Acid Peptic Diseases: Pharmacological Approach to Treatment

Alex Mejia, MD; Walter K Kraft, MD, MS, FACP


Expert Rev Clin Pharmacol. 2009;2(3):295-314. 

In This Article

Physiology of Acid Secretion

The stomach consists of an epithelium made up of pits and glands. The two primary functional zones are the oxyntic gland area, representing approximately 80% of the organ, and the pyloric gland area representing the remaining 20%.[5] Parietal cells, which predominate in the oxyntic glands, secrete hydrochloric acid and intrinsic factor. They are located in the lower two-thirds of the oxyntic glands and are largely limited to the fundic region of the stomach. Chief cells, located at the base of the oxyntic glands, are responsible for secreting the digestive enzyme precursor pepsinogen. Neuroendocrine cells containing hormonal and paracrine signaling agents that regulate the activity of the parietal cell reside within the glands. These include D cells, enterochromaffin-like (ECL) cells, A-like cells and enterochromaffin (EC) cells.[6]

Regulation of Acid Secretion

Parietal cell acid secretion is initiated by a variety of factors related to food ingestion. Regulation is via central, peripheral and cellular mechanisms. Acid is generated by the carbonic anhydrase-mediated catalysis of CO2 and H2O to form H+ and HCO3 -. H+ ions are then exchanged for K+ by the H+K+-ATPase pump and later coupled with CL- ions entering the parietal cell from the blood in exchange for HCO3 -.

Most of the vagal fibers supplying the stomach are afferent[5,7] and relay information to the brain regarding mechanical and chemical changes in the stomach.[8] The efferent fibers are preganglionic neurons that do not directly innervate the parietal cells, but rather synapse with postganglionic neurons in the wall of the stomach. These neurons contain neurotransmitters, such as acetylcholine, gastrin-releasing peptide (GRP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), nitric oxide and substance P.[9] Through these messengers, postganglionic neurons are able to regulate acid secretion directly by influencing the parietal cell, or indirectly by modulating the secretion of hormonal and paracrine ligands. Sympathetic receptors of the stomach consist of unmyelinated nerve endings located within the smooth muscle layer. These detect chemical stimuli more than mechanical stimulation and play a role in conveying pain sensation associated with inflammatory states, such as gastritis.

The principal stimulants for acid secretion are histamine, gastrin and acetylcholine released from postganglionic enteric neurons.[5] These raise intracellular levels of adenosine 3´,5´,-cyclic monophosphate (cAMP), inositol triphosphate (IP3), diacylglycerol and calcium.[5,10] This sequence of events induce H+K+-ATPase rich tubulovesicles to fuse into the apical plasma membrane allowing the H+K+-ATPase to secrete protons directly into the lumen of the canaliculus of the parietal cell and then into the lumen of the gastric gland.

Histamine. Histamine is produced in ECL cells located in the oxyntic mucosa. It serves as the major paracrine stimulator of acid secretion. Histamine is produced in ECL cells by decarboxylation of L-histidine by histidine decarboxylase (HDC). In the gut, H2 receptors on the parietal cell increase adenylate cyclase activity and generate cAMP.[11] HDC promoter activity is upregulated by gastrin, H. pylori and PACAP. Targeted gene disruption of HDC and the H2 receptor demonstrate the key role of gastric acid secretion mediated by hormones such as gastrin or PACAP. HDC-knockout mice produce little or no histamine, resulting in impaired acid secretion and a failure to respond to gastrin.[12] However, functional antagonists of the H2 receptor only partially inhibits acid secretion stimulated by cholinergic agents. H2 receptors are also localized in smooth muscle and cardiac myocytes, which may explain why certain cardiac arrhythmias have been observed with rapid infusion of intravenous H2 antagonists. H3 agonists stimulate acid secretion indirectly by inhibition of somatostatin-induced histamine release.[13,14,15] There are no approved drugs specifically targeting the H3 receptor.

Gastrin. Gastrin, the main stimulant of acid secretion during meal stimulation,[5] is produced in response to luminal amino acids derived from dietary intake. Initially, gastrin is synthesized as a precursor molecule that is cleaved post-translationally into acid-stimulatory peptides, of which gastrin-17 and gastrin-34 are the most abundant, and N-terminal fragments, of which progastrin 1-35 and progastrin 1-19 dominate.[16] Gastrin is the most potent endogenous stimulant for gastric acid secretion by favoring synthesis and release of histamine from ECL cells.

