Conclusions
As demonstrated for digoxin, the present approach of PK/PD modeling in the perfused rat heart provides estimates for the proportions of receptor subtypes in the mixture of receptor populations as well as the affinity constant for each receptor subtype. In contrast to methods based on equilibrium concentration-response curves, this method permits discrimination between the effects of receptor occupation and effectuation (signal transduction) in response generation. NCX inhibition led to a delay and saturation in the stimulus-response relationship. Using this model, it was possible to gain further quantitative insights concerning the role of transport,receptor binding and postreceptor events in determining the positive inotropic effect of cardiac glycosides.