Regulation Of Acid Secretion Research Articles

Effect of amogastrin on the release of various prostaglandins into gastric lumen in man.

The effect of amogastrin on the release of 5 types of prostaglandins (PGs) [PGE2, 6-keto-PGF1 alpha, PGF2 alpha, PGD2, and thromboxan B2 (TXB2)] into the gastric lumen was evaluated in seven healthy volunteers. Gastric juice was obtained under basal and amogastrin-stimulated conditions. The 5 types of PGs in the gastric juice were separated by high-performance liquid chromatography and then measured by radioimmunoassay. PGE2 was the major component in gastric juices among the PGs measured in this study. The release of 5 types of PGs increased after amogastrin administration. The rate of increase was high for PGE2 and 6-keto-PGF1 alpha (3.48 and 3.98 respectively), whereas it was low for PGD2 (1.54). It is suggested that endogenously synthesized PGs, especially PGE2 and PGI2 (assayed as 6-keto-PGF1 alpha), play important roles in the gastric mucosal protection and the regulation of acid secretion.

Mechanisms of Gastrointestinal Toxicity of Nonsteroidal Anti-Inflammatory Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) induce GI damage by multiple, in some cases interrelated, mechanisms. They vary in ulcerogenic activity in different regions of the GI tract. These differences in ulcerogenicity of NSAIDs are due to (a) differing kinetics of absorption in various regions of the GI tract, intracellular distribution within the mucosal cells, and systemic availability, and (b) quantitative and qualitative differences in the biochemical or physiologic systems affected by the drugs. In the stomach, where acid/pepsin influence the ulcerogenic effects of most NSAIDs, prostaglandin (PG)-dependent and PG-independent factors are responsible for the ulcerogenicity of NSAIDs. PG-dependent factors can include the influences of PGs on mucus-bicarbonate secretion, regulation of acid secretion, and blood flow. Recent evidence suggests that CO inhibition may, by diversion of arachidonate, cause enhanced production of vasoconstrictor peptidoleukotrienes and oxyradicals produced by the lipoxygenase pathway, and this may contribute to the genesis of vascular and other mucosal changes induced by NSAIDs. Non-PG-dependent effects of NSAIDs include (a) physical effects of the acidic molecules on surface mucosal cell membranes and mucus, (b) oxyradical production, (c) cytotoxic effects on parietal cells, and (d) inhibitory effects on mucus synthesis, mitochondrial ATP production, cyclic nucleotide production, and a range of other cellular metabolic effects influencing mucosal metabolism and cellular regeneration. In the intestinal tract, two major factors influence the ulcerogenicity of NSAIDs: their capacity to undergo enterophepatic recirculation and the presence of bacteria, which may in part contribute to a immunoinflammatory changes.

Effect of truncated glucagon-like peptide 1 on cAMP in rat gastric glands and HGT-1 human gastric cancer cells

We tested the truncated 7–37 glucagon-like peptide 1 (TGLP-1), a naturally occurring porcine intestinal peptide, and other members of the glucagon family, including pancreatic glucagon (G-29), GLP-1 and GLP-2 for their ability to activate the cAMP generating system in rat gastric glands and HGT-1 human gastric cancer cells. In rat fundic glands, TGLP-1 was about 100 times more potent (EC 50 = 2.8 × 10 −9M) than GLP-1 of G-29, and 10 times more potent than G-29 in the HGT-1 cell line. Our results support the notion that TGLP-1 plays a direct role in the regulation of acid secretion in rat and human gastric mucosa.

Role of the Cholinergic Nervous System in Acid Secretion

Stimulation of acid secretion by muscarinic agents involves receptors with a higher apparent affinity to the M1-antagonists, pirenzepine and telenzepine, than those regulating heart rate and salivary secretion. However, the localization of the proposed M1-receptors regulating acid secretion remains unclear. Studies with parietal cells isolated from several species indicate that parietal cells have a muscarinic receptor with low affinity for the M1-antagonists. Our studies with somatostatin cells isolated from canine fundic mucosa indicates that the muscarinic receptor inhibiting somatostatin release also is of low affinity for M1-antagonists. We have found no evidence for regulation of histamine release from canine fundic mast cells, whereas there is evidence that acetylcholine induces histamine release from the enterochromaffin-like cells of the rat and rabbit fundic mucosa. Further studies will be necessary to determine which of the muscarinic receptors potentially involved in the regulation of acid secretion is responsible for the M1-behavior of this pathway.

Comparative development of gastrin and somatostatin cell populations in the pancreas, stomach, and duodenum of the rat during the perinatal period.

