Mitchell L. Schubert

Control of Gastric Acid Secretion in Health and Disease

Recent milestones in the understanding of gastric acid secretion and treatment of acid-peptic disorders include the (1) discovery of histamine H(2)-receptors and development of histamine H(2)-receptor antagonists, (2) identification of H(+)K(+)-ATPase as the parietal cell proton pump and development of proton pump inhibitors, and (3) identification of Helicobacter pylori as the major cause of duodenal ulcer and development of effective eradication regimens. This review emphasizes the importance and relevance of gastric acid secretion and its regulation in health and disease. We review the physiology and pathophysiology of acid secretion as well as evidence regarding its inhibition in the management of acid-related clinical conditions.

Regulation of gastric somatostatin secretion in the mouse by luminal acidity: A local feedback mechanism

The present study was designed to determine whether somatostatin secretion induced by histamine or pentagastrin in the isolated luminally perfused mouse stomach was a direct effect of the secretagogues on gastric somatostatin cells or an indirect effect mediated by the increase in luminal acidity. Perfusion of the lumen with exogenous acid (80-480 nmol/min) caused an increase in somatostatin secretion in proportion to the increase in luminal acidity. The increase in somatostatin secretion was resistant to tetrodotoxin and attained maximal levels (61.6% +/- 8.7% above basal level) similar to those elicited by maximal doses of secretagogues. Conversely, neutralization of basal acid secretion with bicarbonate (20-160 nmol/min) caused a decrease in somatostatin secretion in proportion to the decrease in luminal acidity. Similarly, neutralization of the secretagogue-induced increments in acid secretion with bicarbonate or inhibition of the increments with cimetidine abolished the corresponding increments in somatostatin secretion. It is proposed that acid-induced release of somatostatin in proximity to parietal cells serves as a negative feedback mechanism restraining acid secretion.

Somatostatin receptor subtype 2 mediates inhibition of gastrin and histamine secretion from human, dog, and rat antrum

BACKGROUND & AIMS In gastric antrum, somatostatin exerts a tonic inhibitory influence on gastrin and histamine secretion. Five different subtypes of somatostatin receptors, designated sst1-5, have been identified. sst2, sst3, and sst5 subtypes have been localized to the stomach by molecular biological techniques. The aim of this study was to identify the sst subtype regulating gastrin and histamine secretion in human, dog, and rat stomach. METHODS Mucosal segments from human, dog, and rat antrum were superfused with various concentrations of somatostatin 14 and somatostatin analogues selective for sst2, sst3, and sst5. Gastrin and histamine were measured by radioimmunoassay. RESULTS Somatostatin 14 and the sst2 agonist EC 5-20 inhibited gastrin and histamine secretion from all three species in a concentration-dependent manner, whereas the sst3 and sst5 agonists had no significant effect. Neutralization of endogenous somatostatin with the somatostatin antibody increased gastrin and histamine secretion. The increases were not affected by the gastrin antagonist but were abolished by the sst2 agonist, implying that the inhibitory influence of ambient somatostatin is exerted directly on the histamine cell rather than indirectly via changes in gastrin secretion. CONCLUSIONS Somatostatin inhibits gastrin and histamine secretion in human, dog, and rat antrum by activating sst2 receptors on gastrin and histamine cells.

Dual inhibitory pathways link antral somatostatin and histamine secretion in human, dog, and rat stomach

BACKGROUND & AIMS The secretion and function of antral histamine are not known. The aims of this study were to characterize the mechanisms of histamine release from the gastric antrum of humans, dogs, and rats and to determine whether histamine can influence the secretion of somatostatin and gastrin. METHODS Somatostatin, gastrin, and histamine secretion from superfused antral segments was measured using radioimmunoassay. RESULTS Superfusion with thioperamide (H3 antagonist) increased somatostatin and decreased gastrin and histamine secretion in all three species; superfusion with (r)-alpha-methylhistamine (H3 agonist) had the opposite effect. The pattern implied that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion, which in turn regulates gastrin secretion. Superfusion with somatostatin antibody increased histamine secretion; the increase was not affected by the gastrin antagonist L-365,260, implying that it was not mediated by the concurrent increase in gastrin but by suppression of an inhibitory pathway linking somatostatin and histamine. Superfusion with methacholine alone and in the presence of either the H3 agonist or antagonist confirmed the existence of reciprocal inhibitory pathways linking somatostatin and histamine. CONCLUSIONS Antral histamine in humans, dogs, and rats is linked to antral somatostatin via reciprocal inhibitory paracrine pathways that serve to amplify the regulatory influence of somatostatin.

