Pharmacological characterization of muscarinic receptors involved in McN‐A‐343‐induced effects on intestinal motility and heart rate in conscious dogs

Abstract

1. Intravenous injection of the muscarinic agonist, McN-A-343, in conscious dogs equipped with an ileal Thiry fistula produced a dose-related inhibition of intestinal phasic contractile activity, and an increase in heart rate. 2. The inhibitory action of McN-A-343 on motility was antagonized with different potencies by antimuscarinic drugs. The non-selective drug, N-methylatropine, blocked the McN-A-343 effect as well as the reflex phasic activity. The M1-selective compound, pirenzepine (1-30 micrograms kg-1), was a potent antagonist of the McN-A-343 effect, whereas the cardioselective M2-antagonist, AF-DX 116, and the smooth muscle selective compound, 4-diphenylacetoxy-N-methyl piperidine (4-DAMP), were completely ineffective at the doses tested. 3. The McN-A-343-induced inhibition of intestinal motility was blocked by locally applied lignocaine, suggesting the involvement of a neural inhibitory pathway. The resistance to hexamethonium and (alpha 1-, alpha 2- and beta-) adrenoceptor blocking drugs excluded transmission through a nicotinic synapse or release of catecholamines. 4. McN-A-343-induced tachycardia was also the result of muscarinic receptor activation. It was very sensitive to antagonism by 4-DAMP, while being completely unaffected by AF-DX 116. Pirenzepine displayed an intermediate profile, reducing tachycardia at doses fully active in reversing the agonist-mediated effect on intestinal motility. Propranolol partially reduced McN-A-343 tachycardia, suggesting catecholamine release. 5. The two McN-A-343 effects investigated in the present study appear to be mediated by different muscarinic receptor subtypes. While the inhibitory action on intestinal motility results from stimulation of Ml-muscarinic receptors, the tachycardia is mediated by receptors blocked selectively by 4-DAMP.