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A K Sandvik

Publications and source records attributed to A K Sandvik.

101 records · Page 6Linked to original sources
PubMed1989

Bioactivity studies on new gastrin analogues.

Gastrin antagonists may be useful in the treatment of peptic ulcer disease and gastrointestinal malignancies. The aim of the present study was to synthesize gastrin analogues and test them for their ability to inhibit gastrin-stimulated acid secretion. Five peptides were synthesized: peptide [2], in which methionine was replaced by leucine, and the COOH-terminal amide was replaced by the thiomethylamide; peptide [3], in which the COOH-terminal phenylalanine was removed, and the aspartic acid thioamidated; peptide [5], in which methionine was replaced by leucine, and the peptide bond between leucine and aspartic acid was replaced by a thioamide; peptide [7], in which the bond between leucine and aspartic acid was replaced by a ketomethylene amino bond; and, finally, peptide [8], in which a beta-bend was induced in the COOH-terminal region by the introduction of a D-phenylalanine in place of glycine. The biologic effect of the peptides was tested in the totally isolated, vascularly perfused rat stomach. The peptides were tested in concentrations of 10(-9), 10(-7), and 10(-5) M for agonist activity and together with gastrin 1-17, 5.2 X 10(-10) M, at a concentration of 10(-5) M for antagonist activity. Peptide [2] had full biologic activity but greatly reduced potency, and peptide [7] had a faint biologic activity. None of the peptides showed any antagonist activity.

Amino Acid Sequence↗
PubMed1988

The effect of somatostatin on baseline and stimulated acid secretion and vascular histamine release from the totally isolated vascularly perfused rat stomach.

The effect of somatostatin-(1-14) (S1-14) on the gastrin- and histamine-induced acid secretion and gastrin-evoked vascular histamine release was studied in isolated vascularly perfused rat stomachs being continuously perfused by a gassed buffer containing 10% ovine erythrocytes and 50 microM isobutyl methylxanthine (IMX). Concentrations of gastrin (520 pM) and histamine, (0.5 microM) were chosen to give acid secretion in the same range (61.5 +/- 7.0 and 49.4 +/- 9.4 mumol/60 min). S1-14 induced a concentration-dependent decrease in acid secretion stimulated by both gastrin and histamine. Even at the lowest concentration examined (0.1 nM) somatostatin gave a significant inhibition of both gastrin- and histamine-stimulated acid secretion. The inhibitory effect was, however, most marked for gastrin-stimulated acid secretion (P less than 0.05 at 1 nM concentration of S1-14). Gastrin gave an immediate and marked vascular histamine release which was inhibited by somatostatin in the higher concentrations (1.0 and 5.0 nM). Somatostatin at the lowest concentration tested (0.1 nM) did not inhibit the gastrin-induced vascular histamine release although it did inhibit acid secretion. Furthermore, baseline histamine release was not affected by somatostatin. This study suggests that somatostatin inhibits acid secretion both via a direct effect of the parietal cell and by inhibiting gastrin-induced histamine release. Baseline histamine release is regulated by a mechanism not sensitive to somatostatin.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Ionized calcium influences gastrin stimulated histamine release and acid secretion, but not histamine stimulated acid output in the totally isolated vascularly perfused rat stomach.

When changing from bovine serum albumin to dextran T70 as colloid without adjusting the total calcium concentration in the vascular perfusate of the totally isolated vascularly perfused rat stomach, we noticed a drastic fall in gastrin-stimulated acid secretion. In the present study the effect of the two colloids on ionized calcium in the vascular perfusate as well as the effect on acid secretion and vascular histamine release were studied. There was no difference in gastrin-stimulated acid secretion or vascular histamine release between the two colloids after adjusting the total calcium concentrations so that ionized calcium was similar. Whereas baseline acid secretion showed no marked dependency of ionized calcium within the range tested (0.73-1.54 mmol l-1, gastrin-stimulated acid secretion was highly dependent on ionized calcium being reduced at the higher concentration of Ca2+. Histamine stimulated acid secretion, on the other hand, was virtually unaffected by the concentration of ionized calcium in the same range. Like gastrin-stimulated acid secretion, gastrin-stimulated histamine release was inhibited at higher Ca2+ concentrations. Thus, elevated Ca2+ concentrations seemed to reduce gastrin-stimulated acid secretion by inhibiting vascular histamine release.

Animals↗
PubMed1988

Muscarinic M2 stimulation releases histamine in the totally isolated, vascularly perfused rat stomach.

