Effects of telenzepine and L-364,718 on canine pancreatic secretion before and after vagotomy

Abstract

In six conscious dogs we compared the action of the M1-receptor antagonist telenzepine (20.25-81.0 nmol.kg-1.h-1), the cholecystokinin (CCK) antagonist L-364,718 (0.025-0.1 mg.kg-1.h-1), and combinations of both on the pancreatic secretory response to intraduodenal tryptophan, given against a secretin background before and after truncal vagotomy. Before vagotomy, the higher doses of telenzepine and of L-364,718 significantly (P < 0.05) decreased the protein response to tryptophan by up to 97%. After vagotomy, all doses of L-364,718 abolished the protein response, whereas telenzepine had no further effect. Before and after vagotomy, all combinations abolished the protein response. The plasma CCK-like immunoreactivity basally, during secretin, and in response to tryptophan was not altered by vagotomy, telenzepine, and/or L-364,718. These findings indicate that in dogs 1) potentiation exists between M1 receptors and CCK for stimulation of the pancreatic enzyme response to intraduodenal tryptophan, 2) the cholinergic fibers of the enteropancreatic reflex activated by tryptophan run within the vagus nerves and end at least in part on M1 receptors, 3) CCK acts in part independently of the vagal nerves, and 4) the CCK release by intestinal tryptophan is not influenced by vagotomy, telenzepine, and/or L-364,718.

Control of pancreatic exocrine secretion via muscarinic receptors: Which subtype(s) are involved?

“…In contrast to endogenous stimulation, exogenous stimulation of the canine pancreatic protein output with cerulein is not affected by telenzepine [47,48]. This is in accordance with earlier findings that in dogs neither atropine nor vagotomy had any significant effect on pancreatic secretory response to exogenous CCK or cerulein [50][51][52] and with the inefficacy of pirenzepine on CCK-8-stimulated amylase release from isolated pancreatic acini [35,36] or isolated perfused pancreas [53].…”

“…This inhibition was more pronounced (up to 100%) when low loads of tryptophan were given, indicating that low loads of intraduodenal amino acids stimulate pancreatic enzyme output predominantly by cholinergic mechanisms involving M1 receptors. In contrast to basal enzyme output, telenzepine had no effect on tryptophan-stimulated pancreatic protein output in vagotomized dogs [47]. This finding supports the hypothesis that intraduodenal tryptophan initiates an enteropancreatic reflex [8] that activates intrapancreatic postganglionic neurons ending on acinar M1 receptors.…”

“…With these low doses of the two antagonists, a potentiation of the inhibitory potencies was observed, i.e. the magnitude of inhibition was significantly greater then the sum of the inhibitory effects of each antagonist when given alone [47]. This potentiation points to the existence of both modes (i.e.…”

“…Since this effect was still evident in truncal vagotomized dogs [47], the M1 receptors involved in the regulation of basal pancreatic secretion seem to be part of the intrinsic nervous system of the pancreas.…”

“…Basal pancreatic enzyme output was decreased in dogs by telenzepine by up to 85% [47,48], indicating that M1 receptors are important mediators of basal pancreatic enzyme secretion. Since this effect was still evident in truncal vagotomized dogs [47], the M1 receptors involved in the regulation of basal pancreatic secretion seem to be part of the intrinsic nervous system of the pancreas.…”