Effects of fast and slowly acting antagonists on the time course of the muscarinic response in guinea-pig atrial muscle.

In sino-atrial and atrial preparations of the guinea-pig heart the effects of slowly and rapidly reversible antagonists on the time course of the acetylcholine or carbachol-evoked hyperpolarization (muscarinic response) were studied using double-barreled micropipettes for ionophoretic drug application. The muscarinic response can be inhibited not only if an antagonist is applied before or simultaneously with the agonist but also during its late decay phase. Local ionophoretic application of a slowly reversible (atropine-like) antagonist results in a prolongation of time-to-peak of a subsequently evoked muscarinic response, whereas bath application of this type of antagonists only results in an inhibition without affecting the time course. It is concluded that the remaining response after ionophoretic ejection of a small amount of this type of antagonists is due to activation of more distant receptor populations, which give a slower contribution to the integral response than receptors close to the source of release. Both, local and bath application of rapidly reversible antagonists (TEA, Pentyl-TEA) causes a faster time course of the muscarinic response. This can be explained by the apparent equilibrium constant of the agonist receptor complex to be increased in the presence of a true competitive antagonist. Under this condition proximal receptors, which should respond faster are less inhibited than distant ones. The results strongly suggest that the duration of the muscarinic response in the heart is governed by diffusion of agonist molecules on the surface or inside the cardiac muscle.