The present study examines the role of histamine in the stimulation of acid secretion induced by vagal nerve stimulation and by the muscarinic M1 agonist McN-A-343 in the totally isolated, vascularly perfused rat stomach. The stimuli were combined with an agent stimulating the cAMP system (isobutyl methylxanthine (IMX) or forskolin), a muscarinic antagonist (atropine or pirenzepine), or a histamine H2 antagonist (ranitidine). IMX and forskolin potentiated McN-A-343-stimulated acid secretion, yielding acid outputs of 280% and 260% of the sum of McN-A-343- and IMX-, or McN-A-343- and forskolin-stimulated outputs, respectively. Ranitidine inhibited acid secretion stimulated by McN-A-343 alone or in combination with IMX, whereas the forskolin-stimulated secretion was not influenced by the H2 antagonist. This strongly indicates that endogenous histamine potentiates muscarinic M1-stimulated acid secretion by increasing parietal cell cAMP. Vagal nerve stimulation with IMX increased acid output from 12.2 +/- 3.0 to 49.2 +/- 9.3 mumol/60 min (mean +/- SEM). The M1 antagonist pirenzepine and the M1/M2 antagonist atropine both significantly (p less than 0.01) inhibited vagally stimulated acid secretion. Histamine output as measured in the venous effluent was unchanged by McN-A-343, whereas nerve stimulation induced a clear increase in venous histamine output, from 101 +/- 21 before to 212 +/- 28 pmol/min (mean +/- SEM) after initiation of nerve stimulation. Histamine release was reduced to base-line levels by atropine but only insignificantly inhibited by pirenzepine, indicating a muscarinic M2 stimulation of histamine release in the rat stomach.

1-Methyl-3-isobutylxanthine↗
PubMed1988

The effect of misoprostol on base-line and stimulated acid secretion and on gastrin and histamine release in the totally isolated, vascularly perfused rat stomach.

The effects of the prostaglandin E1 analogue misoprostol on base-line and stimulated (gastrin, histamine, and the muscarinic M1 agonist McN-A-343) acid secretion, base-line and gastrin-stimulated histamine release, and base-line and McN-A-343-stimulated gastrin release in the totally isolated, vascularly perfused rat stomach were studied. At a concentration of 1 nM, misoprostol significantly (p less than 0.01) inhibited base-line acid secretion from 13.7 +/- 2.7 to 4.8 +/- 0.7 mumol/60 min, histamine-stimulated acid secretion from 99.9 +/- 15.1 to 21.8 +/- 8.2 mumol/60 min, maximal gastrin-stimulated secretion from 92.5 +/- 11.4 to 3.1 +/- 0.6 mumol/60 min, and maximal McN-A-343-stimulated secretion from 60.0 +/- 8.9 to 6.8 +/- 2.6 mumol/60 min (mean +/- SEM). Likewise, misoprostol significantly inhibited base-line vascular histamine release (p less than 0.05) from 10.1 +/- 2.3 to 3.7 +/- 0.7 nmol/60 min and gastrin-stimulated release (p less than 0.01) from 54.7 +/- 7.9 to 20.2 +/- 4.1 nmol/60 min (mean +/- SEM). The gastrin release was not affected by misoprostol. We conclude that misoprostol inhibits acid secretion both by a direct effect on the parietal cell and by inhibiting endogenous histamine release.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1987

The effect of secretin on acid and pepsin secretion and gastrin release in the totally isolated vascularly perfused rat stomach.

The effect of secretin on acid and pepsin secretion and gastrin release in the totally isolated vascularly perfused rat stomach was studied. With the phosphodiesterase inhibitor isobutyl methylxanthine (IMX) added to the vascular perfusate, baseline acid secretion was 4.7 +/- 1.1 (mean +/- S.E.M.) mumol/h and baseline pepsin output 1147 +/- 223 micrograms/h. Secretin significantly inhibited acid output to a minimum of 1.4 +/- 0.2 mumol/h at a concentration of 25 pM in the vascular perfusate (P less than 0.01). Pepsin output was not significantly different from baseline at any of the secretin doses tested. Threshold secretin concentration for acid inhibition was 5 pM. IMX stimulated gastrin output from 48 +/- 9 pM in the basal state to 95 +/- 13 pM after IMX (P less than 0.01). Secretin inhibited gastrin release only at the maximal dose of 625 pM, when gastrin concentration in the venous effluent decreased from 93 +/- 19 to 68 +/- 19 pM after secretin. Thus, in the totally isolated vascularly perfused rat stomach secretin in physiological concentrations inhibits acid secretion by a direct action on the acid secretory process and not via gastrin inhibition. The study also suggests that gastrin release at least in part is mediated via increased intracellular cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Gastrin produces an immediate and dose-dependent histamine release preceding acid secretion in the totally isolated, vascularly perfused rat stomach.

