Methylation of a critical carboxyl group in guinea-pig left atrium with trimethoxonium ion leads to loss of excitability. The critical group(s) could be protected with a number of cationic drugs, so that on washout of the protecting drug and reaction products full excitability returned. Tetrodotoxin, edrophonium, cholinergic agonists and amantadine protected the preparation. During the recovery period readmission of these drugs led to the same pharmacological response as during the control period, suggesting protection of specific site(s). This thesis was confirmed in crossover experiments, in which the atrium was exposed to the methylating agent in the presence of one protecting drug, then exposed to another during recovery. The expected pharmacological responses were obtained. Assay of muscarinic receptors with [ 3H]-quinuclidinyl benzilate after methylation without protection or in the presence of tetrodotoxin or acetylcholine suggested that these receptors are not involved in the maintenance of excitability. It is postulated that the Na + channel and the K + channel are located in the same macromolecular membrane complex, and that the K + channel has a cholinoreceptive sub-site.