Inhibitory effect of somatostatin analog, SMS 201-995, on exocrine secretion from isolated rat pancreatic acini]

In vitro effect of somatostatin analog, SMS 201-995 (SMS), on pancreatic exocrine secretion was investigated using isolated rat pancreatic acini. SMS had no effect on basal, cholecystokinin octapeptide (CCK-8)- or secretin-stimulated amylase release. SMS inhibited pancreatic amylase release in response to simultaneous stimulation with secretin and CCK-8 in a dose-dependent manner. Significant inhibition was observed with 10 nM SMS and maximal inhibition with 0.1-1 microM SMS. Amylase release in response to the combination of 100 pM CCK-8, 1 nM secretin and 0.1-1 microM SMS was similar to that to 100 pM CCK-8 alone. Secretin significantly increased acinar cell cAMP content. SMS partially inhibited an increase in cAMP content induced by secretin. The present study has demonstrated, therefore, that SMS directly inhibits the potentiating effect of secretin on exocrine secretion in part by inhibiting an increase in secretin-induced cAMP accumulation in rat pancreatic acinar cells.     

Effect of SMS 201-995 on exocrine pancreatic secretion in a patient with external pancreatic fistula.

The effect of SMS 201-995 on pancreatic exocrine function was studied. The SMS 201-995 was administered to a patient with an artificial external pancreatic fistula following pancreaticoduodenectomy. Variations in pancreatic exocrine function were assessed by determining the volume and components of the fistula fluid during the following periods: 5 d prior to SMS 201-995 administration, for 5 d during actual administration, and for 5 d after it had been discontinued. The SMS 201-995 was administered by subcutaneous injection of 100 micrograms every 12 h for the first 2 d and then 100 micrograms every 6 h for 3 d. This experiment demonstrated that SMS 201-995 has a strong inhibitory effect on pancreatic exocrine function, markedly reducing the amount of fistula fluid and the production of amylase, total protein, and bicarbonate.     

Effect of SMS 201-995 on exocrine pancreatic secretion in a patient with external pancreatic fistula

The effect of SMS 201-995 on pancreatic exocrine function was studied. The SMS 201-995 was adminis-tered to a patient with an artificial external pancreatic fistula following pancreaticoduodenectomy. Varia-tions in pancreatic exocrine function were assessed by determining the volume and components of the fistula fluid during the following periods: 5 d prior to SMS 201-995 administration, for 5 d during actual administration, and for 5 d after it had been discontinued. The SMS 201-995 was administered by subcu-taneous injection of 100 μg every 12 h for the first 2 d and then 100 μg every 6 h for 3 d. This experiment demonstrated that SMS 201-995 has a strong inhibitory effect on pancreatic exocrine function, markedly reducing the amount of fistula fluid and the production of amylase, total protein, and bicarbonate.     

Effects of SMS 201-995 on basal and stimulated pancreatic secretion in rats

Somatostatin (SRIF) is a potent inhibitor of most gastrointestinal and pancreatic functions. Recently, we showed that SRIF given either iv or intraduodenally (id) strongly inhibited stimulated pancreatic secretion induced by pancreatic juice diversion (PJD) from the duodenum. In this study we evaluate the effects of iv and id infusion of a long acting analog of SRIF, SMS 201-995 (SMS), on pancreatic secretion during basal conditions (pancreatic juice returned) and PJD. Conscious rats prepared with bile, pancreatic, duodenal, and jugular cannulae were studied 3-8 days postoperatively. Protein and fluid outputs were evaluated, and plasma cholecystokinin (CCK) was measured by bioassay. iv SMS infusion (5 micrograms kg-1 h-1) inhibited basal pancreatic protein and fluid secretion by 84 and 64%, respectively. Addition of atropine (500 micrograms kg-1 h-1 ip) did not cause further inhibition. During PJD, SMS iv from 0.005-1.28 micrograms kg-1 h-1 for 3 h caused a dose-dependent inhibition with maximal 90% and 75% reductions of protein and fluid, respectively, at 1.28 micrograms SMS. Plasma CCK was also reduced by 83% from 3.01 +/- 1.15 to 0.51 +/- 0.22 pM. SMS, id at 1.7 micrograms kg-1 h-1 for 1.5 h before and 2 h after PJD, caused inhibition of basal secretion by 25% and that induced by PJD by 60%. Plasma CCK, measured 1.5 h after diversion, increased from 1.55 +/- 0.06 to 5.9 +/- 1.14 pM in the presence of SMS. Intravenous SMS was 20 times more potent than SRIF in inhibiting pancreatic protein and volume secretion stimulated by PJD. Iv SMS inhibited basal and stimulated fluid and protein pancreatic secretion as well as plasma CCK levels. SMS was also effective when given id in inhibiting fluid and protein pancreatic secretion, but id SMS increased plasma CCK levels. This effect on plasma CCK may be due to the inhibition of hormonal inhibitors of CCK release.     

