Alterations in muscarinic receptors of ventricular muscle in carbachol-induced short-term desensitization.

The inhibitory action of a muscarinic agonist on the contractile response of cardiac muscle is transient due to short-term desensitization of muscarinic cholinergic receptors. Studies were made on the binding of the muscarinic antagonist L-[3H]-quinuclidinyl benzilate ([3H]QNB) to the muscarinic receptor in the membrane fraction of ventricular muscle of guinea pigs desensitized by perfusion with carbachol for 10 min. Desensitization did not change the maximum binding or equilibrium dissociation constant (Kd) of [3H]QNB, but shifted the inhibition curves of [3H]QNB binding by carbachol to the right both in the presence and absence of 5-guanylyl imidodiphosphate (GppNHp). Analysis of these inhibition curves with a multiple site model suggested that superhigh and high affinity agonist binding sites were converted to low affinity sites in the desensitized state. GppNHp has additive effects to the prior exposure to carbachol, suggesting a different site of action from short-term exposure of agonist. We conclude that agonist-induced short-term desensitization of the muscarinic receptor of ventricular muscle is caused by reduction in the affinity of the receptor for agonist without reduction in its amount or affinity for antagonist.