Phase Of Gastric Secretion Research Articles

Is Peptic Ulceration a Hormonal Deficiency Disease?

TO THE EDITOR: There is evidence that Helicobacter pylori (H. pylori) infection may cause a deficiency of the hormone secretin that allows peptic ulcer disease to develop by impairing the body's defenses to gastric acid. Secretin is released into the circulation from the S cells of the duodenal crypts in response to gastric acid entering the duodenum. Once in the circulation, secretin has five well-documented effects that protect the upper intestine from gastric acid: it stimulates secretion of bicarbonate rich exocrine pancreatic juice, it stimulates secretion of alkaline bile, it stimulates secretion of alkaline mucus from the duodenal submucosal glands of Brunner, it inhibits the humoral phase of gastric secretion, and it inhibits gastric motility, thereby delaying gastric emptying (1). Impaired secretin release and reduced duodenal S cells have been documented in peptic ulcer patients compared to control patients (2,3). The clinical evidence that patients with H. pylori infection and peptic ulceration have increased gastric secretion (4) and decreased duodenal bicarbonate response to gastric acid (5), which normalize after eradication of the infection, could be explained by reversible impairment of the secretin mechanism (Table 1). Gastric metaplasia in the duodenum with H. pylori infection is known to reduce the S-cell population (6). The fact that not all patients with H. pylori infection develop peptic ulceration suggests that degree of secretin deficiency, determined by extent of the infection, must reach a critical level for peptic ulceration to occur (7). Peptic ulceration may be a hormonal deficiency disease, a result of secretin deficiency caused by H. pylori infection. It may be the first example of a specific hormonal deficiency disease caused by a specific bacterial infection.

The inhibitory action of a locally applied antihistamine on the antral phase of gastric secretion in dogs.

The inhibitory action of a locally applied antihistamine on the antral phase of gastric secretion in dogs.

Preliminary characterization of enterooxyntic activity on the guinea pig oxyntic cell.

Stimuli originating in the small intestine enhance gastric acid secretion, an effect termed the intestinal phase of gastric secretion. A humoral agent, enterooxyntin (EO) may mediate this effect. Mechanical distension of an ex vivo-perfused segment of canine jejunum caused the release of EO measured by cytochemical quantification of hydroxyl ion production (HIP) in guinea pig gastric oxyntic cells, an index of acid secretion. The H2 receptor antagonist, cimetidine (10(-5) M), and diamine oxidase, which hydrolyzes endogenous histamine, reduced HIP by 60% and 48%, respectively. Atropine (10(-5) M), the muscarinic cholinergic antagonist, reduced HIP by 75%. EO-induced HIP was also inhibited partially by the Ca2+ antagonist EGTA (10(-6) M) and by blockade of calcium channels with LaCl3 (10(-6) M). EO does not appear to operate through any single pathway. EO may be a single substance, different from gastrin, or a mixture of substances that have stimulatory effects on the oxyntic cell. Its action on the oxyntic cell is apparently mediated by both histaminergic and cholinergic pathways. Since neither cimetidine nor atropine completely inhibited EO-induced HIP, a direct effect of EO on the oxyntic cell seems likely and appears to depend on Ca2+. Isolation and purification of EO will be necessary to better assess the potency, efficacy, and the detailed cellular mechanisms of EO action.

Catecholamines and the cephalic phase of gastric secretion

Methoxamine, an α-adrenergic agent, and isoproterenol, a β-adrenergic agent, significantly augmented indirect vagally stimulated (intravenous 2-deoxy-D-glucose) acid and pepsin secretion from the main stomachs of conscious dogs. Heidenhain pouch secretion in the same dogs was unaffected.

Non-gastrin, intestinal-phase secretion. Experimental confirmation in the dog.

Four mongrel dogs were prepared with a Heidenhain pouch, a gastric fistula, and a 90-cm-long Thiry-Vella loop. After recovery, dose-response curves were obtained with different doses of pentagastrin, and the maximal acid output was determined. The jejunal loop was perfused for 3 h with either 5% liver extract or with 0.15 M NaCl at a rate of 114 ml/h. To verify that the stomach could release gastrin and that the assay could detect that change, antral perfusion with liver extract was performed. Serum gastrin levels and acid output were measured every 30 min. Perfusion of the jejunal loop with liver extract resulted in a significant increase in acid output from the Heidenhain pouch and the gastric fistula, whereas perfusion with saline solution failed to show any changes. The magnitude of acid response from the Heidenhain pouch and gastric fistula was 11% and 18%, respectively, as compared with maximal pentagastrin stimulation. The serum gastrin levels remained unchanged during both liver extract and saline perfusion of the jejunal loop, in contrast to the marked increase in serum gastrin level after antral perfusion. The results confirm the existence of the intestinal phase of gastric acid stimulation in dogs as an entity and show that the magnitude of this phase is significantly lower than has been suggested by results of earlier studies. Furthermore, the results suggest that the intestinal phase of gastric secretion in dogs is most probably elicited through a humoral agent other than gastrin.