Decreased efficacy of polyethylene glycol lavage solution (Golytely) in the preparation of diabetic patients for outpatient colonoscopy : a prospective and blinded study

OBJECTIVES:The aim of the present study was to compare, in a prospective and blinded fashion, the efficacy of 6 L of polyethylene glycol–based lavage solution (Golytely) administered on an outpatient basis in diabetic versus nondiabetic patients.METHODS:A total of 54 consecutive nondiabetic and 45 consecutive diabetic patients requiring outpatient colonoscopy underwent colonic cleansing by drinking 6 L of Golytely the evening before the procedure. The entire procedure, from rectum to cecum, was videotaped and coded for later review by the Chief of Endoscopy who was blinded to the identity and medical history of the patients. The primary outcome measure was the quality of the preparation score, numerically rated on a 14-point scale (0–13) based on the surface area of the mucosa that could be examined and the consistency of the residual stool.RESULTS:There was a significant difference in the quality ratings for the bowel preparations, with an overall superior preparation in the nondiabetic group (2.4 ± 1.6 vs 5.4 ± 3.1, p < 0.001). A total of 97% of the nondiabetic patients had a preparation rated as good or better, compared with only 62% of the diabetic patients (p < 0.001). Preparations rated as poor or futile, necessitating repeat colonoscopy, occurred in no nondiabetic but in 9% of diabetic patients (p < 0.01). Within the diabetic group, there was no significant difference in bowel preparation scores between those patients aged >70 yr and those <70 yr, those requiring and those not requiring insulin, those with Hb A1c values >8% and those with values <8%, and those with and without peripheral neuropathy.CONCLUSION:We conclude that diabetic patients (irrespective of insulin use, diabetic control, or diabetic neuropathy) have a significantly poorer response to a 6-L Golytely preparation than do nondiabetic patients.

Gastric exocrine and endocrine secretion.

Purpose of review This review summarizes the last years literature regarding the regulation and measurement of gastric exocrine and endocrine secretion. Recent findings Parietal cells, distributed along much of the length of the oxyntic glands, with highest density in the neck and base, secrete HCl as well as transforming growth factor-alpha, amphiregulin, heparin-binding epidermal growth factor-like growth factor, and sonic hedgehog. Acid facilitates the digestion of protein and absorption of iron, calcium, vitamin B12 as well as prevents bacterial overgrowth, enteric infection, and possibly food allergy. The major stimulants of acid secretion are gastrin, histamine, and acetylcholine. Ghrelin and orexin also stimulate acid secretion. The main inhibitor of acid secretion is somatostatin. Nitric oxide and dopamine also inhibit acid secretion. Although Helicobacter pylori is associated with duodenal ulcer disease, most patients infected with the organism produce less than normal amount of acid. The cytoskeletal proteins ezrin and moesin participate in parietal cell acid and chief cell pepsinogen secretion, respectively. Summary Despite our vast knowledge, the understanding of the regulation of gastric acid secretion in health and disease is far from complete. A better understanding of the pathways and mechanisms regulating acid secretion should lead to improved management of patients with acid-induced disorders as well as those who secrete too little acid.

Gastrin secretion induced by distention is mediated by gastric cholinergic and vasoactive intestinal peptide neurons in rats

BACKGROUND The present study was designed to identify the mechanism by which distention regulates gastrin secretion. METHODS The distal stomach of the isolated vascularly perfused rat was distended to varying degrees for 10-minute periods with an air-filled balloon. RESULTS Low distention caused a decrease in gastrin (39% +/- 5%; P < 0.001) and an increase in somatostatin (58% +/- 4%; P < 0.001) secretion. High distention caused an opposite effect, i.e., an increase in gastrin (49% +/- 11%; P < 0.01) and a decrease in somatostatin (44% +/- 11%; P < 0.01) secretion. All responses were abolished by the axonal blocker, tetrodotoxin. Atropine had no effect on the responses to low distention, but converted the pattern of response with high distention to that observed with low distention. Both high and low distention were accompanied by a sustained increase in vasoactive intestinal peptide (VIP) secretion. The selective VIP antagonist, VIP[10-28], abolished both the gastrin and somatostatin responses to low distention. CONCLUSIONS Low gastric distention activates preferentially VIP neurons that stimulate somatostatin and thus inhibit gastrin secretion. Increasing distention leads to progressive recruitment of cholinergic neurons that cause a reversal in the pattern to one of increase in gastrin and decrease in somatostatin secretion.

