Gastric mucosa carbonic anhydrase

The enzyme carbonic anhydrase facilitates the reaction between carbon dioxide and water to form carbonic acid, which then breaks down to hydrogen (H" ) and bicarbonate (HCOj") ions. This process is fundamental to the production of either acid or alkaline secretions and high concentrations of carbonic anhydrase are present in the gastric mucosa, pancreas, eye and kidney. Because the number of available to exchange with Na" in the proximal tubule is reduced, sodium loss and diuresis occur. But HCOg reabsorption from the tubule is also reduced, and its loss in the urine leads within days to metabolic acidosis, which attenuates the diuretic... 

Carbonic anhydrase and sodium bicarbonate together neutralize the acids produced by bacterial metabolism of dietary carbohydrate (Fig. 12.2). When salivary carbonic anhydrase is swallowed, it adheres to the mucosal surface of the stomach where it remains active and forms carbonic acid from sodium bicarbonate in the gastric mucosa. A lack of salivary carbonic anhydrase causes acid to remain longer in the stomach, contributing to peptic disease in addition to dental caries (Sect. 15.3.3). 

The gastric mucosa is able to generate a proton gradient of 10 1. The energy required for this transport can in principle be delivered by an ATPase and a search for such an enzyme was indicated. The earlier suggestion that a membrane-bound anion-sensitive ATPase in cooperation with carbonic anhydrase would be responsible, has been considered in Section 2 and found to be unlikely. 

The gastric mucosa attempts to replace the lest H by the carbonic anhydrase reaction but the result Is formation of HCOs" which accumulates In the blood Increasing the pH... 

Carbonic anhydrase is assumed to be located at the surface of the membrane of the tubular cells [47, 48]. Carbonic anhydrase is a small zinc protein found in many animal tissues, but its concentration is highest in the kidney tubules cells, the erythrocyte, and some cells of the gastric mucosa. The substrates of the carbonic anhydrase reaction are carbon dioxide and water the product is carbonic acid. The enzyme has been purified from erythrocytes, and its molecular weight is about 30,000. The purified enzyme preparation contains 0.21% zinc, probably 1 atom of zinc per molecule of enzyme. The zinc is tightly bound to the enzyme molecule and cannot be removed by dialysis or electrodialysis. The presence of zinc in the molecule is essential to activity because when zinc is removed from the molecule by extended incubation with 1-10 phenanthroline, the enzyme s activity reflects the zinc content of the preparation. 

When N. U. Meldrum and F. J. W. Roughton found carbonic anhydrase in erythrocytes, they failed to find it in the stomach for reasons that have nothing to do with laboratory work. In late May 1938 R. B. Fisher, persuaded by observations such as those of Brown and Vineberg that the stomach s ability to secrete acid is influenced by the carbon dioxide in the blood, attempted to persuade me to look for carbonic anhydrase in the gastric mucosa. I found it in the first week of June 1938, and the next week I learned Meldrum and Roughton s method for measuring carbonic anhydrase in Cambridge. ... 

Figure 1-16. Ordinates, carbonic anhydrase concentration in arbitrary units in slices of oxyntic mucosa of the cat. Abscissae, 1,000 oxyntic cells in adjacent slices of the oxyntic mucosa of the cat. (From Davenport H W. Gastric carbonic anhydrase. I Physiol Lond 97 32-43, 1939.)... 

Mann and Keilin quite naturally wanted to compare sulfanilamide with thiocyanate as inhibitors of acid secretion, but because they were biochemists, they had to ask a physiologist who knew how to anesthetize an animal to help them. The result was a brief note in Nature reporting that sulfanilamide in concentrations that largely inhibit carbonic anhydrase in extracts of gastric mucosa have no appreciable effect upon acid secretion, whereas thiocyanate in concentrations having no appreciable effect upon the enzyme does inhibit acid secretion (Fig. 1-19). "... 

After acetazolamide, a more potent inhibitor of carbonic anhydrase, became available in the early 1950s, a flood of papers reported that an adequate dose of the carbonic anhydrase inhibitor can reduce the rate of secretion by human, dog, and frog gastric mucosa." I had no interest in the subject, for in 1940 I had become convinced of the following ... 

Discovery of the HCOf -stimulated ATPase revived interest in the possibility that carbonic anhydrase participates directly in secretion of acid. In 1970 Shirley Cross, working for Smith, Kline and French in England, applied the latest version of the cobalt sulfide histochemical method for locating carbonic anhydrase in the rat stomach. She floated frozen sections of gastric mucosa on a solution of cobalt sulfate and sodium bicarbonate. As carbon dioxide evolved from the solution over... 

Lately, extensive research has been devoted to metalloenzymes. " Thus, carbonic anhydrase is a very effective catalyst for conversion of CO2 to carbonic acid (H2CO3), and vice versa This enzyme is found in red blood cells, gastric mucosa, pancreatic cells, and renal tubules. Carbonic anhydrase plays an important role in respiration by influencing CO2 transport in the blood. The enzyme also functions in the formation of hydrochloric acid by the stomach. 

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