The intestinal phase hormone.

The existence of a stimulatory intestinal phase of gastric acid secretion has been suspected, but largely ignored, for many years. Recently, however, it has become clear that the intestinal phase plays an important role in acid production during digestion. The intestinal phase is of additional interest in relation to the profound gastric acid hypersecretion associated with portacaval shunt (PCS). Substantial evidence indicates that PCS-related gastric hypersecretion is due to unmasking of the intestinal phase by hepatic bypass of a humoral stimulant in portal blood that is normally degraded to a considerable extent by the liver. Studies in our laboratory during the past 12 years have provided strong physiologic evidence for humoral mediation of both the intestinal phase of gastric secretion and of PCS-related hypersecretion by a hormone that arises in the small intestine, particularly in the jejunum. Furthermore, our studies have demonstrated that this intestinal phase hormone (IPH) exists in humans as well as in dogs, rats, and pigs. Additionally, recent work by a number of investigators, as well as by our group, has provided convincing evidence that IPH is different from any of the known gastric stimulatory hormones. With these physiologic observations as a background, we have used a classical method for extracting acidic peptides to prepare a hog intestinal mucosa extract (HIME) that has all of the known physiologic properties of an IPH. Specifically, HIME contains a potent stimulant of gastric acid secretion that acts according to a linear dose-response relationship; that is not gastrin in any of its immunoassayable forms; that significantly augments the maximal acid secretory responses to pentagastrin, gastrin, CCK, and histamine; and that is substantially degraded by the liver, in contrast to gastrin and CCK. Efforts at isolating the gastric stimulatory substance in HIME suggest that it is a peptide of low molecular weight. Work directed at isolating IPH in pure form and identifying it is in progress.

Some Properties Shared by Amino Acids and Entero-oxyntin

The intestinal phase of gastric secretion has been thought to be due to the release of a hormone from the gut mucosa, and several properties have been attributed to this as-yet unidentified hormone. An amino acid solution, known to stimulate gastric secretion, was tested to see if it possesses several of these properties, i.e., inactivation by the liver, and the ability to augment the maximum responses to pentagastrin and histamine. In six dogs with Heidenhain pouches the gastric secretory responses to peripheral and portal intravenous administration of a solution of mixed L-amino acids were measured. The mean peak response of three such separate peripheral infusions in each dog was 370 microEq/30 minutes while the peak response to intraportal infusion was only 45 microEq/30 minutes (p < .05). In three dogs with Heidenhain pouches the intravenous administration of amino acids together with pentagastrin resulted in significant augmentation of the peak response to pentagastrin alone (p < .025). Similarly, administration of amino acids with histamine resulted in augmentation of the peak response to histamine alone (p < .05). Because amino acids mimic the actions of the "intestinal phase hormone" in these respects it is suggested that they may account, at least in part, for the intestinal phase of gastric secretion. In addition, amino acids absorbed during protein digestion may contribute to the gastric hypersecretion which is regularly seen with portosystemic shunts.

Characteristics of intestinal phase of gastric secretion.

In four dogs provided with special gastroduodenal fistulas allowing for the complete separation of stomach and duodenum without interrupting the vagal connections between them, the magnitude of the gastric and intestinal phases was compared and their contribution to the total gastric response to a meal was established. A liver extract (LE) meal, confined to the stomach and maintained at pH 5.0 by an intragastric titration technique, produced acid output reaching 66% of the maximal response to histamine (MRH). Perfusion of the LE meal into the duodenum resulted in acid secretion amounting to 57% of MRH. The combination of the gastric and intestinal phases caused the highest acid output, amounting to about 90% of MRH. Gastric and intestinal phases induced separately were accompanied by a significant elevation in serum gastrin concentrations which reached the highest values when both phases were evoked simultaneously. Acidification of the intestinal meal resulted in pH-dependent inhibition of gastric secretion falling to the basal values at pH 1.0. These secretory changes were mimicked by exogenous secretin. Serum gastrin levels remained essentially unaffected by the acidification of the intestinal meal while exogenous secretin significantly lowered them. In conclusion, in the intact stomach with undisturbed nervous connections between the stomach and duodenum, a peptone meal in the intestine is capable of evoking a potent gastric acid and pepsin stimulation by a mechanism involving the release of antral hormone.

