Allosteric interactions of three muscarine antagonists at bovine tracheal smooth muscle and cardiac M 2 receptors

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The kinetics of [ 3H]dexetimide dissociation from muscarine receptors in bovine cardiac left ventricular and tracheal smooth muscle membranes were studied in the absence and presence of three muscarine antagonists. It was found that [ 3H]dexetimide dissociation from cardiac muscarine receptors was monophasic and very fast (half life < 1 min) and was slowed by the cardioselective muscarine antagonists, gallamine, methoctramine and AF-DX 116, concentration dependently. [ 3H]Dexetimide dissociation from tracheal muscarine receptors was biphasic, with a fast phase (half-life < 1 min) followed after 4–5 min by a slow phase (half-life = 38.5 min. The fast component, but not the slow component, was slowed by the muscarine antagonists with concentration dependencies very similar to those found in the heart. We conclude from these data that the major population of tracheal smooth muscle muscarine receptors resembles the cardiac M 2 type not only with respect to equilibrium binding affinities but also with respect to the secondary, allosteric binding site on the muscarine receptor. The results also imply that the cardiac receptor subtype is much more sensitive to allosteric modulation than the glandular/smooth muscle receptor subtype.