Regulation Mechanism of Gastrirc Secretion
Short and Long Reflexes
Neural input provides an important mechanism for regulation of gastric secretion. Reflexes contribute to both the stimulation and inhibition (e.g., CGRP) of secretion. For example, distension of the stomach wall, sensed by stretch receptors, activates reflexes that stimulate acid secretion at the level of the parietal cell. These reflexes may be so-called short reflexes, which involve neural transmission contained entirely within the enteric nervous system. In addition, long reflexes also contribute to the control of secretion. These involve the activation of primary afferents that travel through the vagus nerve, which in turn are interpreted in the dorsal vagal complex and trigger vagal outflow via efferent nerves that travel back to the stomach and activate parietal cells or other components of the secretory machinery. These long reflexes are aslo called vagovagal reflexes. The relative contribution of short and long reflexes to the control of secretion is unknown. However, it is clear that selective gastric vagotomy eliminates some, although not all, of the gastric secretory response to distension as well as a portion of related gastric motor responses.
Acetylcholine is an important mediator of both short and long reflexes in the stomach. It participates in the stimulation of parietal, cheif, and ECL cells; the supression of D cells; and the synapses between nerves within the enteric nervous system. In addition, a second imporant gastric neurotransmitter is gastrin releasing peptide, or GRP. This neuropeptide is the mammalian homologue of one known as bombesin originally isolated from frog skin. GRP is released by enteric nerves in the vicinity of gastrin-containing G cells in the gastric antrum.
- Short reflexes, ENS (ACh)
- Long reflexes/vagovagal reflexes, ANS (ACh)
The gastric secretory response is also regulated by soluble factors that originate from endocrine and other regulatory cell types, such as ECL cells. The primary endocrine regulator of gastric secretion is gastrin, which actually consists of a family of peptides. Gastrin travels through the bloodstream from its site of release in the antral mucosa to stimulate parietal and ECL cells via their CCK2 receptors.
PS: CCK2 receptors are expressed on the parietal and ECL cells.
Gastric secretion is also modified by paracrine mediators. Histamine is released from ECL cells under the combined influence of gastrin and ACh, and diffuses to neighboring parietal cells to activate acid secretion via histamine H2 receptors. At one time histamine was thought to be the final common mediator of acid secretion, based in part on the clinical observation that histamine H2 receptor antagonists can profoundly inhibit acid secretion. However, it is now known that parietal cells express receptors for not only histamine, but also ACh (muscarinic m3) and gastrin (CCK2). Because histamine H2 receptors are linked predominantly to signaling pathways that involve cAMP, while ACh and gastrin signal through calcium, when the parietal cell is acted upon simultaneously by all three stimuli, a potentiated, or greater than additive, effect on acid secretion results. The physiological implication of this potentiation, or synergism, is that a greater level of acid secretion can be produced with relatively small increases in each of the three stimuli. The pharmacological significance is that simply interfering with the action of any one of them can significantly inhibit acid secretion.
Acid secretion is also subject to negative regulation by specific mediators. Specifically, somatostatin is released from D cells in response to an axon reflex that release CGRP (calcitonin gene-related peptide) in the antral mucosa when luminal pH falls below 3, and inhibits the release of gastrin from G cells. Elsewhere in the stomach, somatostatin can also exert inhibitory influences on ECL, parietal, and chief cells. The SSTR2 somatostatin receptor is responsible for the inhibitory effects of the peptide in the stomach. In fact, there is data to support the idea that gastirc secretion under resting conditions is tonically suppressed by somatostatin. When stimulated responses occur, they are due not only to the active stimulatory mechanisms disscussed above, but also specific suppression of the inhibitory effects of somatostatin, involving the actions of both ACh (via m2 and m4 receptors) and histamine (via H3 receptors) on D cells.
