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Updated: 04/08/08 12:52 PM |
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D. Gastric Acid Secretion and Its Control
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Acid secretion by the parietal cells and pepsinogen secretion by the chief cells are regulated by a complex interplay between stimulation and inhibition.
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1. A review of Hormonal Communications in the GI tract
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Neuroendocrine transmission is like having a telephone line which delivers hormonal messages from centers like the dorsal vagal complex to cells having the appropriate receptors. Some examples are: acetylcholine; vasoactive intestinal polypeptide; cholecystokinin; nitric oxide.
Endocrine transmission delivers hormones into the blood stream which reach cells having receptors attuned to the specific messenger. Some examples: gastrin; cholecystokinin; adrenocorticoids; glugagon-like polypeptide; glucose-dependent insulinotropic polypeptide (GIP). Paracrine transmission delivers a hormonal signal only to appropriate cells in the immediate vicinity, or to the very same cell which initiated the signal (autocrine transmission). Some examples: histamine; serotonin; somatostatin; prostoglandins. Immune transmission, as from a lymphocyte, delivers a message only to a target cell in its immediate vicinity. Hydrophobic (water-hating) molecules, such as the adrenocorticoids, can cross cell membranes and influence intracellular metabolism. Hydrophilic (water-loving) molecules interact with receptors linked to G proteins on target cell surfaces to initiate intracellular second messengers to prompt increases in Ca++, or in cyclic AMP. |
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2. Gastrointestinal Hormones
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| GI hormones are divided into structural families: |
The GI hormones and other related peptides can be divided into structurally homologous families. The first group consists of gastrin and cholecystokinin (CCK) which share the same carboxy-terminal pentapeptide. Each hormone is more active at its own receptor site than at the other's. For example, CCK can bind to the gastrin-receptor (gastrin/CCK-B) as well as to its more specific sites (CCK-A receptors). Both have active fragments which are less potent than the parent compound. For example, pentagastrin consists of the five carboxy-terminal amino acids of gastrin; it is used to stimulate parietal cells during tests of gastric secretory function.
The second group of peptides includes secretin, vasoactive intestinal peptide (VIP), glucose-dependent insulinotropic peptide (GIP, formerly gastric inhibitory peptide) and glucagon. There are no known active fragments of these peptides. |
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Gastrin secretion from antrum and proximal duodenum.
Secretin secretion from duodenum and jejunum |
Some hormones, such as gastrin, are transported in the blood to a target organ after they are released in one part of the body. Gastrin – containing endocrine cells are concentrated in the antral and proximal duodenal mucosa. Other endocrine cells are scattered throughout the gastrointestinal mucosa; some of these cells secrete hormones (paracrine secretion) which influence local effector cells.
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Gastrin → ↑ parietal cell secretion & ↑ fundal epithelial growth.
Somatostatin → ↓ gastrin secretion through paracrine action. |
We know that vagal stimulation, food peptides and amino acids all stimulate release of antral gastrin, and that acid (pH< 3) inhibits release of gastrin. The primary physiological actions of gastrin are stimulation of parietal cell secretion, and stimulation of growth of the fundal gland epithelium. Somatostatin down-regulates gastrin secretion through local paracrine action. Within the antrum, cytoplasmic extensions of somatostatin-containing D cells make contact with gastrin cells.
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3. Molecular Biology of the Parietal Cell
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Parietal cells have three receptors on their basolateral membranes that stimulate acid secretion: histamine; cholinergic receptors; and a CCK-B receptor for gastrin.
a. Histamine: |
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| Stimulators-histamine |
Histamine is the most important; it is released from enterochromaffin like (ECL) cells, and mast cells in the lamina propria. Histamine binds to a histamine (H-2) receptor on the parietal cell.
b. Acetylcholine: |
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| - Ach |
Acetylcholine, released from nerve endings, interacts with a receptor on the parietal cell, and with receptors on ECL cells (which release histamine), and on D cells (to down-regulate the release of the inhibitory peptide, somatostatin).
C. Gastrin |
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| -gastrin |
Gastrin is released from G cells in the antrum by food (especially amino acids), antral distension, and by neural release of gastrin-releasing peptide (GRP). Gastrin binds to gastrin/CCK-ß receptors on the parietal cell, and on ECL cells (which stimulate parietal cell secretion by releasing histamine).
d. Potentiation (Figure 6): |
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Second messengers
Optimal time to give oral PPIs is 30 min. before a meal |
Potentiation occurs when two or more peptides bind to their receptors on the parietal cell: the combined response is greater than the sum of the individual responses. Following binding to receptors on the parietal cell surface, intracellular messengers such as Ca++ and cAMP activate protein kinases which prompt secretion of acid. The final pathway is secretion of H+ into canalicular lumens in exchange for K+ by the action of a proton pump (H+/K+ ATPase) which is located within the luminal membrane of the secretory canaliculae of the parietal cell. Substituted benzimidazoles (omeprazole, lansoprazole) accumulate in acidic spaces where they are activated. They then bind to the H+K+-ATPases, thereby inactivating the enzymes. For optimal therapeutic efficiency, proton pump inhibitors (PPIs) should be ingested about 30 minutes before a meal so that they can be absorbed and be able to accumulate in parietal cell canaliculae as the H+K+-ATPases are being stimulated by the meal.
