Subtypes of Muscarinic Receptors in Pancreatic Exocrine Secretion in Anesthetized Dog

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Abstract
Characterization of muscarinic receptor subtypes on the dog pancreas in situ was examined by using specific muscarinic receptor antagonists to study pancreatic exocrine secretion. Bethanechol caused an increase in pancreatic exocrine secretion, with a high concentration of protein and little effect on bicarbonate concentration. Thus bethanecol may mainly affect the muscarcinic receptors of the acinar cells. Bethanechol-stimulated secretion was inhibited by pirenzepine (a specific M1 muscarinic antagonist), 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP, a specific M3 muscarinic antagonist), and atropine (a mixed muscarinic receptor antagonist). However, [11-[[2-(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepine-6-one (AF-DX 116, a specific cardioselective M2 antagonist) did not have any effects on bethanechol stimulated secretion. Increased protein section in pancreatic juice stimulated by bethanechol was significantly inhibited by 4-DAMP and atropine and was suppressed by pirenzepine, but was not modified by AF-DX 116. Bicarbonate concentration was not modified by these antagonists. 4-DAMP, atropine, and pirenzepine caused a progressive parallel rightward shift in the dose-response curve of pancreatic secretion for bethanechol. Schild analysis of the data indicated a pA2 value of 8.7 for 4-DAMP, 7.9 for atropine, and 6.2 for pirenzepine, respectively. Thus 4-DAMP has 7.5 times and 440 times greater potency than atropine and pirenzepine to inhibit bethanechol-stimulated secretion. The slope of the Schild regression line was not different from 1. These results suggest that inhibitions of bethanechol-stimulated pancreatic secretion are competitive for 4-DAMP, atropine, and pirenzepine and that bethanechol-stimulated pancreatic secretion is mediated by M3 muscarinic receptors in dogs.

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