Characterization of the muscarinic receptor subtype in isolated gastric fundic cells of the rabbit

The characteristics of the muscarinic receptor in isolated gastric fundic cells from rabbit were determined by radioligand binding techniques and functional tests. The dissociation constants ( K Ds) of selective (hexahydrosiladifenidol and pirenzepine) and non-selective ( N-methylscopolamine and atropine) muscarinic receptor antagonists obtained in competition experiments vs [ 3 H]-N- methylscopolamine were compared with the pA 2 values of the drugs as inhibitors of carbachol-stimulated [ 14C]-aminopyrine accumulation (an index of acid secretion) in the gastric fundic cells. Good correlations were found between the ability of the drugs to inhibit acid secretion and their affinity for muscarinic receptors in the gastric fundic cells. The rank order of potency in both tests was N-methylscopolamine > atropine > hexahydrosiladifenidol > pirenzepine. The character of the muscarinic receptor subtype present on gastric fundic cells was established by comparing the affinity values of the compounds for this receptor with those for the receptors in other rabbit tissues. It was found that only pirenzepine and hexahydrosiladifenidol displayed tissue selectivity in their binding profiles. The K Ds for pirenzepine were 13 nM for the M 1 receptor of the cerebral cortex and about 500 nM for the M 2 receptors of the submandibular and gastric glands and heart. Differently from pirenzepine, hexahydrosiladifenidol showed about 10-fold discrimination between the M 2 subtype of the gland ( K D = 31 nM) and the M 2 subtype of the heart ( K D = 330 nM).