Reconstructive jejunogastroplasty as a method of studying the intestinal phase of gastric secretion

Reconstructive jejunogastroplasty as a method of studying the intestinal phase of gastric secretion

Effect of vagotomy and-or antrectomy on gastric secretion stimulated by intravenous infusion of bethanechol chloride. Study on rats with gastric fistula.

The interdigestive phase of gastric secretion was investigated for 24 hr in rats bearing permanent gastric fistulas. Intact controls, vagotomized, antrectomized and vagotomized-antrectomized animals were studied. Vagotomy, alone or combined with antrectomy, abolished the secretory function of parietal and zymogenic cells during the spontaneous interdigestive phase of secretion. This was considered due to the fact that the interdigestive secretion is vagus dependent and represents a true cephalic phase. Antrectomy did not result in the decrease of spontaneous secretion of HCl or pepsin. Intra-arterial stimulation with a stable choline ester, bethanechol, produced adequate secretory response in intact rats and partially restored the function of parietal cells in vagotomized rats. The action of bethanechol on HCl secretion in antrectomized rats was less marked. However, bethanechol has a very marked stimulatory effect on the secretion of pepsin in intact, vagotomized and antrectomized rats. Sensitivity of gastric mucosa to bethanechol was nearly abolished in vagotomized-antrectomized rats.

Effect of 2-deoxy-D-glucose on gastric secretion in rats.

Stimulation of gastric secretion was produced in gastric fistula bearing rats infused i.v. for 24 h with 2-deoxy D-glucose (2-DG). When 2-DG was infused simultaneously with maximal dose of histamine, gastric secretion was higher than when stimulated with either of these stimulants given separately Bilateral vagotomy abolished the secretory function of Vagotomy parietal and zymogenic cells during the non-stimulated, interdigestive phase of gastric secretion in rats. Bilateral vagotomy abolished also 2-DG stimulated gastric secretion and significantly decreased the post-histamine gastric secretion. It appears that 2-DG acts on gastric mucosa only in the presence of intact vagi. The presence of vagi also enhances the action of histamine on gastric secretion.

The effect of extensive resection of the proximal and distal portions of the small intestine on canine gastric secretion

Experiments were carried out on dogs with Pavlov or Heidenhain pouches and Basov fistulas. Gastric secretion was studied after resection of 60–70% of the proximal or distal regions of the small intestine. Extensive resection caused gastric changes in both the initial conditioned reflex and subsequent neurochemical phase of gastric secretion indicating the involvement of both nervous and humoral factors. After excision of the superior part of the small intestine there was an increased gastric secretion in response to food, and the acidity and digestive power were also enhanced. In some dogs removal of the distal portion caused some reduction of gastric secretion and an increased acidity and pepsin concentration. These differences were evidently related to the functional and morphological features of the jejunum and ileum and to the nature of their reflex connections with the stomach.

Significance of Vagal Release of Gastrin During the Nervous Phase of Gastric Secretion in Dogs

Summary The acid secretory response to sham feeding in Pavlov pouch dogs increased by several hundred per cent following antrumduodenum exclusion. Since pylorotomy did not essentially affect the augmented postexclusion response, regurgitation of duodenal contents into the excluded antrum could not have been an appreciable contributory stimulus. Antral denervation abolished the hypersecretion. On concurrent mechanical stimulation of a denervated antral pouch there was a manifold increase of the sham feeding response, whereas mechanical stimulation of the denervated antrum alone resulted in a liminal or moderate secretion. It is concluded that (1) synergism exists between gastrin and the physiologic vagal excitation of the acid-secreting glands, that (2) vagal release of gastrin from the antrum may cause a manifold increase of the acid secretory response during the nervous phase. The secretory response to insulin hypoglycemia and to sham feeding were determined in the same dogs after the operative measures. The findings demonstrate that the two stimuli in the presence of the antrum similarly reflect the nervous phase of gastric acid secretion. A method for localization of the antrumcorpus boundary during operation is described.

The study of the biphasic curve of gastric secretion following insulin stimulation.

