Comparison of the effects of the M₁-receptor antagonist telenzepine and the CCK-receptor antagonist loxiglumide on the pancreatic secretory response to intraduodenal tryptophan in dogs

In six conscious dogs with chronic gastric and pancreatic fistulas we compared the action of different doses (20.25 to 81.0 nmol/kg/h) of the muscarinic M₁-receptor antagonist telenzepine, the cholecystokinin (CCK) antagonist loxiglumide (2.5 to 10.0 mg/kg/h) and several combinations of both drugs on the pancreatic secretory response to intraduodenal perfusion of graded loads of tryptophan (0.37-10,0 mmol/h) given against a background of secretin (20.5 pmol/kg/h i.v.). Except for 20.25 nmol/kg/h telenzepine, all tested doses of telenzepine and/or loxiglumide decreased the 180-min integrated bicarbonate response to tryptophan by 55 to 119%. Except of 20.25 nmol/kg/h telenzepine and/or 2.5 mg/kg/h loxiglumide, all tested doses of telenzepine and/or loxiglumide inhibited the tryptophan stimulated integrated pancreatic protein response by 54 to 88%. While telenzepine mainly inhibited the bicarbonate and protein response to the lower loads of tryptophan (0.37- 1.1 mmol/h), loxiglumide decreased the response to all loads of tryptophan. The inhibition evoked by the combinations of telenzepine and loxiglumide was not significantly greater than that by single infusion of either drug. The CCK plasma levels basally and in response to tryptophan were not significantly altered by telenzepine and/or loxiglumide. These findings indicate that (1) both enteropancreatic cholinergic reflexes and the hormone CCK are mediators of the protein response to intraduodenal tryptophan, (2) enteropancreatic cholinergic reflexes are probably the dominant mediators of the response to low amounts of tryptophan, whereas CCK is the major mediator of the response to high loads of tryptophan, (3) the two mediators seem to act independently of each other, and (4) the release of CCK by intestinal tryptophan is not influenced by telenzepine or loxiglumide.