Search

The histamine H2-receptor antagonist metiamide is an inhibitor of endogenous and stimulated gastric-acid secretion. It appears to have therapeutic possibilities in duodenal-ulcer disease. Three patients exhibiting the Zollinger-Ellison syndrome have been treated with this drug for six months or more. Rapid symptomatic improvement occurred in each case, followed by ulcer healing. There were also reductions in gastric secretion and consistent changes in the fasting serum-gastrin concentration. One patient relapsed temporarily during therapy. There have been no side effects. It is concluded that, in the short term, metiamide is of benefit in the Zollinger-Ellison syndrome.

Advances in the understanding of physiologic control of gastric secretion raise the hope that an effective nonsurgical therapy for peptic ulcer disease will be developed soon. This paper reviews these advances with special emphasis upon those aspects of hormonal control, cyclic nucleotide function, and histamine activity which may have therapeutic applications.

1. The influence on the basal gastric secretion of 50 mg. of Probanthine, administered orally 30 minutes before intubation and after histamine, was observed in 14 patients. 2. The average concentration of pepsin fell by 39 per cent in the basal secretion, and by 37 per cent after histamine (P 0.05). 5. Probanthine did not influence the acidity of the gastric juice substantially. A decrease of 6 to 9 per cent is not considered significant.

Data are presented on the pH and acid content of beverages in common use in American hospitals at this time. Pineapple and citrus juices, and most carbonated drinks, have a pH low enough to activate pepsin and have an acid content comparable to or exceeding the basal gastric secretion. Suggestions are made for elimination of some of these products from the diet of the patient with an active peptic ulcer.

This is a young woman in whom gastric acid and pepsin levels decreased to low values during the course of her pregnancy. Some correlation between emotional states and gastric secretory levels was observed. The case is presented because it is the first to be recorded where gastric aspiration was carried out during pregnancy in an ulcer patient.

In the attempt to find a method of producing experimental achlorhydria, we studied the effects of a large variety of substances on the gastric secretion of man and dog. Although a diminution of acid secretion has been produced in some instances, no method that is practical for clinical use has yet been found. We wish to express our appreciation to Miss Vivian Bass for her technical assistance. Part of the expense of this investigation was defrayed by contribution from the E. L. Dawes Fund.

The effect of combined cholinergic and histamine stimulation on gastric secretion was investigated in 5 trained dogs in whom esophagostomy and gastrostomy had been performed and the MHR (acid secretory response to maximal histamine stimulation) had previously been established. Mecholyl and sham feeding were employed as cholinergic stimuli, and the effect of “periodic activity” of the digestive tract on the response to histamine stimulation was also studied. Potentiation with regard to acid secretion was evident when Mecholyl was superimposed on small or moderate doses of histamine, and to pepsin secretion when histamine was superimposed on Mecholyl. The mean maximum acid output in response to combined cholinergic and histamine stimulation (MAOHC) ranged from 5.6 to 12.9 mEq./15 min., and was significantly greater than the respective MHR values in 4 of 5 dogs. The MAOHC was found to be a linear function of the volume of the acid-bearing mucosa. A series of experiments with graded doses of Mecholyl suggested a quantitative relationship between Mecholyl dosage and acid output, pepsin output, and secretory volume, and confirmed the previously reported dosage-reversal effect of very large doses of Mecholyl on gastric secretion.

Gastric secretory studies to determine the effectiveness of heteronium bromide as an anticholinergic agent were undertaken using 7 elderly patients with peptic ulcer who were shown to have elevated basal and post-Histalog gastric secretion.

The action of aminoguanidine on gastric secretion was studied in rats with 4-hour pylorus ligation. Aminoguanidine produced only a moderate elevation in gastric secretion, with a great increase in the number of ulcers, ecchymoses in the glandular stomach, and histologic changes throughout the glandular mucosa.

Diversion of gastric contents away from the duodenum by means of gastrojejunostomy led to increases in Heidenhain pouch secretion in 8 dogs previously subjected to total antrectomy. It is suggested that acid in the duodenum may exert a chronic depressant effect on Heidenhain pouch secretion in the antrectomized dog.

Insulin inhibition of gastric electrolyte secretion during a histamine infusion in 8 dogs was completely and rapidly reversed by an intravenous injection of KCl and the reversal maintained for 1–1 1/2 hr. after the injection. The continuous infusion of KCl after insulin prevented any change in the concentrations of H+, Cl−, and Na+, but there was partial inhibition of K+ and volume secretion. The results suggested that the mechanism of insulin inhibition might be a redistribution of intracellular K+ with depletion of K+ from sites essential to secretion, and replenishment by injected K+ with resulting restoration of secretion.

