ACTIVATION AND BLOCKADE OF CARDIAC MUSCARINIC RECEPTORS BY ENDOGENOUS ACETYLCHOLINE AND CHOLINESTERASE-INHIBITORS

Abstract

Cholinesterase inhibitors potentiate the effects of acetylcholine (ACh) and vagal stimulation on the [rat] myocardium. Cholinesterase inhibitors (ChEI) have activity in isolated atria in the absence of extrinsic cholinergic stimulation and, depending on the ChEI, either indirect stimulation or direct blockade of cardiac muscarinic receptors can occur. Muscarinic agonists inhibit cAMP formation in atria, and the ChEI physostigmine, neostigmine and echothiophate produce a marked attenuation of isoproterenol-stimulated cAMP accumulation. The effect of physostigmine appears to result from muscarinic receptor activation by endogenous ACh as it is blocked by atropine. The ChEI ambenonium does not stimulate but instead blocks muscarinic receptors coupled to cAMP accumulation. Radioligand binding studies provide direct evidence that both ambenonium and demecarium are relatively potent muscarinic receptor antagonists, whereas physostigmine and other ChEI have little direct receptor activity. Physostigmine and ambenonium also have different effects on heart rate in vivo, the former potentiating and the latter apparently blocking vagal tone. The inhibition of cAMP formation produced by physostigmine can be used as a measure of the concentration of endogenous ACh available at muscarinic receptor sites. Physostigmine blocks cAMP formation in atria incubated in the absence of Ca or in the presence of tetrodotoxin, suggesting that endogenous ACh is spontaneously released in the absence of neuronal activity or depolarization-secretion coupling.