Increasing doses of gastrin 1-17 (G1-17) were administered to totally isolated, vascularly perfused rat stomachs prestimulated with the phosphodiesterase inhibitor isobutyl methylxanthine (IMX). Vascular and luminal histamine outputs and luminal acid output were monitored at short intervals. G1-17 induced an immediate histamine release to the vascular perfusate, preceding the increase in acid secretion by approximately 10 min. Vascular histamine output increased from a base line (IMX only) of 4.0 +/- 0.4 to a maximum of 34.5 +/- 7.3 nmol/60 min (mean +/- SEM) after 1040 pM G1-17, and acid output from 8.0 +/- 2.8 to 61.5 +/- 7.0 mumol/60 min after 520 pM G1-17. Acid output was correlated to vascular histamine release (r = 0.64, p less than 0.001). Gastrin produced a histamine release giving gastric venous concentrations of the same magnitude as the concentration of histamine necessary to induce a comparable acid response. Histamine release to the lumen, on the other hand, paralleled the acid secretion in time, suggesting it to be a passive phenomenon secondary to acid secretion. Thus, the present study for the first time shows that gastrin induces vascular histamine release of such a magnitude that this substance could be the mediator of the gastrin effect on acid secretion.

Animals↗
PubMed1987

Stimulated pepsin secretion after omeprazole-induced acid suppression in the totally isolated, vascularly perfused rat stomach.

The effect of the H2 agonist impromidine, gastrin 1-17 (G1-17), pentagastrin, and the M1 agonist McN-A-343 on pepsin secretion in the acid-inhibited totally isolated, vascularly perfused rat stomach was studied. Omeprazole produced a 97-98% inhibition of stimulated acid outputs. Base-line pepsin output after omeprazole was 712 +/- 278 micrograms/h (mean +/- SEM) and, after stimulation with impromidine, 1528 +/- 164 micrograms/h; G1-17, 1520 +/- 180 micrograms/h; and pentagastrin, 2063 +/- 605 micrograms/h. Output after McN-A-343 was 534 +/- 69 micrograms/h. Pepsin secretion after impromidine, G1-17, and pentagastrin was significantly (p less than 0.01) higher than base-line output. McN-A-343 had no significant effect on pepsin output in this model. Pepsin secretion after impromidine, G1-17, and pentagastrin was considerably lower than found in the same model with uninhibited acid output. This could be caused by decreased tubular 'washout' after acid inhibition, and, accordingly, no conclusions can be drawn as to the possible stimulatory effect of acid on pepsin secretion. However, the present study indicates that pepsin secretion can be stimulated directly by impromidine and (penta)gastrin without concomitant acidification of the gastric glands.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMedDate not supplied

Gastrin-physiological and pathophysiological role: clinical consequences.

Gastrin plays a central role in the regulation of acid secretion. It is released by meals in quantities sufficient to explain meal-stimulated acid secretion. Gastrin stimulates acid secretion mainly by releasing histamine from the enterochromaffin-like (ECL) cell. Whether gastrin has any functional direct effect on the parietal cell remains to be shown. Gastrin stimulates not only the function but also the growth of the ECL cell, and long-term hypergastrinemia may lead to ECL cell carcinoids. The role of the ECL cell in human gastric carcinogenesis is controversial, but it seems wise to avoid long-term iatrogen hypergastrinemia especially in young persons. Interestingly, the oxyntic mucosal D cell, on which gastrin has a negative trophic effect, may play a role in gastric stump carcinoma, and thus hypogastrinemia may also dispose to gastric cancer.

Enterochromaffin Cells↗
PubMedDate not supplied

Relationship of ECL cells and gastric neoplasia.

The enterochromaffin-like (ECL) cell in the oxyntic mucosa has a key role in the regulation of gastric secretion since it synthesizes and releases the histamine regulating the acid secretion from the parietal cell. Gastrin is the main regulator of the ECL cell function and growth. Long-term hypergastrinemia induces ECL cell hyperplasia, and if continued, neoplasia. ECL cell carcinoids occur in man after long-term hypergastrinemia in conditions like pernicious anemia and gastrinoma. There is also accumulating evidence that a proportion of gastric carcinomas of the diffuse type is derived from the ECL cell. Furthermore, the ECL cell may, by producing substances with angiogenic effects (histamine and basic fibroblast growth factor), be particularly prone to develop malignant tumors. Although the general opinion is that gastrin itself has a direct effect on the oxyntic mucosal stem cell, it cannot be excluded that the general trophic effect of gastrin on the oxyntic mucosa is mediated by histamine or other substances from the ECL cell, and that the ECL cell, therefore, could play a role also in the tumorigenesis/carcinogenesis of gastric carcinomas of intestinal type.

Animals↗