Plaunotol stimulates endogenous secretin release and exocrine pancreatic secretion in rats

The effect of the new antiulcer agent plaunotol on the release of endogenous secretin and the pancreatic exocrine secretion was investigated in anesthetized rats. In 48 rats with pancreatic and biliary diversion, continuous intraduodenal infusion of plaunotol in 3 graded doses (5, 20 and 80 mg/h/rat) resulted in significant increases in both circulating plasma secretin concentration and pancreatic exocrine secretion, including volume and bicarbonate output, in a dose-dependent manner (r = 0.655, p less than 0.001; r = 0.598, p less than 0.001; r = 0.436, p less than 0.01, respectively). The pancreatic bicarbonate output was closely correlated to plasma secretin concentrations (r = 0.631, p less than 0.001). Amylase output also increased after plaunotol administration, but not in a dose-dependent manner (r = 0.092, n.s.). These findings suggest strongly that the increase in pancreatic secretion of fluid and bicarbonate output was mainly due to increased endogenous secretin release resulting from plaunotol administration.     

Endogenous nitric oxide mediates pancreatic exocrine secretion stimulated by secretin and cholecystokinin in rats

Nitric oxide (NO) is one of the important biologic mediators in regulation of gastrointestinal (GI) functions, but the influence of NO on the release of secretin and cholecystokinin (CCK) and exocrine pancreatic secretion has not been adequately investigated in the rat. The aim of this study was to determine the role of NO on endogenous and exogenous secretin- or CCK-stimulated pancreatic exocrine secretion both in anesthetized and conscious rats. Experiments were carried out in four different groups of rats with duodenal pancreatobiliary cannulas and jugular vein catheters. Group 1: During duodenal infusion of 0.05N HCl or 15% casein (pH 7.0), N-nitro-L-arginine (NNA), an inhibitor of NO-synthase in graded doses (2.5, 5, 10 mg/kg/h), was infused intravenously. Group 2: One hour after starting intravenous secretin at 5 pmol/kg/h or intravenous CCK-8 at 0.06 microg/kg/h, NNA in graded doses was administered intravenously. Group 3: In conscious rats, NNA (5 mg/kg/h) was given intravenously for 1 hour after a meal. Group 4: L-Arginine at 100 mg/kg/h was infused intravenously during the period of NNA (5 mg/kg/h) infusion in groups 1, 2, and 3. Pancreatic juice was collected at 30-minute intervals to measure volume, as well as output of bicarbonate and protein. At the end of the experiment, plasma secretin, vasoactive intestinal polypeptide (VIP) and CCK levels were determined by radioimmunoassay (RIA). NNA dose dependently inhibited the pancreatic secretion of fluid and bicarbonate stimulated by duodenal acidification, exogenous secretin, and a meal. NNA dose dependently inhibited the pancreatic secretion of protein stimulated by duodenal infusion of casein, exogenous CCK, and a meal. L-Arginine significantly reversed the NNA-induced inhibition of pancreatic secretion in all experiments. NNA did not alter significantly the plasma levels of secretin, VIP, and CCK. Our results indicated that endogenous NO plays a significant role in the regulation of pancreatic exocrine secretion stimulated by secretin and CCK. However, NO does not influence the release of secretin, VIP, or CCK in the rat.     

