Shin-ichiro Watanabe

Secretin is released by digestive products of fat in dogs

We investigated the effect of fat or digestive products of fat on the release of endogenous secretin in 15 gastric fistula dogs with either pancreatic fistulas or duodenal fistulas. In 4 dogs with both gastric and duodenal cannulas, intraduodenal administration of corn oil (Lipomul) at a dose of 15 mmol resulted in a significant increase in plasma secretin concentration, whereas in another group of 4 dogs with complete pancreatic duct ligation, the same amount of triglyceride failed to increase the secretin concentration. When Lipomul incubated with pancreatic enzymes was administered in the duodenum, a marked increase in plasma secretin concentration occurred in the 4 dogs with pancreatic duct ligations. In the 7 dogs with chronic pancreatic fistulas, intraduodenal administration of Lipomul resulted in a significant increase in both plasma secretin concentration and pancreatic secretion of bicarbonate when the pancreatic juice was allowed to flow into the duodenum, whereas no increase in either the secretin concentration or bicarbonate output was apparent using the same amount of Lipomul when the pancreatic juice was diverted from the duodenum. In 4 of these 7 dogs so studied, intraduodenal administration of oleic acid emulsion, with pH adjusted to 5.0 in graded doses, resulted in a dose-related increase in the secretin concentration that paralleled pancreatic bicarbonate output. The increases in both secretin concentration and pancreatic bicarbonate secretion were completely abolished by intravenous infusion of a rabbit antisecretin serum in the 4 dogs. Thus we conclude that release of endogenous secretin plays an important role in the mechanism of exocrine pancreatic secretion stimulated by digestive products of fat in dogs.

Mediation of Trypsin Inhibitor-Induced Pancreatic Hypersecretion by Secretin and Cholecystokinin in Rats

We investigated a hormonal mechanism in a trypsin inhibitor-induced pancreatic hypersecretion in rats. Intraduodenal administration of a synthetic trypsin inhibitor, camostat, resulted in significant increases in plasma concentration of both secretin and cholecystokinin in a dose-related manner that paralleled a significant increase in exocrine pancreatic secretion. To eliminate the effect of circulating secretin in rats, a rabbit antisecretin serum was given IV that resulted in a 77% reduction in bicarbonate secretion stimulated by intraduodenal camostat. A cholecystokinin receptor antagonist, MK-329, also inhibited significantly the camostat-induced increase in pancreatic secretion; volume and bicarbonate output were reduced by 35% each and amylase output by 73%. The combined administration of antisecretin serum and MK-329 completely abolished the pancreatic exocrine secretion stimulated by camostat. These observations indicate that the camostat-stimulated pancreatic exocrine secretion is mediated by the increased release of both secretin and cholecystokinin in rats.

Release of cholecystokinin and exocrine pancreatic secretion in response to an elemental diet in human subjects.

We investigated in human volunteers the effects of an elemental diet (ED) containing amino acids on release of endogenous cholecystokinin (CCK) using a highly sensitive and specific radioimmunoassay of CCK and exocrine pancreatic secretion using a dye dilution technique with polyethylene glycol 4000 as a nonabsorbable marker. Intrajejunal administration of ED at three different infusion rates (12.5, 25, and 50 ml/30 min) resulted in a significant increase in plasma CCK concentration in a dose-related manner. Plasma concentrations of gastrin or secretin, however, did not change. Pancreatic secretion of protein, amylase, and bicarbonate also increased significantly. The change in pancreatic secretion of protein, amylase, and bicarbonate output paralleled that of the circulating CCK level but not that of plasma secretin. Thus, the dose of amino acid contained in ED recommended for clinical use can significantly stimulate the release of CCK from the upper small intestine, raising the plasma concentration of CCK. This level can evoke a significant increase in exocrine pancreatic secretion.

