The kinetics of action of acetylcholine antagonists in smooth muscle

Abstract

The rate-limiting step in recovery of acetylcholine sensitivity in smooth muscle after exposure to atropine or hyoscine could be the dissociation of drug-receptor complexes (dissociation-limited model) or diffusion of drug away from the neighbourhood of the receptors (biophase model). These two models differ in the details of the predicted kinetics of development and decline of antagonism. Their theoretical kinetic properties have been worked out mathematically with the aid of an analogue computer, and compared with experimental measurements made in guinea-pig ileum longitudinal muscle preparations. The kinetic properties of antagonists applied singly could be explained either by the dissociation-limited model, or by the biophase model, provided that the size of the biophase bore a certain relation to the binding capacity of the receptors. In studies of the interaction of fast-and slow-acting antagonists, it was found that the dissociation-limited model could alone account for the observed effects. It was concluded that the kinetics of action of hyoscine and atropine reflected their rate of reaction with receptors, and that measurements of antagonist kinetics were a valid guide to drug-receptor rate constants. A consequence of the dissociation-limited model, that persistent antagonists should fail to show the classical parallel shift of log-dose effect curves when tested against agonists of low efficacy, was borne out experimentally, and this effect was used to estimate indirectly the equilibrium constants of alkyltrimethylammonium salts.