Dynamic mechanisms of non-classical antagonism by competitive AT(1) receptor antagonists

Selective competitive angiotensin AT(1) receptor antagonists exhibit divers e patterns of antagonism of angiotensin-II-mediated responses in functional assays. These range from the classical parallel rightward shift of agonist concentration-response curves with no depression of the maximum response t o an apparently straightforward insurmountable antagonism with complete dep ression of the maximum response and no rightward shift. This article review s some earlier equilibrium-based models that have been used to explain the insurmountable antagonism, and suggests that a kinetic model might provide a more satisfactory account of the observations. Such a model might provide deeper insights into the pharmacology of G-protein-coupled receptors than the more popular equilibrium models.