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Several new compounds have become available recently which are potent inhibitors of gastric secretion. The therapeutic potential of these inhibitors in the peptic ulcer diathesis is reviewed and it is concluded that the histamine H2-receptor antagonists show most promise at present. The prostaglandins and gastro-intestinal polypeptides are of considerable physiological interest but are unlikely to have clinical importance in the immediate future.

Cimetidine infusion (100 mg h-1) reduced the acid secretory response to insulin infusion (0.03 units Kg-1h-1) when compared to paired control tests in 6 healthy volunteers. There was no significant difference between cimetidine and control tests in terms of pepsin output or serum gastrin concentrations. Cimetidine also reduced the acid secretory response when administered after 90 minutes of insulin had established a secretory response in extended tests in 3 additional volunteers. Cimetidine may have therapeutic potential in the peptic ulcer diathesis.

The secretory potency and disappearance rates of pure synthetic human non-sulphated minigastrin (HG-14-I) and pure natural human non-sulphated heptadecapeptide (HG-17-I) were compared in five dogs with gastric fistulas and Heidenhain pouches. Intravenous infusion of equimolar doses of the two gastrins produced equimolar increases over basal of serum immunoreactive gastrin and no statistically significant differences in acid output. Also HG-14-I and HG-17-I did not differ significantly in half-times for disappearance, clearance rates, calculated volumes of distribution, or mean plateau serum levels.

Gastric acid secretion was studied in conscious cats with gastric fistulas. Dimaprit and Nalpha,5-dimethylhistamine produced higher maximal responses than histamine. In the presence of pyrilamine, the maximal response to histamine was equal to that of dimaprit. Pyrilamine increased submaximal but not maximal responses to pentagastrin. Cimetidine decreased the potency of dimaprit but did not alter the maximal response. Gastric acid secretion continued for 90 min after infusion of dimaprit was stopped. Possible mechanisms for the enhancement of acid secretion by pyrilamine include: (a) blocking of an inhibitory histamine H1-receptor and (b) inhibition of histamine methyltransferase.

Metiamide, an antagonist of histamine H(2) receptors, was administered intravenously to normal subjects and to patients with a peptic ulcer during vagal stimulation with a constant infusion of insulin. In normal and peptic-ulcer subjects there were reductions of 70% and 71% respectively in gastric-acid output compared with control tests on the same subjects. The decreased acid output resulted from a reduction in both volume of secretion and acid concentration. Metiamide is therefore a potent inhibitor of vagally-induced gastric acid secretion.

1. An apparatus for intragastric titration has been devised and its validity tested. Both when attached to a beaker simulating a pouch and when attached to a pouch whose secretion was suppressed by infusing cimetidine, the apparatus accurately measured added acid when the endpoint setting was between pH 3.0 and 9.0. At pH 2.0 and 1.0 with liver extract and at pH 1.0 with saline, the amount of acid added was markedly underestimated.2. In dogs with vagally denervated pouches, during stimulation by I.V. infusion of histamine or pentagastrin, the rate of acid secretion as measured by intrapouch titration was uninfluenced by changes in luminal pH between 2.0 and 9.0. The apparent decrease in acid secretion at pH 1.0 could be shown to be due entirely to artifact in that no change in acid secretion was found when the gain in mass of acid was simultaneously measured by using a non-absorbable dilution indicator to measure volume gain and titration of samples to pH 7.0 to measure acid concentration.3. During stimulation of acid secretion by solutions of liver extract or of L-histidine instilled into the pouch, the rate of acid secretion was found to increase markedly as pH was increased from 3.0 to 9.0 thus confirming our earlier findings.4. We conclude that while stimulation of acid secretion by topical stimulants is highly dependent on luminal pH, secretion increasing as pH increases, stimulation by parenteral agents such as histamine and pentagastrin is not influenced by luminal pH in the range from pH 1.0 to 9.0.

The gastric acid response to graded doses of insulin given by continuous infusion was studied in four dogs, each surgically provided with a gastric fistula. All doses of insulin resulted in a prolonged plateau of hypoglycaemia and the degree of hypoglycaemia correlated significantly (p <0.05) with the insulin dose, up to 0.15 u/kg hr. Similarly, graded doses of insulin (up to 0.15 u/kg hr) produced graded acid responses and both the peak acid output and the total acid output correlated significantly with blood glucose changes. No initial inhibitory phase of acid secretion followed the start of the infusion, but a dose-related delay in the onset of the acid response was observed. Our results indicate that insulin provides a quantitative glycopenic stimulus producing a quantitative vagal acid response.

In view of the disadvantages of the standard insulin test for completeness of vagotomy a continuous insulin infusion test has been developed. Twenty-six tests were carried out on 12 healthy male volunteers. A dose of 0.04 unit of soluble insulin/kg/hr was found to produce the highest acid secretion with the least severity of symptoms of hypoglycaemia. The pattern of response was a plateau of acid secretion and of hypoglycaemia, and repeated studies in six subjects showed that the results were reproducible. Evaluation of this test after vagotomy and comparison with the standard insulin test are now required.

The effect of orally administered prostaglandin E(2) and its synthetic 15-methyl analogues on gastric secretion in man was studied. The parent E(2) compound did not inhibit basal secretion, whereas both the 15 (S) 15-methyl-E(2) methyl ester and its isomer, 15 (R) 15-methyl-E(2) methyl ester inhibited basal acid secretion. This action is likely to be a direct one on the parietal cell, and it could prove of value in the treatment of peptic ulcer.