Somatostatin analog, SMS 201-995, inhibits pancreatic exocrine secretion and release of secretin and cholecystokinin in rats

We studied the effect of a synthetic octapeptide somatostatin analog, SMS 201–995 (sandostatin), on pancreatic exocrine secretion and on plasma secretin and cholecystokinin (CCK) levels in vivo in anesthetized rats. The exocrine pancreas was stimulated by either intravenous infusion of both secretin (0.06 CU/kg/h) and cholecystokinin octapeptide (CCK-8) (0.03 u-g/kg/h) or intraduodenal infusion of oleic acid (pH 6.5) in a dose of 0.25 mmol/h. Intravenous administration of SMS 201–995 in three different doses of 100, 200, and 400 ng/kg/h resulted in dose-related inhibition of pancreatic secretion in terms of volume, bicarbonate, and amylase stimulated by exogenous secretin and CCK. Intraduodenal oleic acid stimulated pancreatic secretion, including volume, bicarbonate, and amylase, and this was accompanied by a significant elevation in the plasma concentrations of secretin and CCK. Intravenous administration of SMS 201–995 in the three different doses described above caused dose-dependent suppression of the increase in pancreatic exocrine secretion as well as the plasma concentration of secretin and CCK induced by intraduodenal infusion of oleic acid. It is concluded that SMS 201–995 inhibits pancreatic exocrine secretion and the release of endogenous hormones, such as secretin and CCK, in rats.

Potentiating Effect of CCK and Secretin on Rat Exocrine Pancreas and its Cholinergic Dependence

We investigated whether physiological doses of cholecystokinin (CCK) potentiate the stimulating effect of a physiological dose of secretin on exocrine pancreatic secretion, and the effect of atropine on this potentiating action in rats. Pure pancreatic juice was collected from anesthetized rats prepared by pancreatic duct and bile duct cannulation. Intravenous infusion of CCK-8 in three different doses, 0.03, 0.06, and 0.12 μg/kg/h, significantly increased pancreatic juice volume and amylase output, dose-dependently. Simultaneous infusion of CCK-8 in graded doses with secretin in a dose of 0.03 CU/kg/h, produced a dose-related increase in pancreatic secretory response significantly greater than the response to CCK-8 alone (p < 0.05) and greater than the sum of the response to secretin alone and CCK-8 alone. The incremental pancreatic secretion, including juice volume and amylase output, in response to intravenous infusion of CCK-8 with secretin, was significantly suppressed by intravenous administration of atropine in a dose of 100 μg/kg/h (p < 0.01). Thus, it is concluded that CCK-8 and secretin in physiological doses potentiate each others stimulatory action on exocrine pancreatic secretion and this potentiating action appears to be cholinergic-dependent.

Role of endogenous secretin and cholecystokinin in intraduodenal oleic acid-induced inhibition of gastric acid secretion in rats

We investigated a possible role of endogenous secretin and cholecystokinin (CCK) in inhibition of gastric acid secretion induced by intraduodenal administration of oleic acid in rats. Intraduodenal administration of oleic acid emulsion in a dose of 1 mmol/hr resulted in significant inhibition of gastric acid secretion stimulated by intravenous infusion of pentagastrin (0.3 μg/kg/hr), and this was accompanied by an increase in the plasma concentration of both secretin and CCK, from 1.2±0.08 pM and 20.6±1.2 pM to 4.3±0.18 pM and 31.6±0.9 pM, respectively (P<0.001). Intravenous infusion of secretin (0.05 CU/kg/hr) inhibited pentagastrin-stimulated gastric acid secretion, but CCK-8 (0.03 μ/kg/hr) failed, although intravenous infusion of secretin, and CCK in those doses produced plasma levels comparable to the levels achieved in response to oleic acid administration. Furthermore, the oleic acid-induced suppression of gastic acid secretion was blocked significantly by intravenous injection of rabbit anti-secretin serum (0.1 ml), but not by intravenous infusion of a CCK-receptor antagonist, CR 1409 (5 mg/kg/hr). Thus, the results of this study indicate that endogenous secretin rather than CCK is involved in the hormonal mechanism regulating the inhibition of gastric acid secretion by intestinal fat in rats.

Effect of CCK antagonists CR 1409 and CR 1505 on rat pancreatic exocrine secretion in vivo.