If one is aware ofTrichostrongylus Orientalis, the “pseudo-hookworm,” which differs from the usual “hookworm” in that there is absence of hooks in the mouth, but which has ova almost exactly similar to those of hookworm, one will not treat fruitlessly patients withTrichostrongylus infestation.

The infusion of Histalog can produce constant maximal stimulation of the gastric acid and volume, without adverse effects. This technique would seem to be an excellent tool for human gastric experimentation. It has been especially useful in our laboratory in the evaluation of gastric inhibitory agents.

The gastric secretory responses of vagally denervated canine fundic pouches stimulated by endogenous gastrin have been defined following exposure to acetic acid. In order to compare the secretory changes induced by exposing both the resting and the actively secreting mucosa to acetic acid, the organic acid was placed in the pouches either before or 1–1/4 hours after stimulation by a standard meat meal. Exposure to acetic acid caused inhibition of secretion, which was more pronounced when the organic acid was placed in the resting pouches. The organic acid also caused enhanced exchange-diffusion which was reflected by increased exsorption of Na+. The outputs of Na+ were higher when acetic acid was placed in the actively secreting as opposed to the resting pouches; this was probably a reflection of differences in availability of H+. The electrolytic interrelationships in the gastric juice were not altered by exposure of the pouches to acetic acid.

Although the total number of persons studied was insufficient to allow statistical validation of the date, the following conclusions can be drawn

Control and post-treatment values of basal gastric secretions, measured 3 hours after the last dose of medication, were determined in 24 fasting subjects. As part of the study, 10 patients received 30 mg. of prochlorperazine daily and 14 received 20 mg. of prochlorperazine and 10 mg. of isopropamide daily; all medications were taken for 2 weeks. The statistical significance of the values for control and post-treatment total HCl output, total volume output, and free HCl was determined. Conclusions: 1. Prochlorperazine does not produce statistically significant changes in the volume or acidity of gastric secretion. 2. When administered together, prochlorperazine and isopropamide produce a statistically significant decrease in the volume and acidity of gastric secretion.

1. Adult male rats with permanent gastric fistulas were infused intravenously for 24 hr. with histamine dihydrochloride in normal saline. The infusion rate was 100 ml./kg./24 hr.; doses of histamine tested in this study were 5, 10, 25, 50, 75, 100, 125, 250, 500, 1000, 1500, and 2000 mg./kg./24 hr.

A detailed study of the altered gastrointestinal physiology and findings at autopsy in a patient with Zollinger-Ellison syndrome is presented. The results warrant certain considerations with regard to mechanisms involved in the altered physiology.

1. Variation in the electrolytes of the gastric secretion, in response to several different stimuli, were determined in a patient with complete esophageal stenosis and a permanent gastric fistula, and are generally in agreement with those previously reported from this laboratory under a variety of conditions.

1. Single, orally administered doses (0.25 mg. to 0.5 mg.) of reserpine such as are used in the management of hypertension, stimulate HCl secretion only mildly; this effect is prevented by simultaneous administration of a therapeutic dose of an anticholinergic drug. Prolonged therapy with reserpine in these doses does not lead to gastric hypersecretion.

In summary, the vascular bed of the stomach is an area of great potential importance to both gastric and vascular physiologists. There are available many technics for its investigation. Simultaneous study of both hemodynamic and secretory phenomena can be conducted on the stomach. In the next few years information concerning the circulation of the stomach may help elucidate problems in the physiology and pathology of gastric secretion. Hightower observed recently: “The topic of visceral circulation, particularly as it pertains to the digestive tract, has not been commented upon in recent...Reviews of Physiology. This subject has become increasingly important in the past few years and is an area with which physiologists interested in the digestive system will become more and more concerned.”33

When rats were stressed by restraint in a wire jacket for 20 hr., hemorrhagic gastric erosions consistently developed in the glandular mucosa. Previously vagotomized rats were partially protected from stress ulcers, whereas hypophysectomy or adrenalectomy were without effect. Measurement of 6-hr. gastric secretory output in rats submitted to the same restraint stress revealed a 94 per cent inhibition of gastric secretory activity in comparison with unstressed controls.

The effect of localized hypothermia on gastric secretion was studied in dogs with gastrostomies and vagally innervated and denervated pouches.

In gastric fistula dogs actively secreting under the influence of insulin hypo-glycemia, the injection of 25 gm. glucose, I.V., 30 min. after injection of insulin, reduced acid and pepsin output by about 60–65%, but only for 45 min. In other experiments, glucose injected 90 min. after injection of insulin reduced acid by 35% but did not reduce pepsin secretion. This suggests that the response of the gastric secretory vagus to insulin is not a simple all-or-none mechanism related solely or even critically to the concentration of glucose in the blood or brain.

