MUSCARINIC RECEPTOR HETEROGENEITY REVEALED BY INTERACTION WITH BRETYLIUM TOSYLATE - DIFFERENT LIGAND-RECEPTOR CONFORMATIONS VERSUS DIFFERENT RECEPTOR SUBCLASSES

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  • 1 January 1985
    • journal article
    • research article
    • Vol. 27  (1) , 27-31
Abstract
The interaction of the antiarrhythmic drug, bretylium tosylate, with the muscarinic receptor in tissue homogenates from regions of rat brain and heart and from submandibular gland and ilial wall was investigated. Competition binding experiments were carried out using the highly specific tritiated anatagonist N-methyl-4-piperidyl benzilate. Bretylium displayed heterogeneous binding characteristics. The binding of the drug to neural and glandular preparations was best fitted by a 1-site model in each case. In the case of muscle preparations (heart and ileum), a 2-site model yielded a signficantly better fit for the binding data than that given by a single site model. High affinity sites for the drug were detected in the muscle tissue only, with equilibrium binding constants of 0.24 .+-. 0.12, 0.97 .+-. 0.27 and 0.57 .+-. 0.41 .mu.M for the atrium, ventricle and ileum, respectively. The low affinity binding constants in the muscle tissues were similar (.apprx. 10 .mu.M) to those in the neural and glandular tissues examined, i.e., the cortex, the hippocampus, the medulla pons and the submandibular gland. The drug had no effect on agonist-binding characteristics. The heterogeneous binding of bretylium is compared to that of another nonclassical antagonist, pirenzepine. The results are discussed in relation to 2 alternative hypotheses put forward to account for antagonist heterogeneity in binding, the one involving ligand-receptor conformations and the other receptor subclasses.