histamine in guinea pig isolated right atria.