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

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Abstract
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. 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 μg 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. 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 (α1‐, α2‐ β−) adrenoceptor blocking drugs excluded transmission through a nicotinic synapse or release of catecholamines. 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. 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 M1‐muscarinic receptors, the tachycardia is mediated by receptors blocked selectively by 4‐DAMP.