It has been believed for many years that during pregnancy peptic ulcer rarely appears, rarely flares up and often heals.

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.

The purpose of this study was to evaluate the possible role of the lung as an organ for inactivation of exogenous gastrin. Human synthetic gastrin was infused into the right and left atria of 4 mongrel dogs with Heidenhain pouches. The mean rate of acid secretion in response to right atrial gastrin infusion was 0.39 mEq/15 min, as compared to the mean rate of 0.36 mEq/15 min when the gastrin was infused via the left atrium. The difference in gastric acid secretory response to infusion of gastrin into the right or left atrium was not statistically significant.

The electrolyte pattern of gastric juice after vagal stimulation induced by insulin hypoglycemia is presented.

In 13 dogs with gastric cannulas the acid output per hour was determined after: (a) subcutaneous injection of 0.1 mg histamine (base), (b) subcutaneous injection of 1.0 mg histamine (base), (c) teasing with meat (10 min interval), (d) intravenous injection of 1.0 units/kg of insulin. The pepsin concentration was also determined after the intravenous injection of 1.0 units/kg of insulin. The range and average acid output and pepsin concentration were established for each test condition per dog. Vision was compromised in the dogs by ablation of the orbits, collapse of the orbits, and by occipital cortical lesions. Gastric secretory studies were repeated at intervals over a 4 month period. There was marked inhibition of acid output and pepsin concentration in all dogs for the entire 4 month period to all gastric stimuli.

1. Tubeless gastric acidity was studied in “normal” geriatric patients 80–100 years of age, male and female. 2. Achlorhydria was found in 30% of “normal” geriatric patients while acidity was present in 70% of the patients. 3. Gastro-intestinal x-rays showed normal studies in 52% of the patients. Only one case of gastric malignancy, two of gastric ulcer, and one of duodenal ulcer were encountered. 4. Positive tubeless gastric acidity values (69.5%) approximated the normal and varied insignificant gastro-intestinal x-ray findings (70.4%). 5. Discrepancy between the negative tubeless gastric acidity method and the positive gastric intubation for acidity was 11.1%. 6. The convenience and economy of the tubeless gastric acidity method makes it possible to screen large numbers of geriatric patients and eliminate unnecessary x-ray examinations. 7. The urinary test for gastric secretion of hydrochloric acid (tubeless method) should be advocated in geriatric patients and in conditions that would contra-indicate intubation.

In 3 dogs with gastric fistulae, partial denervation of the acid secreting area of the stomach halved the insulin-stimulated acid secretion. Completion of a “highly selective” (proximal gastric) vagotomy resulted in a further fall of the peak acid output after insulin to 4% of control values, and there was no further change when selective and truncal vagotomy were performed. The pentagastrin dose-response curve was shifted to the right after partial denervation and remained so shifted after subsequent operations. At low doses there was a considerable decrease in acid output, and the maximal acid output was unchanged but achieved only with a higher dose of pentagastrin. These results suggest that the gastric secretory response after vagotomy is not an all-or-none phenomenon and that the fall in peak acid output after insulin is related to the extent of the acid-secreting mucosa denervated. Tailored vagotomy operations might lower the acid secretion sufficiently to heal an ulcer without interfering with other aspects of gastrointestinal function.

1. The effects of proximal duodenal acidification on basal unstimulated, maximal histamine-stimulated, and maximal insulin-stimulated gastric secretion in the 2-hr, pylorus-ligated male Sprague-Dawley rat (250–300 gm.) has been determined.

1. The transplantation of approximately half of the gastric antrum into a Heidenhain pouch, where it was exposed to an acid environment, resulted in no significant depression of gastric secretion.

1. Gastric secretion was estimated serially using Diagnex Blue in a group of subjects with no alimentary symptoms. Three types of stimulus to gastric secretion were used.

This experimental study was performed to measure directly the composition of the two components of gastric juice by using vagally innervated fundal gastric mucosa in dogs before and after loss of parietal cells had been induced by explantation. The concentrations of acid, sodium, potassium, chloride, and hexosamine found were compared with those reported previously for parietal and nonparietal components of gastric juice. The concentrations of electrolytes secreted by the explanted mucosa compared favorably with previous estimates of composition of nonparietal component of gastric juice.

The effect of antrectomy on acid secretion was studied in Pavlov-pouch dogs from which the duodenal inhibitory mechanism was excluded prior to antrectomy. The secretion was stimulated with graded doses of histamine, gastrin, and a combination of graded doses of histamine and gastrin plus a fixed dose of Urecholine.

Gastric secretion studied in vivo in the rat and dog, and in vitro by the frog membrane method, was found to be inhibited by the administration of bile salt compounds. Of those agents studied, sodium desoxycholate appeared to have the strongest inhibitory effect.

