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Comparison of the biological potency of a new synthetic preparation of secretin with that of natural porcine secretin in the dog.

The biological activity of the new synthetic secretin, Roche, on exocrine pancreatic secretion was determined in conscious dogs with chronic gastric and duodenal fistulae and compared with that of pure porcine secretin (GIH, Karolinska Institutet, Stockholm). The two secretin preparations were found to be equipotent as to pancreatic volume and bicarbonate response on a molar basis. It was concluded that the new synthetic secretin is useful for clinical and research purposes.

Animals↗

A sensitive method for the biological assay of secretin and substances with "secretin-like" activity in tissues and biological fluids.

The isolated perfused pancreas is extremely sensitive to secretin and can be used to assay very small quantities of secretin. The addition of theophylline to the perfusate increases the sensitivity of the preparation 4 to 10 fold so that in a good preparation as little a 0.001 C.U. may be detected. Secretin-like activity was detected in biopsy samples of jejunal mucosa taken perorally from man, in the blood of some patients suffering from a profuse watery diarrhoea, and in a metastatic tumour obtained from one such patient. It was also observed that 1 clinical unit of secretin was equal to 4.4 Crick, Harper, Raper units.

Adult↗

Effect of low dose secretin and caerulein on pure pancreatic bicarbonate secretion and plasma secretin in man.

In six healthy volunteers pure pancreatic juice was obtained by endoscopic cannulation of the main pancreatic duct. Following a 20-min basal period, secretin (0.03 CU/kg, h) was intravenously infused alone for 20 min and then with caerulein 15 ng/kg, h for further 20 min. From a basal level of 28 +/- 13 mu mol/5 min, secretin by itself significantly increased pancreatic bicarbonate to 182 +/- 24 mu mol/5 min. A further significant two-fold increase to 396 +/- 50 mu mol/5 min was observed during caerulein. The increment in plasma secretin of 2.1 +/- 0.3 pmol/l is comparable to the rise that may be observed post-prandially. It is concluded that secretin in combination with cholecystokinin may indeed play a physiological role in the regulation of duodenal pH.

Adult↗

Chemical and biological properties of porcine secretin and secretin analogues modified in positions 3 and 4.

The synthesis of secretin does not offer fundamental difficulties any longer. The problem of the stability of the hormone seems to be solved from a practical point of view. However, the mechanism of the inactivation of secretin in solution is not yet satisfactorily explained, alpha-beta Rearrangement of the Asp-Gly bond may play a role, but some observations indicate that inactivation is not a straight reaction. Like secretion [Ala-4] secretin shows beta-sympathomimetic activity. The availability of a suitable depot preparation permits physiological studies with secretin and its analogues after subcutaneous administration.

Animals↗

Spatial approximation between a photolabile residue in position 13 of secretin and the amino terminus of the secretin receptor.

The amino-terminal domain of class B G protein-coupled receptors is critically important for natural peptide agonist binding and action. The precise role it plays and the molecular basis of the interaction between ligand and this domain are not well understood. In the current work, we have developed a new probe for affinity labeling the secretin receptor through a photolabile benzoyl-phenylalanine residue in position 13. This represented a high affinity ligand (K(i) = 56 +/- 8 nM) that was a potent full agonist to stimulate cellular cAMP (EC(50) = 236 +/- 22 pM). It covalently labeled the secretin receptor saturably in a single site. This was localized to the amino-terminal domain near the first transmembrane segment using a series of chemical and enzymatic digestions. Edman degradation sequencing of radiolabeled cyanogen bromide and skatole digestion products that were attached to glass beads and further cleaved with endoproteinase Asp-N demonstrated that the labeled residue represented Val(103). This is in contrast with previous photoaffinity labeling through positions 6, 18, 22, and 26 of secretin that all labeled the distal end of the amino terminus of this receptor. Together, these five pairs of residue-residue approximations provide important constraints to better understand the molecular conformation of the agonist-bound receptor.

Amino Acid Sequence↗

A comparison between secretin alone and sequential and simultaneous secretin and cholecystokinin administration in the assessment of pancreatic function.

Pancreatic volume, bicarbonate and enzyme secretion were studied after sequential and after simultaneous secretin and cholecystokinin (CCK) stimulation and the results compared. No statistical difference between sequential or simultaneous stimulation was noted. A comparison of secretin alone with simultaneous secretin plus cholecystokinin stimulation showed that the combination yielded a significantly higher trypsin concentration. Volume and bicarbonate were unchanged.

Bicarbonates↗

Physiological significance of secretin in the pancreatic bicarbonate secretion. I. Responsiveness of the secretin-releasing system in the upper duodenum.

In nine normal subjects intraduodenal pH was measured by means of a glass electrode placed in the passage from the first to the second part of the duodenum. The physiological variations in pH were simulated by intraduodenal injection of 2.5, 5, or 10 ml of 0.1 mol x 1(-1) HCl and subsequent neutralization by injection of bicarbonate. A total of 26 injections of acid was followed by a pH spike from a median pH of 7.0 to a median of pH 2.1 Median spike duration was 45 sec. The concentration of secretin in plasma increased from a median of 1.2 pmol x 1(-1) to a peak value of 2.2 pmol x 1(-1) after 4 min. It is concluded that the secretin response to a brief acidification of the first 4--6 cm of the duodenum is sufficient to explain the physiological variations in the concentration of secretin in human plasma.