Gastrin-producing ovarian cystadenocarcinoma: sensitivity to secretin and SMS 201-995

We report a patient with severe peptic ulcer disease and a right ovarian mass that was found to be a gastrin-producing cystadenocarcinoma. Gastrin production by the tumor was stimulated by secretin and inhibited by the long-acting somatostatin analogue SMS 201-995. Following resection of the tumor, serum gastrin levels and the gastrin response to secretin returned to normal. Histologic examination, including Alcian blue staining for mucin and immunoperoxidase staining for gastrin, revealed gastrin at the base and mucin at the apex of the tumor cells. This report demonstrates secretin stimulation and somatostatin inhibition of gastrin secretion from a cell that is apparently not of endocrine origin.     

Use of long-acting somatostatin analog SMS 201-995 in patients with pancreatic islet cell tumors

Natural somatostatin reduces plasma concentrations of many peptides, and is of short term benefit in patients with islet cell tumors, but has to be given as a continuous intravenous infusion. We review the published experience with the long acting synthetic somatostatin analogue SMS 201-995 in patients with islet cell tumors. Fifteen of 18 patients with vasoactive intestinal peptide-producing tumors, 8 of 8 patients with glucagonomas, 7 of 7 patients with unresectable insulinomas, and 3 of 3 patients with growth hormone releasing factor-producing tumors had a good sustained symptomatic response to SMS 201-995. Patients with benign insulinomas responded variably and are best treated by surgery. Patients with gastrinomas are best treated by oral gastric antisecretory agents. In all these syndromes, the clinical response to SMS 201-995 did not necessarily parallel the change in plasma concentration of marker peptide, suggesting that SMS 201-995 may have actions at various sites. The effect of SMS 201-995 on tumor size has been assessed in 46 patients, less than 20% of whom showed a reduction in tumor size. Side effects have been mild, but include steatorrhea and gastrointestinal disturbances. More studies will be required to fully assess the effects of longterm administration of SMS 201-995.     

Effects of somatostatin analog SMS 201-995 on enterotoxigenic diarrhea

Somatostatin analog SMS 201-995 causes a dose-related suppression of the release and/or action of several gastrointestinal hormones and impairs several anterior pituitary functions. Some patients with illness involving abnormal hormonal activity have responded to treatment with SMS 201-995, including resolution of severe secretory diarrhea. This study examined SMS 201-995 inhibition ofEscherichia coli heat-stable enterotoxin STa (STa) effects and effects of the analog in the rabbit RITARD model with enterotoxigenicEscherichia coli. SMS 201-995 did not alter STa binding to its receptor on piglet brush border membranes. The analog, at concentrations of 0.1 g/ml (0.1 M) and 1 g/ml (1 M) did not significantly alter STa activation of intestinal epithelial cell particulate guanylate cyclase. At maximal dosing the analog significantly reduced intestinal fluid secretion in suckling mice that was induced by either 8-bromo cyclic GMP or STa. In piglets, the analog reduced by 37–44% the amount of diarrhea induced by STa. However, even with maximal dosing, the piglets still had significant diarrhea, although of a lesser amount. In the rabbit RITARD model the drug failed to alter the severe diarrheal response seen when dosing the animals with enterotoxigenicEscherichia coli. Overall, SMS 201-995 had a significant but incomplete effect in reducing the STa effects seen in the various assays. Additionally, in the RITARD model the analog did not alter the clinical responses to various enterotoxigenic bacteria. SMS 201-995 should be useful as a probe into the mechanisms involved in intestinal fluid secretion, but a clinical role in enterotoxigenic gastrointestinal disease was not supported by this study.This work was supported by the Ralston Purina Co., St. Louis, Missouri, by Sandoz Inc., East Hanover, New Jersey, and by the Department of Veterans Affairs.The work was presented in part at the Sixth International Symposium on Gastrointestinal Hormones, July 1986, Vancouver, British Columbia, Canada.     

Glucagon inhibition of secretin and combined secretin and cholecystokinin stimulated pancreatic exocrine secretion in health and disease

The effect of glucagon infusion on secretin and combined secretin and cholecystokinin stimulated exocrine pancreatic secretion was studied in normal subjects and in patients after acute and with chronic pancreatic disease. Glucagon inhibited pancreatic protein secretion and had no inhibitory effect on volume or bicarbonate secretion.     