Insulin was administered intravenously to 5 unanesthetized pigtail monkeys with isolated, vagally innervated, gastric pouches, and to 5 with Heidenhain pouches. Analysis of 45 tests demonstrated an obvious increase of gastric acid during the first 2 hr. in the group with vagally innervated pouches. Reliable evidence of the second or late phase of gastric secretion was not found.

Variability of gastric secretory response to insulin hypoglycemia in fistulous beagle dogs.

The gastric secretory response to a uniform dosage of insulin (1.5 U/kg) was studied in seven beagle dogs with a Thomas fistula. The resting secretion was mucoid in character and alkaline. Variations in acid output after insulin stimulation showed a parallel reduction of volume and concentration, indicating that these changes were not the result of incomplete sample collections. In 43 of 50 insulin experiments, maximum gastric output occurred between 30 and 60 min after insulin administration. Thirty minutes after insulin there was a mean 42.5% reduction of blood glucose below fasting values, although the exact time of the nadir could not be determined. Different experiments in the same animal showed no statistical correlation between blood glucose levels and acid concentration or output. A late phase of gastric secretion was defined as an increase in acid output of 0.5 mEq/30 min which occurred at least 120 min after insulin administration. Late phases were seen in eight experiments, seven of which occurred in two animals. In the remainder of the experiments, initial maximum acid output was reached within 60 min and the basal state was reached within 180–240 min, when the blood glucose values had returned to fasting levels.

Relationship between Interdigestive Phase of Gastric Secretion and Behavior in Chronic Fistula Rats

Relationship between Interdigestive Phase of Gastric Secretion and Behavior in Chronic Fistula Rats

Inhibition of cephalic and antral phases of gastric secretion by antral chalone.

The effect of antral acidification on the antral and cephalic phases of gastric secretion has been studied. Cross-transfusions were carried out between pairs of dogs in which blood from the portal vein of one dog was administered to another dog with a denervated fundic pouch. Transfusion of blood collected during acidification of the antrum resulted in a diminution of Heidenhain pouch acid secretion in response to food and to topical acetylcholine of 64% and 83%, respectively. The effect of antral acidification on gastric secretion stimulated by insulin hypoglycemia was studied in dogs prepared with Pavlov and isolated antral pouches (innervated and denervated). Irrigation of the antral pouch with .1 n hydrochloric acid resulted in a 92% decrease in Pavlov pouch acid output.

Role of the vagus nerve in the second phase of gastric secretion

This work was conducted on 4 dogs esophagotomy and gastric fistula, isolated Pavlov's pouch, gastric fistula and Heidenhain's pouch, fistula of the stomach and isolated gastric pouch made of pylorus), in which one of the vagus nerves was enclosed into a cuff on the neck, and the other divided. As shown by experiments, the compression of the cuff by a force a little over 120 mm Hg provokes a block of the vagus conductivity, which may be estimated by the acceleration of the pulse and the appearance of Horner's syndrome. This excludes the first and the second phases of the gastric secretion, as well as secretion provoked by stimulating the mucous membrane of the isolated pyloric pouch.

Factors affecting gastric secretion in thoracic-duct lymph of dogs.

Thoracic-duct lymph was collected from dogs during various phases of gastric secretion. The lymph samples were injected intravenously into dogs with vagally innervated and denervated pouches while these were secreting at slow rates in response to the continuous intravenous injection of small quantities of histamine. About half the samples inhibited gastric secretion. The rest produced transient stimulation or had no effect. The greatest degree of inhibition occurred when lymph collected immediately after a meal was injected. When fatty lymph was separated into fat and nonfat fractions, the fat-containing portion of lymph stimulated gastric secretion slightly, while the nonfat fraction carried the inhibitory influence when it was present. Systemic reactions were noted in one-third of the animals that had an inhibitory response. The occurrence of stimulatory or inhibitory factors in the lymph did not appear to be related to particular phases of gastric secretion.

Therapeutic principles in management of peptic ulcer. 2. Anticholinergic agents.

The employment of antisecretory drugs as an adjunctive measure in the medical management of peptic ulcer can be quite flexible. The anticholinergic agent may be given before meals and at bedtime to assist neutralization by antacids given on a regular schedule, or it may be employed solely at bedtime. Since the studies described in this paper have been performed on basal secretion, the use of anticholinergic drugs at bedtime, as basal conditions are approached, seems reasonable. Their use during the day before meals may also cause a decrease in acid output extending through the digestive phase of gastric secretion, but in all likelihood prolonged anacidity from them alone is rarely if ever attained; numerous studies have already reported such programs to be therapeutic failures.