MEK inhibits secretin release and pancreatic secretion: roles of secretin-releasing peptide and somatostatin

Abstract

We investigated the mechanism of action of methionine enkephalin (MEK) on HCl-stimulated secretin release and pancreatic exocrine secretion. Anesthetized rats with pancreatobiliary cannulas and isolated upper small intestinal loops were perfused intraduodenally with 0.01 N HCl while bile and pancreatic juice were diverted. The effect of intravenous MEK on acid-stimulated secretin release and pancreatic exocrine secretion was then studied with or without coinfusion of naloxone, an anti-somatostatin (SS) serum, or normal rabbit serum. Duodenal acid perfusate, which contains secretin-releasing peptide (SRP) activity, was collected from donor rats with or without pretreatment with MEK, MEK + naloxone, or MEK + anti-SS serum, concentrated by ultrafiltration, and neutralized. The concentrated acid perfusate (CAP), which contains SRP bioactivity, was infused intraduodenally into recipient rats. MEK increased plasma SS concentration and inhibited secretin release and pancreatic fluid and bicarbonate secretion dose-dependently. The inhibition was partially reversed by naloxone and anti-SS serum but not by normal rabbit serum. In recipient rats, CAP increased plasma secretin level and pancreatic secretion. CAP SRP bioactivity decreased when it was collected from MEK-treated donor rats; this was partially reversed by coinfusion with naloxone or anti-SS serum. These results suggest that in the rat, MEK inhibition of acid-stimulated pancreatic secretion and secretin release involves suppression of SRP activity release. Thus the MEK inhibitory effect appears to be mediated in part by endogenous SS.

Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic Kidney and Liver Disease

“…Somatostatin is also known to blunt secretin-induced cAMP accumulation and fluid secretion in cholangiocytes, [11][12][13] arginine vasopressin-induced cAMP accumulation and water permeability in collecting ducts and toad urinary bladder, 14 -17 and secretin release. 10 Although vasopressin is the major adenylyl cyclase agonist in renal collecting ducts and distal nephron, secretin is the major adenylyl cyclase agonist in cholangiocytes. Secretin contributes to adenylyl cyclase-dependent urinary concentration along with vasopressin.…”

“…8 Downstream activation of mTOR likely contributes to cystogenesis. 9 Somatostatin may blunt cyst development by acting at multiple levels: inhibition of secretin release by the pancreas 10 ; inhibition of secretin-induced cAMP generation and fluid secretion in cholangiocytes [11][12][13] ; vasopressin-induced cAMP generation and water permeability in collecting ducts 14 -17 by its effects on Gi protein-coupled receptors; and suppression of the expression of IGF-1, vascular endothelial growth factor, and other cystogenic growth factors and of downstream signaling from their receptors. 14 -18 To determine whether octreotide could be effective in the treatment of PLD, we examined the effects of octreotide in the PCK rat, a recessive model of polycystic liver and kidney disease.…”

Neural hormonal regulation of exocrine pancreatic secretion

“…10). Moreover, treatment of donor rats with methionine-enkephalin, which is known to inhibit PES and secretin release, also reduced the SRP activity of CAP [142]. These observations suggest that the release and action of LSRP in response to duodenal acidification is neural mediated and that Met-ENK may be an inhibitory mediator of SRP release.…”

Effect of tetramethylpyrazine on exocrine pancreatic and bile secretion

“…In the present study, intraperitoneal application of TMP increased secretion of pancreatic-bile juice (PBJ), but the protein content and pH value were not affected. It is known that PBJ consists of both bile and pancreatic juice, the volume of the basal secretion (or agonist induced) of pancreatic juice is normally very low, only about 9-18 µL in 15 minutes in rat [17,18] , as compared to that of the liver. Although TMP increased the secretion of PBJ by 26-83 µL in 15 minutes, it was difficult to assess the contribution to exocrine pancreatic secretion from our experiments in vivo.…”

“…Midline abdominal incisions were made under xylazine and ketamine anesthesia (13 and 87 mg /kg body weight, respectively, im), followed by insertion of a polyethylene tube into the proximal duodenum for diversion of PBJ to the duodenum. A pancreatic duct cannula was made by inserting a polyethylene tube at the junction between the pancreatic duct and the duodenal wall for collection of PBJ [17][18][19] . Collection and measurement of exocrine pancreatic-bile secretions The animals were divided into two groups randomly: TMP group (TMP 80 mg/kg, ip.…”