Time course of isolated rat fundus response to muscarinic agonists: A measure of intrinsic efficacy

The establishment of a dose-response relationship and its quantification is the usual procedure for analysing drug action on an isolated organ. Howeve r, the time course of the effect seems to be an inherent characteristic of the agonist which produces it. In our study, we have analyzed the time-resp onse curves of four cholinergic agonists (acetylcholine, methacholine, carb achol and bethanechol) which produce tonic contractions of the isolated rat gastric fundus. The order of affinity of agonists to muscarinic receptors on the rat fundus were carbachol > bethanechol > methacholine > acetylcholi ne (K-A values: 46 +/- 12, 84 +/- 21, 380 +/-110 and 730 +/- 120 nM, respec tively). The effective concentrations which produced 60% of the maximal res ponse (EC60) were used for establishing the time-response curves. The time- response curves were also recorded after partial alkylation of muscarinic r eceptors with phenoxybenzamine, after exposure of the isolated rat fundus t o physostigmine and after addition of supramaximal concentrations of the ag onists. The experimental time-response curve for acetylcholine was on the e xtreme left, followed by curves for methacholine, bethanechol and carbachol , respectively. Phenoxybenzamine and supramaximal doses of the agonists did not change the order of response development in time, but supramaximal dos es shifted all curves to the left and phenoxybenzamine shifted all time-res ponse curves to the right. Only physostigmine shifted the time-response cur ve for methacholine to the right. The results of our study suggest that the response rate of the isolated rat gastric fundus to cholinergic agonists d epends on the intrinsic activity of these agents, but not on their affinity for muscarinic receptors.