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Pharmacological aspects of acid secretion

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Abstract

The secretion of gastric acid is regulated both centrally and peripherally. The finding that H2-receptor antagonists are able to reduce or abolish acid secretion due to vagal, gastrinergic, and histaminergic stimulation shows that histamine plays a pivotal role in stimulation of the parietal cell. In the rat, the fundic histamine is released from the ECL cell, in response to gastrin, acetylcholine, or epinephrine, and histamine release is inhibited by somatostatin or by the H3-receptor ligand, R-α-methyl histamine. The parietal cell has a muscarinic, M3, receptor responsible for [Ca]i regulation. Blockade of muscarinic receptors by atropine can be as effective as H2-receptor blockade in controlling acid secretion. However, general effects on muscarinic receptors elsewhere produce significant side effects. The different receptor pathways converge to stimulate the gastric H+, K+-ATPase, the pump responsible for acid secretion by the stomach. This enzyme is an α,β heterodimer, present in cytoplasmic membrane vesicles of the resting cell and in the canaliculus of the stimulated cell. It has been shown that acid secretion by the pump depends on provision of K+Cl− efflux pathway becoming associated with the pump. As secretion occurs only in the canaliculus, this K+Cl− pathway is activated only when the pump inserts into the canalicular membrane. Transport by the enzyme involves reciprocal conformational changes in the cytoplasmic and extracytoplasmic domain. These result in changes in sidedness and affinity for H3O+ and K+, enabling active H+ for K+ exchange. The acid pump inhibitors of the substituted benzimidazole class, such as omeprazole, are concentrated in the canaliculus of the secreting parietal cell and are activated there to form sulfenamides. The omeprazole sulfenamide, for example, reacts covalently with two cysteines in the extracytoplasmic loops between the fifth and sixth transmembrane and the seventh and eighth transmembrane segments of the α subunit of the H+,K+-ATPase, forming disulfide derivatives. This inhibits ATP hydrolysis and H+ transport, resulting in effective, long-lasting regulation of acid secretion. Therefore, this class of acid pump inhibitor is significantly more effective and faster acting than the H2 receptor antagonists. K+ competitive antagonists bind to the M1 and M2 transmembrane segments of the α subunit of the acid pump and also abolish ATPase activity. These drugs should also be able to reduce acid secretion more effectively than receptor antagonists and provide shorter acting but complete inhibition of acid secretion.

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Authors and Affiliations

  1. UCLA and Wadsworth VA, 90073, Los Angeles, California, USA

    Basil I. Hirschowitz MD, David Keeling PhD, Miguel Lewin PhD, Susumo Okabe, Michael Parsons PhD, Karl Sewing PhD, Björn Wallmark PhD & George Sachs DSc, MBChB

  2. UAB, Birmingham, Alabama, USA

    Basil I. Hirschowitz MD, David Keeling PhD, Miguel Lewin PhD, Susumo Okabe, Michael Parsons PhD, Karl Sewing PhD, Björn Wallmark PhD & George Sachs DSc, MBChB

  3. Astra Hässle AB, Mölndal, Sweden

    Basil I. Hirschowitz MD, David Keeling PhD, Miguel Lewin PhD, Susumo Okabe, Michael Parsons PhD, Karl Sewing PhD, Björn Wallmark PhD & George Sachs DSc, MBChB

  4. Inserm, U10, Hopital Bichat, Paris, France

    Basil I. Hirschowitz MD, David Keeling PhD, Miguel Lewin PhD, Susumo Okabe, Michael Parsons PhD, Karl Sewing PhD, Björn Wallmark PhD & George Sachs DSc, MBChB

  5. Kyoto University, Kyoto, Japan

    Basil I. Hirschowitz MD, David Keeling PhD, Miguel Lewin PhD, Susumo Okabe, Michael Parsons PhD, Karl Sewing PhD, Björn Wallmark PhD & George Sachs DSc, MBChB

  6. University of Sussex, UK

    Basil I. Hirschowitz MD, David Keeling PhD, Miguel Lewin PhD, Susumo Okabe, Michael Parsons PhD, Karl Sewing PhD, Björn Wallmark PhD & George Sachs DSc, MBChB

  7. Hannover University, Hannover, Germany

    Basil I. Hirschowitz MD, David Keeling PhD, Miguel Lewin PhD, Susumo Okabe, Michael Parsons PhD, Karl Sewing PhD, Björn Wallmark PhD & George Sachs DSc, MBChB

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Hirschowitz, B.I., Keeling, D., Lewin, M. et al. Pharmacological aspects of acid secretion. Digest Dis Sci 40 (Suppl 2), 3S–23S (1995). https://doi.org/10.1007/BF02214869

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