Characterization of the muscarine receptor type on paracrine cells activated by McN-A-343 in the mouse isolated stomach

Abstract

An attempt was made to characterize the muscarine receptor type(s) involved in acid secretion in the mouse isolated stomach when stimulated by the muscarinic agonist McN-A-343. A series of 8 muscarinic antagonists was used with preference for M1 receptors (telenzepine and pirenzepine), M1 and M2 receptors (secoverine), M2 receptors (AF-DX 116 and himbacine) and M1 and M3 receptors (p-F-HHSiD and HHSiD). BTM-1086 was used as a high affinity antagonist at the M1 receptor however with little selectivity. Receptor type preferences were determined in binding experiments with [3H]telenzepine in cortical membranes (M1) and [3H]N-methylscopolamine in atrial (M2) or salivary gland (M3) membranes, derived from guinea pigs. No antagonist with M3 preference could be identified in the binding studies. A fixed antagonist concentration of 1 mumol/l was used to antagonize acid secretion stimulated by 10 mumol/l McN-A-343. By plotting the percentage inhibition obtained in the functional test against the Ki values determined in binding experiments for each antagonist at M1, M2 and M3 binding sites, an affinity-inhibition curve could only be constructed when based on the antagonist affinities to the M1 receptor. No statistically significant fit was found using antagonist affinities to the M2 or M3 receptor. Thus, in accordance with the presumed M1 selectivity of the agonist McN-A-343, the rank order of potencies of different antagonists point to the M1 nature of the muscarine receptor which stimulates acid secretion in the mouse isolated stomach upon activation by McN-A-343.(ABSTRACT TRUNCATED AT 250 WORDS)