Somatostatin analog SMS 201-995 and insulin needs in insulin-dependent diabetic patients studied by means of an artificial pancreas

SMS 201-995 is a new somatostatin analog which is 10-60 times more potent and specific than somatostatin as an inhibitor of GH and insulin release. The aim of this study was to assess its value as an adjunct to insulin therapy in insulin-dependent diabetic- (IDD) patients. Six IDD patients were studied. Their average insulin doses ranged from 22-46 U/day, and hemoglobin A1c levels varied between 6.5-11.5%. Two patients had background retinopathy and mild sensorimotor neuropathy. After 12 h of glucemic stabilization, the patients were kept normoglycemic by connecting them to the Biostator-GCIIS. The study entailed two parts in random order, in which standardised mixed meals were administered at 0800, 1400, and 2000 h with or without sc bolus injections of 50 micrograms SMS 201-995 immediately before meal ingestion. Plasma free insulin, C-peptide, GH, and glucagon were measured by RIA. Postprandial hyperglycemia was significantly diminished by SMS 201-995 after breakfast, lunch, and dinner. Insulin requirements, both total and 2-h postprandially, decreased significantly with a parallel reduction in free insulin levels. Postprandial glucagon levels also significantly decreased, but GH profiles were similar. In conclusion, the somatostatin analog SMS 201-995 has a potential value as an adjunct to insulin in the management of IDD patients.     

Role of secretin and cholecystokinin in oleic acid-stimulated pancreatic secretion in rats.

We investigated the possible role of endogenous secretin and cholecystokinin (CCK) on oleic acid-stimulated pancreatic exocrine secretion in anesthetized rats. Intraduodenal infusion of oleic acid (pH 6.5) in three different doses (0.06, 0.25 and 1 mmole/hr) resulted in dose-related increases in pancreatic juice volume, bicarbonate and amylase outputs (r = 0.665, 0.736 and 0.517, respectively) (P less than 0.001). Plasma secretin and CCK concentrations also elevated significantly in response to oleic acid, in a dose-related manner (r = 0.721 and 0.546, respectively) (P less than 0.001). There were statistically significant correlations between plasma secretin concentrations and bicarbonate outputs, and between plasma CCK concentrations and amylase outputs in response to oleic acid (P less than 0.01). Potent CCK antagonist, CR 1409 (5 mg/kg.hr) administered intravenously suppressed completely increase in amylase output induced by oleic acid, and partially in juice volume and bicarbonate output. It is concluded that both endogenous secretin and CCK play important roles on oleic acid-induced pancreatic secretion in rats.     

Effect of pancreatic proteases on plasma cholecystokinin, secretin, and pancreatic exocrine secretion in response to sodium oleate

The effect of pancreatic proteases or juice on the sodium oleate-stimulated pancreatic secretion and plasma concentrations of secretin and cholecystokinin in anesthetized rats was investigated. Each rat received sodium oleate in a dose of 0.12 mmol.h-1 via a duodenal tube. Sodium oleate infusion significantly increased pancreatic secretion (volume and protein output) compared with the saline given the control group. The increase in pancreatic secretion paralleled significant elevations of plasma concentrations of secretin and cholecystokinin. To determine a possible role of pancreatic proteases on the responses induced by sodium oleate, saline, chymotrypsin, and trypsin, a combination of chymotrypsin and trypsin or pancreatic juice was infused into the duodenum. The pancreatic secretion was significantly reduced by pancreatic proteases or pancreatic juice, and the reduction paralleled the decreases in plasma concentrations of the two hormones. These agents suppressed both pancreatic secretion and plasma hormone levels in the following order of magnitude: (pancreatic juice or chymotrypsin + trypsin) greater than (trypsin) greater than (chymotrypsin). The reduction of pancreatic secretion by pancreatic proteases was reversed by intravenous administration of secretin and cholecystokinin in physiological doses. It is concluded that negative-feedback regulation of pancreatic secretion is operative in the intestinal phase in rats and that both secretin and cholecystokinin are involved in the regulation.     