The comparative growth patterns of endocrine gastrin and somatostatin cell populations were examined in the rat, during the perinatal period, to investigate possible relationships between their development and that of gastric acid secretion, gastrin and somatostatin hormones being implicated in the regulation of acid secretion. Total cell populations were estimated daily in the pancreas, stomach, and duodenum, by using a quantitative morphological method, from 19 days postcoitum to 8 days postpartum. In the pancreas, both cell types were present at 19 days postcoitum. After increasing, gastrin cells abruptly dropped from 4 days postpartum, while somatostatin cells continued to increase. In the stomach, gastrin cells seemed to appear at 19 days postcoitum, increasing with age. Somatostatin cells appeared only after birth and could be precisely quantified from 4 days postpartum. In the duodenum, the two cell types were present in similar numbers at 19 days postcoitum and increased similarly with age. Comparison of gastrin and somatostatin cell developmental behavior with previous data on the ontogeny of acid secretion shows a parallelism between the appearance of basal H+ fluxes at 20-21 days postcoitum and the high daily multiplication of the gastrin cell number in the three organs. Additionally, the marked decrease of pancreatic gastrin cell population at 4 days postpartum and the simultaneous development of the gastric somatostatin cell population might explain, among other mechanisms, the diminution of gastric acid secretion noted after birth.

Inhibition of gastric acid secretion by immunoneutralization of endogenous brain thyrotropin-releasing hormone

Previous studies have shown that intracisternal (i.c.), but not intravenous administration of thyrotropin-releasing hormone (TRH), an endogenous tripeptide ( pGlu-His-Pro-NH 2), produces a time-, dose-dependent and vagus-mediated stimulation of acid secretion in rats. This study was designed to test the hypothesis that endogenous brain TRH plays a role in regulation of acid secretion in the pylorus-ligation model. In confirmation of previous reports, i.c. TRH (1 μg) significantly ( P < 0.01) stimulated gastric acid output, gastric secretory volume and decreased gastric intraluminal pH. Intracerebroventricular (i.c.v.) infusion of TRH antiserum (anti-TRH) 30 min prior to pyloric occlusion significantly reduced acid output, secretory volume and raised gastric pH. This inhibitory gastric acid secretory response to i.c.v. anti-TRH appears to be specific since i.c.v. infusion of normal rabbit serum or antisera raised against neurotensin (NT), Leu-enkephalin (L-enk), gonadotropin-releasing hormone (GnRH), somatostatin (SRIF) and α-melanocyte stimulating hormone (α-MSH) were without measurable effect. The findings of this study indicate that endogenous brain TRH, but not NT, L-enk, GnRH, SRIF or α-MSH plays a physiological role in regulation of acid secretion.

Prostaglandins and acid peptic disease: State of the art

A review of the new concepts concerning the regulation of acid secretion and the pathogenesis of peptic ulcer disease is presented. Advantages and disadvantages of the common pharmacological treatments are described with special emphasis on the drugs which represent, at present, the treatment of choice for peptic ulcer disease, namely, the histamine H 2-receptor antagonists. The role of prostaglandins in health and disease is considered, and the possibility that synthetic compounds derived from natural prostaglandins represent a good alternative to the present medical management of peptic ulcer disease.

Immunohistochemical localization of a specific ileal peptide in the pig.

The tissue distribution of a polypeptide purified from pig ileal mucosa tentatively called porcine ileal polypeptide (PIP) and known to have potent acid secretagogue activity has been studied with immunohistochemical methods together with extraction of different tissues followed by radioimmunoassay for PIP content. Histochemically the peptide is found in superficial epithelial cells in the mucosa of the distal 20% of the small intestine and to some extent in the mucosa of the urinary tract. There is no staining of goblet cells or crypt cells. The staining in the urinary tract mucosa is due to antigenic peptides with Mr identical to PIP. While the presence of PIP in the ileum is compatible with a function as an enterooxyntin, it is not possible at present to explain the physiologic role of PIP entirely as a hormone regulating acid secretion in light of the immunohistochemical distribution.