Inhibition of Acid Secretion by Bombesin Is Partly Mediated by Release of Fundic Somatostatin

The effect and mode of action of bombesin on gastric acid secretion was examined in the isolated, luminally perfused mouse stomach. Bombesin caused a concentration-dependent inhibition of basal and histamine-stimulated acid secretion and an increase in somatostatin secretion. Pertussis toxin was used to determine the contribution of somatostatin to the observed inhibition of acid secretion. Previous studies have shown that at a concentration of 125 ng/ml, pertussis toxin reverses completely the inhibition of acid secretion induced by exogenous and endogenous somatostatin. Preincubation of the stomach for 60 min with pertussis toxin (125 and 1250 ng/ml) reversed partially the inhibitory effect of bombesin on basal and histamine-stimulated acid secretion by 51%-59%, implying that bombesin-induced inhibition was partly mediated by release of somatostatin. The residual inhibition may represent a direct effect of bombesin on parietal cells.

Control of gastric acid secretion

This review of the past years literature focuses on progress in the elucidation of the pathways and mechanisms controlling gastric acid secretion at the central, peripheral, and intracellular levels. Injection of thyrotropin-releasing peptide and neuropeptide Y into the central nervous system stimulates acid secretion; the effects are mediated via the vagus nerve. Elevated intracranial pressure and increasing age also stimulate acid secretion, whereas γ-aminobutyric acid, tachykinins, and prostaglandins act centrally to inhibit acid secretion. The stimulatory effect of gastrin and acetylcholine on acid secretion may be mediated via release of histamine, possibly from enterochromaffin-like cells. Histamine stimulation of the parietal cell is accompanied by increasing cellular levels of cyclic AMP and dephosphorylation of type II cyclic AMP-dependent protein kinase. Besides releasing histamine, muscarinic agonists appear to stimulate the parietal cell directly via the M3-receptor subtype. This subtype is also coupled to release of intracellular calcium and influx of extracellular calcium. Glucagon-like peptide, low concentrations of ethanol, cigarettes, and coffee stimulate acid secretion whereas neurotensin, oxyntomodulin, serotonin, interleukins, and high concentrations of ethanol inhibit acid secretion. Vasoactive intestinal polypeptide exerts dual stimulatory and inhibitory actions on acid secretion; the inhibitory effect is mediated by release of somatostatin. Candidate enterogastrones include secretin, cholecystokinin, somatostatin, and possibly peptide YY.

Adrenomedullin stimulates somatostatin and thus inhibits histamine and acid secretion in the fundus of the stomach.

Adrenomedullin has recently been localized to enterochromaffin-like (ECL) and chief cells in the gastric fundus. It has been proposed that adrenomedullin may play a role in gastric mucosal defense and repair. In the present study, we have used the isolated, luminally perfused mouse stomach and superfused rat fundic segments to examine the effect of adrenomedullin on exocrine and endocrine secretion in this region of the stomach. Addition of adrenomedullin (1 pM to 1 microM) to the isolated mouse stomach caused a concentration-dependent decrease in acid secretion. The EC(50) value was 1.4 x 10(-9) and maximal inhibition of acid secretion was obtained at a concentration of 1 microM (31+/-4% below basal level, P<0.001). In rat fundic segments, superfusion with adrenomedullin (0.1 pM to 0.1 microM) caused a concentration-dependent increase in somatostatin secretion (EC(50), 1 x 10(-10)) that was accompanied by a reciprocal decrease in histamine secretion (EC(50), 1.2 x 10(-11)). Maximal stimulation of somatostatin secretion (60+/-5% above basal level, P<0.001) and inhibition of histamine secretion (50+/-5% below basal level, P<0.01) was obtained at a concentration of 0.1 microM. Changes in acid and histamine secretion induced by adrenomedullin reflected changes in somatostatin secretion and could be abolished by addition of somatostatin antibody. The axonal blocker, tetrodotoxin, also abolished the somatostatin and, consequently, the acid and histamine responses to adrenomedullin, implying that the effect of adrenomedullin on somatostatin secretion was mediated via activation of intramural neurons. We conclude that adrenomedullin, acting via intramural fundic neurons, stimulates somatostatin and thus inhibits histamine and acid secretion. This represents one mechanism by which adrenomedullin might enhance mucosal defense and repair.