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The parietal cell occupies a unique niche among eukaryotic cells in that it develops a proton gradient of more than 4 million-fold across the membrane of the secretory canaliculus. At rest, the cell is still able to develop a proton gradient across intracellular membranes, such that the acid compartment has a pH of less than 4. Acidification depends on the simultaneous presence of ATP, K+ and Cl- as demonstrated in permeabilized cells. With acidification of the luminal side of the proton pump, there is a corresponding alkalinization of the cytosolic face as revealed by carboxyfluorescein fluorescence enhancement. Disposal of the resultant alkali depends on carbonic anhydrase activity and the functioning of a coupled Na+:H+ and Cl-:OH-antiport across the basal lateral membrane. Accordingly, with secretion there is an increased cellular Cl- level, which is exported across the apical membrane in association with K+. The Na+ pump dependent secretion of KCl across this membrane is one of the major sites of the gastric ATPase. Membranes isolated from secreting tissue contain a KCl permeation pathway largely absent from membranes isolated from resting tissue. The pump itself acts as an H+ for K+ exchange ATPase which is most probably composed of at least two peptides of 100 000 Mr. That catalytic cycle consists of formation and breakdown of a covalent aspartyl phosphate. Formation of the intermediate depends on loss of K+ from cytosolic binding sites, and breakdown of the intermediate depends on K+ binding to the luminal face of the enzyme. During breakdown, an acid labile E . P is formed, and, at high ATP concentrations, loss of this form of the enzyme is probably the rate limiting step.

A new class of gastric acid inhibitors, substituted benzimidazoles (H 83/69 and H 149/94), have been tested in an isolated rabbit gastric gland preparation. Acid formation in the glands was stimulated by histamine, dibutyryl cAMP (DBcAMP), and high extracellular K+ concentrations, and the glandular secretory response was measured by changes in oxygen consumption and in accumulation of the weak base [14C]aminopyrine (AP). The substituted benzimidazoles inhibited AP accumulation induced by all stimulants in a dose-dependent noncompetitive manner. In contrast, cimetidine only inhibited histamine-induced AP accumulation. Basal AP accumulation, not affected by cimetidine, was also inhibited by the substituted benzimidazoles, as was the increase in glandular oxygen consumption produced by the addition of histamine and DBcAMP. Basal oxygen consumption was inhibited by about 15%. The substituted benzimidazoles, like AP, are weak bases and were also found to accumulate in the glands. Semiquantitative morphological studies of glands stimulated by histamine plus theophylline did not show any change in the enlarged secretory surface area after stimulation in the presence of inhibitory concentrations of H 149/94 (10(-4) M). The results suggest that substituted benzimidazoles have a mechanism of action different from that of H2-receptor antagonists and indicate a very distal site of action in the events leading to acid formation.

By various means, morphological, response to secretagogues, ion requirements and active membranes, the rabbit gastric gland preparation has been shown to be an adequate substrate for a study of the complete spectrum of the reactions leading to acid secretion. In fact, it is rapidly becoming the model of choice.

In fed rats, acid production was estimated to be 7 X 10(8) molecules of HCl per cell per sec or 5 X 10(5) molecules per sec per mu2 of secretory surface. In stimulated frog mucosa the corresponding values were 3 X 10(8) molecules of HCl per cell per sec 2 X 10(5) molecules per sec per mu2 or secretory surface. The generous assumptions used in making these estimates could have led to large errors.

In seven cats provided with gastric fistula (GF) of the main stomach and a denervated Heidenhain pouch (HP) the structure of the innervated and denervated mucosa was examined by light and electron microscopy. In four of these cats dose-response curves for acid output to pentagastrin were determined before and after vagal denervation of the fundic pouch. Vagal denervation reduced the acid response to pentagastrin by decreasing both the secretory capacity and the sensitivity of the oxyntic glands. Accordingly, in the same cat the parietal cells of the HP were less sensitive to pentagastrin than the cells of the innervated main stomach. Light and electron microscopic investigations revealed that the fundic mucosa was thinner, and the size and proportion of the parietal cells was smaller in the HP than in the GF. It is likely that the morphological changes in the pouch were caused by the vagal denervation rather than by the loss of mucosal contact with food. The secretory and morphological changes produced by the vagotomy are not necessarily related.