Muscarinic receptors in isolated gastric fundic mucosal cells binding-activity relationships

Muscarinic receptors are involved in the control of gastric acid secretion. The characteristics of ( 3 H)-N- methyl- scopolamine [( 3H)-NMS] binding to isolated cells from rabbit fundic gastric mucosa and inhibition of this binding by muscarinic agonists, antagonists and other pharmacological agents known to regulate acid secretion are reported. Specific binding for ( 3H)-NMS was described: antagonists interact with high affinity sites ( K D = 0.5 nM) whereas binding curves for agonists clearly deviated from the simple mass action isotherm with a flattening of the curve suggesting the presence of more than one class of sites. The low affinity sites for agonists are in the micromolar range. Pirenzine, a gastroselective antimuscarinic compound, known to differentiate between M1 and M2 sites, inhibited ( 3H)-NMS binding with an IC 50 of 0.05 μM. On the same gastric cell population, muscarinic agonist carbachol stimulated ( 14C)-aminopyrine accumulation in a dose-dependent manner with an ED-50 of 10 μM, value close to that needed to 50% inhibit ( 3H)-NMS binding. This stimulation was competitively inhibited by muscarinic antagonists and pA 2-values for atropine, QNB and pirenzepine, calculated from linear Schild plots, were in the following order: 9.2 for atropine, 8.6 for QNB and 7.0 for pirenzepine. In conclusion, fundic gastric mucosal cells from rabbit, isolated with collagenase and EDTA, contained specific muscarinic receptors coupled to the acid secretory mechanism and pirenzepine interact with these receptors with an intermediate affinity suggesting the presence of functional M2-sites.

Effect of Antibodies to Somatostatin on Acid Secretion and Gastrin Release by the Isolated Perfused Rat Stomach

The present studies were directed toward examining the effect of somatostatin on gastrin release and acid secretion by the isolated vascularly perfused rat stomach. Rat stomachs were perfused in situ with Krebs-Ringer bicarbonate buffer containing 10% ovine erythrocytes and gassed with 95% O2-5% CO2. Inclusion of pentagastrin in the perfusion buffer increased acid output from 2.2 +/- 0.4 microEq H+/h during control perfusion to 18.8 +/- 1.8 microEq H+/h (p less than 0.01). In order to determine the effect of somatostatin on acid secretion and gastrin release, specific antibodies to somatostatin were included in the perfusate. Inclusion of antibodies to somatostatin in the buffer without pentagastrin did not significantly enhance acid output; however, gastrin concentration in the portal venous effluent increased from 15.1 +/- 2.0 to 25.2 +/- 5.2 pg/ml at 45 min (p less than 0.05). When antibodies to somatostatin were perfused in the presence of pentagastrin, acid output increased by 32% to 24.9 +/- 1.2 microEq H+/h (p less than 0.05); however, no change in gastrin concentration over basal was detected in the portal effluent. Results of these studies indicate that the capacity of the isolated rat stomach to secrete acid permits direct assessment of factors involved in the regulation of acid secretion. Under the conditions of these experiments, gastric somatostatin inhibits basal gastrin release and directly inhibits pentagastrin-stimulated acid secretion without affecting gastrin release.

ONTOGENY OF PARIETAL CELL FUNCTION: RESPONSE TO PGE2

PGE2 decreases H+ production by the parietal cells of mature animals & humans. To study the ontogeny of this effect, the guinea pig mucosal model was used & dose response curves (DRC) to PGE2 in 1, 3, 7, 10 & 14d old animals were established. CoSO4 staining, as an index of OH− production (HIP) & H+ secretion, was used to quantitate cellular response. In 3d old animals PGE2 was a potent inhibitor of HIP over a range of concentrations from 10−11-10−6M; Dmax 10−8M. The DRC for 1d was shifted to the right of 3d. Dmax could not be calculated but at 10−6m there was a 30% decrease in HIP. The DRC of the 14d animal was parallel to the 3d, Dmax-10−8M, % decrease HIP, 15% vs 30% for the 3d. In the 7 & 10d old animals PGE2 increased HIP; Dmax 10−9M; % increase 30 & 20 respectively. HIP was suppressed in all age groups by PGE2 (10−6M); most effectively in 1d with 30% decrease in the others by 10%. In summary, the response of the parietal cell to PGE2 is age dependent & the development of this response is biphasic. Ontogenically PGE2 may play an important role in up and down regulation of acid secretion.

Role of gastrin and somatostatin in regulation of acid secretion during the cephalic phase of a meal

Role of gastrin and somatostatin in regulation of acid secretion during the cephalic phase of a meal

Somatostatin-14 and -28: clearance and potency on gastric function in dogs.