Bicarbonates↗

Curative resection of multiple gastrinomas aided by selective arterial secretin injection test and intraoperative secretin test.

Recently a number of surgeons have recommended radical resection of gastrinomas in Zollinger-Ellison syndrome (ZES). We have developed a useful technique for preoperative localization of gastrinomas--the selective arterial secretin injection test (SASI)--and we recommend an intraoperative secretin test (IOS) for deciding the radicality of resection of gastrinomas. Here the results of SASI and IOS tests in 11 patients with ZES are examined and compared with the results of other techniques. The SASI test localized gastrinomas in all of the patients, while the sensitivity of ultrasonography, computed tomography, arteriography, or portal venous blood samplings was between 1/11 and 5/11. On the basis of the results of the SASI test, radical resection of gastrinoma was performed in four patients (three pancreatoduodenectomies and one extirpation). After pancreatoduodenectomy, immunohistologic study of the specimen revealed multiple microgastrinomas and lymph node metastases in two patients and the coexistence of a microgastrinoma and a gastinoma in one patient. The IOS test was useful in the estimation of the advisability of radicality, and in two patients total gastrectomy was not performed because of the results of the IOS test. These four patients are well and have returned to work, and their serum gastrin levels are below 35 pg/mL. Thus we believe SASI and IOS tests are helpful for planning curative resection of gastrinomas.

Adolescent↗

Effects of secretin and cholecystokinin on motor activity of human jejunum. A radiotelemetering study of jejunal motility during secretin and cholecystokinin intravenous infusion.

The effects of intravenous administration of secretin and cholecystokinin (CCK) on motility of the human jejunum were investigated with pressure-sensitive radiotelemetering capsules. Secretin inhibited and CCK stimulated the spontaneous motor activity of this part of the small intestine. Raising the dosages of the two hormones caused increasing effects. It seems likely, therefore, that both hormones play a role in the regulation of intestinal motility in man.

Adult↗

Secretin-pancreozymin test with synthetic secretin and cholecystokinin octapeptide.

Pancreatic responses to submaximal doses of synthetic secretin (125 ng/kg) and cholecystokinin octapeptide (50 ng/kg) were investigated in controls and patients with pancreatic disease. Doses of stimulants were chosen from dose-response experiments to avoid supramaximal amounts which inhibited the pancreatic response. Injection of secretin resulted in duodenal juice in less trypsin but more lipase activity than that elicited by cholecystokinin octapeptide. The increase of amylase was about the same. Diagnostic efficacy of pancreatic responses to the individual hormones was similar. An overall evaluation of the results seems to be the most reliable method for diagnostic purposes.

Amylases↗

Secretin-induced insulin response. I. Cubital insulin concentration in normal, obese and pancreatectomized patients, including portal insulin concentration in normals after secretin.

Intravenous injection of the gastro-intestinal hormone secretin elicits an increase in the insulin concentration in the cubital vein. In 10 normal weight non-diabetics and 10 obese non-diabetics the latter group gave a hypernormal insulin response. By the simultaneous determination of the insulin concentration in the cubital and portal veins and also by an investigation of 2 pancreatectomized patients, it was demonstrated that an increase in the cubital insulin concentration following intravenous injection of secretin was due to an altered secretion from the pancreas and not to an altered elimination of insulin.

Adult↗

A proform of secretin with high secretin-like bioactivity.

A variant form of the heptacosapeptide amide secretin, with C-terminal -Val-Gly-Lys-Arg instead of valine amide, has been isolated from porcine upper intestinal tissue. Unexpectedly, this triacontapeptide exhibited a substantially higher bioactivity than the heptacosapeptide amide.

Amino Acid Sequence↗

Secretin release in coeliac disease. Plasma secretin concentration and bicarbonate output to the duodenum after intraduodenal acid infusion in coeliac patients before and after treatment.

Infusion of 40 ml 0.1 mol/l HCl into the duodenum in eight untreated coeliac patients was followed by an increase of the plasma immunoreactive secretin (IRS) concentration from 1.6 +/- 0.2 pmol/l to a peak level of 2.4 +/- 0.3 pmol/l (p less than 0.05). After treatment with a gluten-free diet, the same patients showed an increase from 1.4 +/- 0.3 pmol/l to a peak level of 5.5 +/- 0.9 pmol/l after intraduodenal acid infusion, which was significantly higher than before treatment (p less than 0.01). In control subjects, intraduodenal acid infusion was followed by an increase from 1.4 +/- 0.2 pmol/l to 6.7 +/- 1.1 pmol/l, which was significantly higher than in untreated coeliac disease (p less than 0.01) but did not differ from what was found in treated coeliac patients. Significant differences in pH, volume, or bicarbonate content of the duodenal aspirates or the basal IRS levels were not found.

Adolescent↗