Rate of offset of action of slow-acting muscarinic antagonists is fast

Abstract

ATROPINE generally behaves as a competitive antagonist of acetylcholine (ACh) at muscarinic receptors^1–9 but its onset and offset of action are slow. It has been suggested that the rates of onset and offset of atropine blockade are determined by the rates of binding to and dissociation from the ACh receptor^4,5,10 a suggestion which at first sight seems incompatible with competitive blockade. An alternative explanation is that access of antagonist (in contrast to agonist) to the receptors, and escape from their vicinity on washing, is delayed or impeded in some way^11–15. Experiments in which atropine is applied to a small superficial region of the tissue would seem to offer the best chance of reducing this access factor to a minimum and help in deciding which explanation for atropine's slow action is correct. The iontophoretic method presents itself as the method of choice, but until now, no such experiments have been carried out. The results of this type of experiment carried out on smooth muscle are described here. They reveal that the rate of offset of blockade by slow acting muscarinic antagonists can be more than ten times faster than that seen when antagonists are applied by their addition to the solution bathing (or perfusing) the muscle.