To examine the significance of somatostatin-14 (S-14) and somatostatin-28 (S-28) in gastric physiology, we compared their relative potencies on acid secretion in the dog. On a molar infusion basis, S-14 and S-28 appeared to be equipotent, causing 50% inhibition of peptone meal-stimulated acid secretion at a dose of 400 pmol . kg-1 . h-1. However, comparison of the plasma half lives (t 1/2) of the two peptides revealed that S-28 disappeared at a much slower rate (t 1/2 = 2.84 +/- 0.15 min, mean +/- SE, n = 7) than S-14 (t 1/2 = 0.57 +/- 0.06 min). When acid-inhibitory effect was compared against increment in plasma concentrations produced by peptide infusion, S-14 was roughly 10-fold more potent than S-28. No alteration of gastrin response to peptone was observed at a dose of S-14 or S-28 that completely abolished acid secretion, suggesting that regulation of acid secretion is not mediated by gastrin inhibition. Thus, S-14 is a potent and possibly important physiological inhibitor of gastric acid secretion. Although circulating S-28 may have importance in regulation of some biological functions, it appears to play a less prominent role in regulation of gastric secretion.

Aminopyrine uptake by guinea pig gastric mucosal cells mediation by cyclic AMP and interactions among secretagogues

The role of cyclic nucleotides in regulating acid secretion by dispersed mucosal cells from guinea-pig stomach was examined by measuring first the ability of histamine and carbachol to stimulate [ dimethylamine- 14C]aminopyramine uptake and cyclic nucleotide metabolism and secondly, the effect of exogenous cyclic nucleotides on basal and stimulated [ 14C]aminopyrine uptake. The [ 14C]aminopyrine was found in an acidic, osmotically sensitive compartment, probably associated with the initial steps in acid secretion by these cells. Although histamine increased [ 14C]aminopyrine uptake and cyclic AMP synthesis as expected, histamine was approx. 10-fold more potent in inducing [ 14C]aminopyrine uptake. This dissociation of [ 14C]aminopyrine uptake and cyclic AMP metabolism process was further manifested by the observation that prostaglandin E 1 failed to increase [ 14C]aminopyrine uptake, although it did cause a rise in cellular cyclic AMP. Furthermore, prostaglandin E 1 did not alter the [ 14C]aminopyrine uptake caused by histamine. Carbachol was found to increase the [ 14C]aminopyrine uptake and also to potentiate the ability of histamine to increase [ 14C]aminopyrine uptake. Carbachol, however, affected neither the histamine-induced increase in cyclic AMP nor the binding of [ 3H]histamine to the cells. Cimetidine, a histamine H 2 receptor antagonist, blocked the [ 14C]aminopyrine uptake induced either by histamine alone or by the potentiating combination of histamine plus carbachol. These results suggest that cyclic AMP is mediating the action of histamine on [ 14C]aminopyrine uptake but changes in cyclic AMP per se are not necessarily the cause for the potentiated increase in [ 14C]aminopyrine uptake. Furthermore, the potentiated response observed with histamine plus carbachol on [ 14C]aminopyrine uptake occurs at a biochemical step distal to and not obviously related to cyclic AMP generation.

Absence of a relationship between immunoreactive-gastrin and somatostatin-like immunoreactivity secretion in the perfused rat stomach

The possible interaction between somatostatin-like immunoreactivity (SLI) and immunoreactive-gastrin release was studied in an isolated perfused rat stomach preparation. Gastrin release was abolished by antrectomy but basal and gastric inhibitory polypeptide-stimulated SLI levels were unchanged from control experiments, implicating the corpus as the major source of SLI released into the vasculature. Perfused stomachs of vagotomized rats exhibited basal hypergastrinaemia with no alteration in basal or stimulated SLI release, suggesting an uncoupling of SLI and gastrin release. This study indicated that SLI released into the vasculature originated in the acid secretory region of the stomach and therefore may be involved in the regulation of acid secretion at the level of the parietal cell mass.

Amphibians

1. The distribution of bombesin-like immunoreactivity was determined in the gastrointestinal tract of the primitive holostean fish, the bowfin (Amia calva) using immunocytochemistry.2. Immunostaining using two different antisera raised against frog skin bombesin revealed a population of apparent endocrine cells containing bombesin-like immunoreactivity in the epithelium of the antral mucosa in the stomach.3. No bombesin-containing endocrine cells were present in any other segment of the gut. Bombesinergic nerves were not observed anywhere in the bowfin gastrointestinal tract.4. The antral bombesin endocrine cells were of the open type and were distributed diffusely from the base to the tips of antral glands, with some tendency to cluster near the base of the glands.5. These results suggest that a bombesin-like peptide may play an endocrine role in control of gastric functions such as regulation of acid secretion and gastric motility. These results support the hypothesis that bombesin serves a role in bony fish analogous to the role of antral cholecystokinin in amphibia and antral gastrin in amniotes.