A serial neutralization test to assess gastric secretory capacity using intra-gastric pH-telemetering endoradiosonde is described.

The gastric secretory response to chronic injections of nicotine (2000 µg base /kg/day for 14 days) was studied in 2-hour pylorus-ligated male Sprague-Dawley rats (256.8±1.3 g). In sham anterior hypothalamic-lesioned animals, nicotine produced an increase in gastric juice volume and in acid and pepsin outputs. After bilateral electrolytic destruction of the anterior hypothalamic area or the rostral portion of the ventromedial nucleus, the response to chronic nicotine administration was abolished. Bilateral electrolytic lesions in the posterior hypothalamus did not block the gastric secretory stimulation produced by nicotine, whereas bilateral abdominal vagotomy did. It is concluded that the gastric secretory stimulation produced by the chronic administration of nicotine is mediated via the anterior hypothalamic area, the ventromedial nucleus in the anterior hypothalamus and the vagus nerves.

In 4 mongrel dogs with a Heidenhain pouch, selective gastric vagotomy, total gastrectomy, and an esophagoduodenostomy, the influence of vagotomy on inhibition of gastric secretion by fat in the duodenum was assessed. The amount of inhibition with the duodenum vagally innervated was not significantly different from the amount of inhibition when the duodenum was vagally denervated by truncal vagotomy. It is concluded that complete vagotomy does not interfere with the release of the inhibiting humoral substance released by fat in the duodenum.

In 14 dogs the respo se of the gastric secretory rate to alterations in blood flow was measured. In seven animals whose dorsal vagus was intact, increasing blood flow to the stomach was followed by increase in the secretory rate. In the re aining dogs whose vagi were ligated, changes in blood flow had no effect upon gastric secretion. In either vagus intact or ligated stomachs histamine infusion increased or initiated gastric secretion without any change in blood flow. (Author)

1. In the adult rat, I131-induced hypothyroidism did not depress gastric secretion as profoundly as previously reported in young animals. 2. While total acidity, pepsin concentration, and pepsin output did decrease significantly, volume of gastric secretion continued to increase during the 31 weeks of observation. 3. The increase in volume was due partly to a concomitant increase in body weight. 4. Volume, acid concentration, and acid output increased when animals were givenl-thyroxine injections 6 times a week for 12 weeks. These parameters of secretion decreased when cortisone was administered in a like fashion after the animals were made hypothyroid with I131. 5. Differences in circulating thyroxine as measured by serum PBI explained only 9–13% of the variations in gastric secretion. 6. The data also support the concept of seasonal variation in thyroid activity as determined by PBI levels.

In 6 dogs, gastric cannulas were placed in the dependent part of the stomach. Three of the dogs also had esophagostomies. The total acid output per hour was determined after a) teasing with meat, b) sham-feeding with meat, c) insulin-induced hypoglycemia, and d) the subcutaneous injection of 0.01 mg histamine base/kg. The mean total acid output was established for each test condition for each dog. Temporary visual deprivation depressed the total acid output response to teasing with meat and to sham-feeding with meat.

The gastric antisecretory effects of SC-29333, a novel prostglandin E1 analogs, were compared to the reference standard PGE1 methyl ester (PGE1ME) in gsstric fistula and Heidenhain pouch dogs. Secretion was stimulated submaximally by continuous intravenous infusion of either histamine or pentagastrin. Meal-stimulated gastric secretory studies were also conducted. SC-29333 effectively inhibited volume, acid output, and papsin secretion, in a dose-dependent manner. Intravenously (i.v.), SC-29333 was found to be approximately 30 times more potent than PGE1ME. The ranges of active i.v. bolus doses for SC-29333 and PGE1ME were 0.3-3.0 and 10-30 mug/kg, respectively. Unlike PGE1ME, SC-29333 was orally effective at doses of 10-30 mug/kg and was considerably better tolerated and longer acting than PGE1ME at active antisecretory doses. It is concluded, therefore, that SC-29333 is a potent, long-acting, orally effective inhibitor of gastric secretion in the dog.

The use of gastric function tests by American and British gastroenterologic surgeons in different clinical situations has been studied by questionnaire. Clinical practice on both sides of the Atlantic is generally similar. The major difference in thetype of test employed is that pentagastrin cannot be used in clinical practice in the United States. Surgeons in the USA were much more liberal in their indications for gastric secretory tests than were their British counterparts. Significantly more tests were used by American surgeons, if x-ray evidence of duodenal or gastric ulcer existed, and to evaluate, a postgastrectomy patient, whether symptomatic or not. The British surgeons were much less likely to allow the results of secretory tests to influence their surgical approach. The authors discuss indications for and the clinical value of gastric secretion tests and conclude that in most instances far too many tests are being employed.