Gastrin resembles cholecystokinin (CCK), as it possesses an identical C-terminal pentapeptide sequence. Two main classes of gastrin/CCK receptors have been characterized: CCK-1 and CCK-2. CCK-1 receptors are specific for CCK whereas CCK-2 receptors recognize both CCK and gastrin. When CCK-2 receptors become stimulated in parietal and ECL cells, they lead to activation of phospholipase C and release of intracellular calcium.[17,18,19] Gastrin is thought to regulate the secretion of histamine by increasing the release of stored histamine and by increasing the activity and gene transcription of HDC.[20] Gastrin also has a trophic effect on the oxyntic mucosa, particularly on ECL cells, and it can induce hyperplasia, hypertrophia and carcinoids in rats.[6] A number of neoplasms are gastrin sensitive, including gastric carcinoids and cancers of the stomach, colon, pancreas and lung.[21] This observation raised concerns of carcinogenesis in humans owing to long-term PPI-induced hypergastrinemia. However, prolonged retrospective observation in humans has not detected an increased incidence of cancer.[22,23]

In the stomach, gastrin mediates its effects primarily through the CCK-2 receptor. The stimulatory pathways for gastrin release are central and peripheral. Neural pathways to the G cells are both inhibitory and stimulatory. Peripheral pathways to the G cells are initiated by the presence of food in the stomach as signaled by mechanical distention, pH and the presence of amines and specific amino acids. When the pH of the gastric lumen falls below 3, a negative feedback mechanism involving calcitonin-gene related peptide[24,25,26] inhibits gastrin release, while hydrogen ions may also protonate amino acids and reduce their uptake by the G cells. Luminal pH also activates sensory nerve cells, enhancing somatostatin release that acts as a paracrine agent to suppress gastrin secretion.[27]

Acetylcholine. Acetylcholine from parasympathetic vagal efferents modulates basal acid secretion. It is released from postganglionic neurons of the enteric nervous system and directly stimulates acid secretion by binding to muscarinic (M3) receptors on parietal cells. Acetylcholine may also stimulate acid secretion indirectly by inhibiting the release of somatostatin through activation of M2 and M4 receptors on D cells.[5] The importance of acetylcholine in the PUDs has made it a target of anticholinergic drugs. However, the doses usually required to suppress acid secretion are commonly associated with the development of undesirable side effects, such as dry mouth, blurred vision and urinary retention.

Somatostatin. Somatostatin is the major physiological inhibitor of acid secretion.[5] It is released in two forms. Somatostatin 14 is found mainly in the stomach, pancreas and enteric neurons, while somatostatin 28 is the major form present in the small intestine. Somatostatin exerts tonic inhibitory effects on parietal cells, however, the major effects are accomplished by the inhibition of histamine release and gastrin release from ECL cells and G cells.[28,29,30,31] The secretion of somatostatin is increased by gastric acid and by gastrin. It is suppressed by cholinergic activation and increased by vasoactive intestinal peptide activation. The somatostatin analog octreotide has a theoretic potential in the treatment of acute ulcer bleeding, but its efficacy in an era of modern acid suppression agents has not been definitely demonstrated.[32,33,34]

Other Regulators of Acid Secretion. Ghrelin has been studied as a stimulant of acid secretion involving the vagus nerve and histamine release.[35,36] Other neurotransmitters, such as the neuropeptide GRP have been linked with meal-stimulated acid secretion. GRP mediates its effects by gastrin release and it may also be an important neurotransmitter in the vagal-cholinergic pathway, as demonstrated by the GRP antagonist BIM26226, which blocks vagally mediated acid secretion in humans in similar ways to atropine.[37] CCK may also function as a physiologic inhibitor induced by the presence of nutrients in the intestine.[38,39] Other inhibitors of acid secretion that stimulate somatostatin release include glucagon-like peptide, CCK, VIP, leptin, amylin and EGF.

H+K+-ATPase (The Proton Pump)

The H+K+-ATPase, also commonly called the proton pump, is the molecular engine of gastric acid secretion and is solely responsible for the secretion of hydrogen ions into the lumen of the gastric glands and stomach. This represents the last step in the secretion of gastric acid. The proton pump carries out the exchange of luminal K+ for cytoplasmic H+ through ATP hydrolysis. It is composed of two subunits: an α-subunit and a glycosylated β-subunit. The α-subunit carries out the catalytic and transport functions of the enzyme, reacts with ATP, defines cation binding properties, hydrolyzes ATP and is the site for binding of PPIs.[40] The smaller glycosylated β-subunit protects the enzyme from degradation and is essential for the structural and functional stability of the ATPase.[13] Moreover, it appears to play a key role in targeting of the pump to the apical membrane, in the development of the oxyntic mucosa and in recycling the pump from the "active" secretory canaliculi back to the tubulovesicular membranes when the cell reverts to a "resting" state.[41] Interestingly, each subunit is critical for enzyme activity since deletion of either the α-subunit or the β-subunit in mice causes achlorhydria.[42]

The H+K+-ATPase is an enzyme found only on secretory membranes of parietal cells that, in the resting unstimulated state, are contained in abundant membranous structures rich in H+K+-ATPase in the form of microtubules, vesicles and tubulovesicles. When gastric HCl secretion is stimulated there is a morphological transformation leading to migration of the tubulovesicles into the apical plasma membrane, allowing the H+K+-ATPase to secrete protons directly into the lumen of the gastric gland. Upon cessation of secretion, the pumps are retrieved from the apical membrane and the tubulovesicular compartment is re-established.


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