Interaction of bretylium tosylate with rat cardiac muscarinic receptors. Possible pharmacological relevance to antiarrhythmic action.

The interaction of the antifibrillatory antiarrhythmic drug, bretylium tosylate, with the muscarinic receptor in tissue homogenates from regions of rat brain and heart was investigated. Competition-binding experiments were carried out with the highly specific tritiated antagonist N-methyl-4-piperidyl benzilate. Bretylium tosylate competitively displaced the labeled antagonist from the muscarinic receptor. The binding of the drug to the two brain preparations was found to be best fitted by a one-site model in each case. On the other hand, in the case of both heart preparations, a two-site model yielded a significantly better fit for the binding data than that given by a single-site model. The low affinity-binding constants in the atrium and the ventricle were similar (approximately 10 microM) to those in the brain regions examined, namely, the cortex and the medullapons. Sites with relatively higher affinity for the drug were detected in the heart only, with equilibrium-binding constants of 0.24 +/- 0.12 microM and 0.97 +/- 0.27 microM for the atrium and the ventricle, respectively. The drug also exerted anti-acetylcholine activity (K1 = 14 +/- 2 microM) measured physiologically in the guinea pig atrium, which correlated well with the concentration of the drug observed to be efficacious clinically (approximately 10 microM).