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Figure 6 Overview of acid secretion ECL = enterochromaffin-like cell + = up-regulation; - = down-regulation |
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Gastric juice 150 mM H+ 15 mM K+ |
Parietal cells are able to secrete HCl at a concentration one million fold higher than that in blood (0.15 M, pH~1.0 VS 10-7 M, pH 7.4).
In addition to H+, parietal cell secretion contains 10-20 mM K+, and 160mM Cl-. Knowledge of the composition of gastric
juice becomes pertinent when managing a patient who has severe vomiting or whose stomach contents are being aspirated continuously.
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Figure 7 This is an attempt to explain how parietal cells secrete H+. The driving force is the H+/K+ pump. A K+, CI- conductance channel must move these two ions from the interior of the cell into the cell’s exterior canaliculae so that K+ can be exchanged for H+ which is electrically neutralized by CI-. The other product of the hydrolysis of water, OH-, is converted to HCO3- which is secreted into venous blood in exchanged for CI-. |
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e. Inhibition
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Inhibitors Endocrine D-cells release somatostatin |
Somatostatin and prostaglandins down-regulate parietal cell secretion. Somatostatin also suppresses the release of histamine from ECL cells. Pyloric D cell production of somatostatin is stimulated by luminal acid and by circulating CCK. Prostaglandin E analogues reduce acid secretion to the same extent as H2 blockers.
Secretin can suppress gastric acid secretion (probably via prostaglandins). Secretin is released from duodenal S cells in response to luminal acid, and long-chain fatty acids. CCK can compete with gastrin for binding to gastrin/CCK-ß receptors, and it can induce D cells to release somatostatin. |
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Table 1 Inhibition of acid secretion LCFA, long-chain fatty acids (chain length >12 C). In rats, secretin is the inhibitor released by LCFA. |
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It is convenient to think about three phases of gastric acid secretion although such a separation is artificial because the three proceed nearly simultaneously.
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| Three phases of gastric acid secretion: cephalic, gastric, and intestinal |
In the cephalic phase, the sight, smell, and taste of food excites central vagal efferents which stimulate the parietal cells directly to produce acid, and the
chief cells to secrete pepsinogen. Vagal efferents also prompt antral G cells, via Gastrin Releasing Peptide to release gastrin. Sham feeding (chewing food and then
spitting it out) prompts the stomach to secrete about half of its maximal acid secretion.
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Cephalic: Vagus n. stimulates release of acid, pepsinogen, and gastrin Gastric: 1) Food causes ↑ pH which ↑ gastrin release. 2) fundal distension → ↑ parietal cell secretion. |
In the gastric phase, food enters the stomach and buffers the small volume (about 50 ml) of gastric juice. The resulting rise in antral pH permits gastrin to be
released from antral G cells in response to vagal impulses, to distension of antrum, and to peptides in the antral lumen. Caffeine and calcium also stimulate acid
secretion. Gastrin release accounts for up to 90% of the gastric phase of acid secretion. In addition, distension of the fundal gland area also prompts parietal cell
secretion through a vagally-mediated reflex arc. Acid in the fundal gland area activates pepsinogen to pepsin.
The intestinal phase is poorly understood because there is a complex interplay of stimulatory and inhibitory factors. Amino acids in the small intestine stimulate release of gastrin, but chyme in the upper intestine inhibits gastric acid secretion, possibly via secretin which is released in response to H+, and long-chain fatty acids. |
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| Overall Response | The overall response is as follows: The rate of gastric acid secretion rises to a maximum 2-3 hours after beginning a meal. Thereafter, acid secretion slowly declines as gastric distension is relieved by emptying, as a falling antral pH inhibits release of antral gastrin, and as fat, carbohydrate, and hypertonic solutions in the small intestine depress acid secretion by inhibitory hormones and nervous afferents. Cutting the vagus nerves to the stomach halves the responsiveness of the parietal cells to gastrin. Removing the G cells by antrectomy halves the maximum responsiveness of the parietal cells. | |||||||||||||||||||||||||||||
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Next Section (E): Measurement of Gastric Acid Secretion » |
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