Comparison of Somatostatin and Its Highly Potent Hexa- and Octapeptide Analogs on Exocrine and Endocrine Pancreatic Secretion

Abstract The effects on pancreatic responses of highly potent cyclic hexapeptide (cyclo (N-Me-Ala-Phe-D-Trp-Lys-Thr-Phe)) (Veber analog) and octapeptide analogs of somatostatin such as D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol (SMS 201–995), D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121), and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) have been compared with somatostatin tetradecapeptide (SS-14) and atropine. The parameters evaluated were pancreatic responses to secretin and meat feeding in conscious dogs with chronic pancreatic fistula and amylase release from the dispersed pancreatic acini. The analogs were administered intravenously or intraduodenally. The cyclic hexapeptide and octapeptide analogs, given iv in graded doses against a constant background stimulation with secretin, produced similar and dose-dependent inhibition of pancreatic HCO− 3 and protein secretion. Analogs RC-121, RC-160, and the Veber analog were about two to four times more active than SS-14 in suppressing HCO− 3 secretion and equipotent in reducing protein secretion, but SMS 201–995 was only about half as potent as somatostatin in inhibiting HCO− 3. RC-160 was effective in inhibiting secretin-induced protein secretion at lower doses than other analogs. In tests with feeding, SMS 201–995, the Veber analog, RC-121, and RC-160 were more potent inhibitors of exocrine pancreatic secretion of HCO− 3 and protein and exhibited more prolonged inhibitory effects than SS-14. The Veber analog, RC-121, and RC-160 were also more effective after intraduodenal administration. Atropine also caused significant inhibition of both HCO− 3 and protein responses to secretin and meal feeding. All four analogs decreased the postprandial insulin and pancreatic polypeptide release to a similar degree as SS-14. Neither SS-14 nor the analogs tested significantly affected basal or caerulein-, gastrin-, secretin-, or bethanechol-stimulated amylase release from the dispersed canine pancreatic acini. Atropine reduced amylase release induced by bethanechol, but not that stimulated by caerulein, gastrin, or secretin. This indicated that the analogs, as somatostatin, are ineffective as secretory inhibitors in vitro. We conclude that cyclic hexapeptide and octapeptide analogs are more potent and longer acting inhibitors of pancreatic secretion than somatostatin-14 in vivo

Comparison of methionine-enkephalin and morphine in the stimulation of gastric acid secretion in the dog

In dogs with Heidenhain pouches and gastric fistulas, we studied acid secretion in response to systemic or portal infusion of methionine-enkephalin (met-enkephalin), enkephalin-analog, or morphine. All these opiate compounds caused a dose-dependent increase in acid secretion under basal conditions and resulted in a significant rise in pentagastrin- or histamine-induced acid secretion. The stimulation by opiates of gastric secretion was accompanied by an increase in the mucosal blood flow but without any significant change in serum gastrin concentration. Gastric acid stimulation by met-enkephalin and morphine was strongly inhibited not only by naloxone, an opiate antagonist, but also by blockers of H2-receptors (metiamide) or cholinergic receptors (atropine), suggesting a cooperative interaction between opiates and other stimuli of parietal cells. The gastric stimulation by met-enkephalin and its analog, but not by morphine, was markedly reduced by portal administration of these compounds, indicating a marked inactivation of opiate peptides by hepatic transit. This study shows that enkephalin and morphine stimulate gastric acid secretion by a gastrin-independent mechanism sensitive to atropine and H2-blocker and probably involving opiate receptors

Inhibition of pancreatic secretion by enkephalin and morphine in dogs

The nature and extent of enkephalin- and morphine-induced inhibition of pancreatic bicarbonate and protein secretion were studied in dogs with chronic pancreatic fistulae after administering exogenous secretin or octapeptide of cholecystokinin and stimulants for the endogenous release of these hormones. Enkephalin and morphine competitively inhibited the pancreatic bicarbonate secretion induced either by exogenous secretin or duodenal acidification. This inhibition was partially reversed by naloxone, an opiate antagonist. Opiate substances also profoundly inhibited pancreatic protein response to octapeptide of cholecystokinin and to various stimulants of endogenous cholecystokinin release. We conclude that enkephalin and morphine strongly inhibit the pancreatic responses to exogenous and endogenous stimulants by a mechanism involving separate opiate receptors