Treatment of acromegaly with the long-acting somatostatin analog SMS 201-995

Current treatment of acromegaly (surgery, radiation, and bromocriptine) is often unsatisfactory, and a sizeable proportion of patients with this disease continue to have GH hypersecretion after all therapeutic modalities have been exhausted. Fifteen patients with active acromegaly (8 previously treated and 7 newly diagnosed) were treated with the long-acting somatostatin analog SMS 201-995 (Sandoz; 50-250 micrograms, sc, every 6-8 h for up to 21 months). The mean daily plasma GH concentration was significantly suppressed in 13 patients, and it became normal in 10. Two patients, however, did not have GH suppression by SMS 201-995 treatment alone; in 1, a significant decline in mean daily GH was achieved after the addition of bromocriptine. As expected, suppression of GH secretion was associated with normalization of plasma somatomedin-C values and significant clinical improvement. Plasma GH responses to synthetic GHRH-(1-44) and TRH were either abolished or blunted by SMS 201-995. Thyroid function remained normal, and glucose tolerance did not change. Significant shrinkage of pituitary tumors occurred in 7 previously untreated and 2 previously treated patients. Side-effects were minimal. SMS 201-995 is an effective agent for the treatment of acromegaly. Further studies are necessary to establish guidelines for identification of non-responders and to examine the effect of preoperative tumor shrinkage on subsequent surgical outcome.     

Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with the somatostatin analog SMS 201-995

The management of hyperthyroidism due to inappropriate secretion of TSH (IST) includes agents that selectively suppress TSH hypersecretion both in patients with TSH-secreting tumor [neoplastic IST (nIST)] in whom pituitary surgery was unsuccessful and in those with selective pituitary resistance to thyroid hormone action [nonneoplastic IST (nnIST)]. Among such agents, somatostatin administration has proven to be effective in blocking TSH hypersecretion, but its short plasma half-life prevented its use in long term therapeutic trials. The recent availability of a potent and long-acting analog of somatostatin (SMS 201-995, Sandostatin) prompted us to study its effects on serum TSH, alpha-subunit, and free thyroid hormone (FT4 and FT3) concentrations in five patients with nIST and three patients with nnIST. During short term SMS 201-995 administration (100 micrograms, sc, three times daily for 5 days) both serum TSH and alpha-subunit levels decreased in all patients with nIST (mean decrements, -86% and -85%, respectively), with concomitant normalization of serum FT4 and FT3 concentrations. In the three patients with nnIST, this treatment lowered serum TSH levels less well (mean decrement, -47%), although serum FT4 and FT3 levels normalized in one patient. Chronic SMS 201-995 (100 micrograms, sc, every 12 h for 1-7 months) treatment in four hyperthyroid patients (two with nIST and two with nnIST) resulted in a steady euthyroid state in both patients with nIST, with restoration of normal visual fields in one patient. In contrast, in both patients with nnIST, escape occurred after 2 weeks of therapy. We conclude that SMS 201-995 administration is effective treatment for patients with nIST, able to suppress TSH hypersecretion from the adenomatous thyrotrophs and, consequently, to restore clinical and biochemical euthyroidism in such patients. On the contrary, the inhibitory effects of SMS 201-995 on TSH secretion in patients with nnIST are weaker and transient.     

Potentiating effect of secretin on cholecystokinin-stimulated exocrine pancreatic secretion in rats

The potentiating effect of secretin on cholecystokinin (CCK)-stimulated exocrine pancreatic secretion was studied in anesthetized rats. Intravenous infusion of CCK-8 in three different doses of 0.03, 0.06 and 0.12 micrograms/kg-hr increased pancreatic secretion of volume, bicarbonate, amylase and trypsin outputs dose-dependently. Simultaneous infusion of CCK-8 with secretin in a dose of 0.03 CU/kg-hr produced statistically greater pancreatic secretion of volume, bicarbonate, amylase and trypsin outputs than that by CCK-8 alone, and than the sum by secretin alone and CCK-8 alone in each dose. Proglumide (600 mg/kg-hr) significantly suppressed exocrine pancreatic secretion produced by CCK-8 (0.06 micrograms/kg-hr) plus secretin (0.03 CU/kg-hr), to the level induced by secretin alone. These results indicate that CCK-8 increased pancreatic secretion dose-dependently, and secretin in a physiological dose potentiates the stimulating effect of CCK-8 on exocrine pancreatic secretion in rats.     