The action of cholecystokinin (CCK) antagonists CR 1409 and CR 1505 on pancreatic exocrine secretion stimulated by exogenous and endogenous CCK was studied in vivo in anesthetized rats, and compared with proglumide. Intravenous administration of CR 1409 and CR 1505 in graded doses between 0.04 and 25 mg/kg/h resulted in a dose-dependent inhibition in pancreatic juice volume and amylase output stimulated by intravenous infusion of CCK-8 in a dose of 0.06 μg/kg/h. CR 1409 is 1,000 times and CR 1505 is 267 times more potent than proglumide, based on the ED50 (effective dose for half-maximal inhibition) for CCK-8-stimulated amylase secretion. Intraduodenal administration of casein in a dose of 400 mg/h caused significant increases in plasma CCK concentration and pancreatic secretion of juice volume and outputs of amylase and trypsin. Both CR 1409 and CR 1505 in a dose of 5 mg/kg/h suppressed the increases in pancreatic juice volume and both amylase and trypsin outputs induced by casein given intraduodenally. These results indicate that CCK antagonists including CR 1409, CR 1505, and proglumide inhibit pancreatic exocrine secretion stimulated by not only exogenous, but also endogenous CCK in rats.

Effect of licorice extract (Fm100) on release of secretin and exocrine pancreatic secretion in humans.

We investigated the effect of a fraction of licorice extract (Fml00) on release of endogenous secretin in seven human volunteers using radioim-munoassay and exocrine pancreatic secretion using a dye dilution technique with polyethylene glycol 4000 as a non-absorbable marker. Intrajejunal administration of FmlOO (pH 6.5) in three different doses (200, 400, and 800 mgi30 min) resulted in significant increases in both plasma secretin concentration and pancreatic bicarbonate output in a dose-dependent manner (r = 0.737, p <0.001, and r = 0.483, p <0.01, respectively). However, it did not influence pancreatic secretion of protein or amylase. The correlation between plasma secretin concentrations and bicarbonate outputs was also significant (r = 0.483; p <0.01). These results indicate that endogenous secretin is released by FmlOO in humans and suggest strongly that the increased pancreatic bicarbonate secretion is attributable to the increased plasma concentration of secretin.

Secretin as a potential mediator of antiulcer actions of mucosal protective agents.

Recently, we have reported that several nonacid agents including phenylpentol, methanol extract of licorice root (FM 100), plaunotol, and teprenon stimulate release of endogenous secretin in humans, dogs, and rats. The latter three are antiulcer agents developed in Japan that have a protective effect on the gastric mucosa. We have clearly shown that plaunotol inhibits postprandial gastrin release and gastric acid secretion that parallel the increase in plasma secretin concentration. It has also been recently demonstrated that the secretin-induced inhibition of gastric acid secretion in rats is completely blocked by indomethacin, a potent inhibitor of prostaglandin synthesis. It appears that the inhibitory action of secretin on gastric acid secretion is mediated mainly by endogenous prostaglandins. Because the three antiulcer agents FM 100, plaunotol, and teprenon have been shown to increase the content of endogenous prostaglandins in the gastric mucosa, endogenous secretin released by these agents may play a significant role in their mucosal protective action. It is concluded that the antiulcer effect of these drugs could in part be attributable to their unique ability to release endogeneous secretin, and that secretin is a potential mediator of the antiulcer actions of mucosal protective agents.

Effect of fatty acid on secretin release and cholinergic dependence of pancreatic secretion in rats.

We investigated the effects of oleic acid in the duodenum on pancreatic exocrine secretion and plasma secretin, and determined the role of cholinergic dependence on pancreatic secretion and secretin release in response to oleic acid in anesthetized rats. Oleic acid emulsion (pH 6.5) in three different doses of 0.06,0.25, and 1 mmol/h was infused intraduodenally for 1 h with or without intravenous administration of atropine in a dose of 100 μg/kg/h. Intraduodenal administration of oleic acid resulted in significant increases in pancreatic juice volume and bicarbonate output, in a dose-related manner (p < 0.001). Plasma secretin concentration caused dose-dependent elevation (p < 0.001) by oleic acid, which correlated very well with bicarbonate output in response to oleic acid (p < 0.001). Atropine inhibited pancreatic secretion including juice volume and bicarbonate output stimulated by oleic acid in each dose, statistically significantly (p < 0.05–0.01), but did not affect plasma secretin concentration. Thus, we conclude that oleic acid in the duodenum stimulates pancreatic secretion and endogenous secretin release in rats, and that secretin release is not influenced by the cholinergic tone, although pancreatic secretory response is inhibited significantly.