An hypothesis for discovery of inhibitors of gastric acid secretion

Abstract

Davenport discovered that thiocyanate inhibits gastric acid secretion. The original working hypothesis, that this action of thiocyanate is due to inhibition of carbonic anhydrase, was successful in stimulating further work but is now no longer tenable. We propose a new working hypothesis according to which the inhibitory action is dependent on the presence of a nitrogen with a pair of unshared electrons. This hypothesis was tested by studying the effects of nitrite, cyanate, and ammonium ions on the in vitro frog's stomach. It was found that the addition of these compounds to the nutrient side reversibly inhibits H⁺ secretion in the same concentration range as that found for thiocyanate, i.e., 0.5–10 mm. Reduction of the H⁺ rate to approximately zero was associated with an increase in the transmucosal potential difference and electrical resistance to levels characteristic of the resting stomach. Acetate and nitrate in the same and higher concentrations did not inhibit the H⁺ rate. The hypothesis has been fruitful in that three new gastric inhibitors have been discovered, and it is hoped that it will be successful in stimulating much further work before it too becomes untenable.