Effect of somatostatin analog (SMS 201-995) onin vivo intestinal fluid transport in rats

Somatostatin analog, SMS 201-995, effectively inhibits the release of hormones from gastrointestinal endocrine tumors and reduces hormonally mediated diarrheas. Its clinical efficacy in nonhormonally mediated diarrhea is limited, despite a potent antisecretory and proabsorptive effect in vitro. The effect of serosal addition of SMS 201-995 on in vitro short-circuit current responses in rat intestine is dependent upon chloride and more marked in colon and ileum than jejunum. In contrast, in vivo loop studies demonstrated that systemic administration of SMS 201-995 for five consecutive days produced a paradoxical decrease in basal colonic fluid absorption with no effect in jejunum or ileum. Furthermore, systemically administered SMS 201-995 did not alter cholera toxin-stimulated intestinal secretion. We conclude that despite a previously identified intestinal antisecretory and proabsorptive effect of SMS 201-995 in vitro, this effect is not seen in vivo and may explain the limited use of SMS 201-995 as an antidiarrhoeal agent in nonhormonally mediated diarrhoea.     

Role of secretin and cholecystokinin in oleic acid-stimulated pancreatic secretion in rats

We investigated the possible role of endogenous secretin and cholecytokinin (CCK) on oleic acid-stimulated pancreatic exocrine secretion in anesthetized rats. Intraduodenal infusion of oleic acid (pH 6.5) in three different doses (0.06, 0.25 and 1 mmole/hr) resulted in dose-related increases in pancreatic juice volume, bicarbonate and amylase outputs (r=0.665, 0.736 and 0.517, respectively) (P<0.001). Plasma secretin and CCK concentrations also elevated significantly in response to oleic acid, in a dose-related manner (r=0.721 and 0.546, respectively) (P<0.001). There were statistically significant correlations between plasma secretin concentrations and bicarbonate outputs, and between plasma CCK concentrations and amylase outputs in response to oleic acid (P<0.01). Potent CCK antagonist, CR 1409 (5 mg/kg.hr) administered intravenously suppressed completely increase in amylase output induced by oleic acid, and partially in juice volume and bicarbonate output. It is concluded that both endogenous secretin and CCK play important roles on oleic acid-induced pancreatic secretion in rats. The results of this study were presented at The 7th International Symposium of Gastrointestinal Hormones in Shizuoka, Japan, Nov. 1–4, 1988, and appeared in abstract form in Biomedical Research 1988;9(Suppl. 1):114. This work was supported in part by grants from the Japanese Ministry of Education and the Ministry of Welfare. The authors are grateful to Y. Hirasawa, B.S. and M. Takeda, B.S. for their technical assitance.     

Interaction of secretin and glucagon on exocrine pancreatic secretion.

Inhibition of secretin-stimulated pancreatic secretion by glucagon was studied in anesthetized dogs. Two external pancreatic fistulas were prepared in dogs for both simultaneous and separate collection of pancreatic juice secreted by the right and left lobes. Two series of experiments were preformed. In the first, graded doses of glucagon (2.5 to 20 micrograms/kg/hr) were administered against a background infusion of 2 CHR U/kg/hr of secretin. In the second, a constant dose of glucagon (20 micrograms/kg/hr) was given against a background infusion of secretin doubling from 1 to 8 U/kg/hr. Infusion of glucagon was started when flow rate became nearly constant, and continued for 60 minutes in each dose. Glucagon produced the dose-related reduction in flow rate and bicarbonate secretion, but not in amylase secretion. This inhibitory effect was almost the same in size between the right and left lobes. No significant change of plasma secretin was observed during glucagon infusion. Michealis-Menten analysis of the dose in slopes (Km) and similar intercepts of Y-axis (CMR). These results suggest that glucagon inhibits competitively secretin-stimulated pancreatic secretion by acting probably on the same receptor as secretin.