- Somatostatin (negative regulation)
Specific luminal constituents also modulate gastric secretion indirectly. The example of pH is described earlier, but acid output, at least, is also increased by components of the meal. Short peptides and amino acids, derived from dietary protein secondary to the action of pepsin released from chief cells, are capable of activating gastrin release from G cells. Aromatic amino acids are the most potent, and "receptors" for these are assumed to reside on the apical membrane of the open G-type endocrine cells, although their structure remains to be defined.
Gastric acid secretion is also activated by alcoholic beverages, coffee, and dietary calcium. The effects of alcoholic beverages may not be due to ethanol itself, but rather the amino acids present in the veverage, particularly in beer and wine. Likewise, the effect of coffee does not appear to be attributable to caffeine, since decaffeinated coffee also increases secretion.
- Food (bufferring/increasing pH)
- Food (short peptides and amino acids, alcoholic beverages, coffee, dietary calcium)
Summar of Regulators of Gastric Secretion
|Histamine||ECL cells||amplify acid secretion|
|suppress somatostatin secretion|
|Gastrin||G cells||amplify acid secretion|
|amplify histamine secretion|
|GRP||Nerves||stimuate the secretion of gastrin|
|CGRP||Nerves||stimulate the secreton of somatostatin|
|Ach||Nerves||amplify acid secretion|
|amplify pepsinogen secretion|
|amplify histamine secretion|
|suppress somatostatin secretion|
|Somatostatin||D cells||suppress gastrin secretion|
|suppress histamine secretion|
|suppress acid secretion|
|suppress pepsinogen secretion|
Regulation of Gastric Secretion
Regulation of Scretion in the Interdigestive Phase
Between meals, the stomach secretes acid and other secretory products at a low level, perhaps to aid in maintaining the sterility of the stomach. However, because no food is present, and thus no buffering capacity of the gastric content, the low volume of secretions produced nevertheless have a low pH – usually around 3.0. Basal acid output in the healthy human is in the range of 0-11 mEq/h, which can be contrasted with the maximal rates that can be produced by ingestion of a meal, or intravenous administration of gastrin, of 10-63 mEq/h. The basal secretion rate is believed to reflect the combined influences of histamine and ACh, released from ECL cells and nerve endings, respectively, tempered by the influence of somatostatin from fundic D cells. Gastrin secretion during the interdigestive period, on the other hand, is minimal. This is because gastrin release is suppressed by a luminal pH of 3 or below, via the release of somatostatin from antral D cells.
Regulation of Postprandial Secretion
In conjunction with a meal, gastric acid secretion can be considered to occur in three phases – cephalic, gastric, and intestinal. The major portion of secretion occurs during the gastric phase, when the meal is actually present in the stomach. Secretion of other gastric products usually parallels that of the acid.
Even before the meal is ingested, the stomach is readied to receive it by the so-called cephalic phase of secretion. In fact, during the cephalic phase, the functions of several gastrointestinal systems in addition to the stomach begin to be regulated, including the pancreas and gallbladder. Higher brain centers respond to the sight, smell, taste and even thought of food, and relay information to the dorsal vagal complex. In turn, vagal outflow initiates both secretory and motor behavior in the stomach and more distal segments. Gastric secretion occuring during the cephalic phase readies the stomach to receive the meal. Vagal outflow activates enteric nerves that in turn release GRP and ACh. Release of GRP in the vicinity of antral G cells releases gastrin that travels through the bloodstream to activate parietal and chief cells in the endocrine fashion. ACh also suppresss ongoing somatostatin release.
The gastric phase of secretion is quantitatively the most important. In addition to vagal influences continuing from the cephalic phase, secretion is now amplified further by mechanical and chemical stimuli that arise from the presence of the meal in the lumen. These include the luminal signals discussed earlier, and signals arising from stretch receptors embedded in the wall of the stomach. Thus, as the stomach distends to accommodate the volume of the meal, these receptors initiate both short and long reflexes to further enhance secretory responses either directly, via the release of ACh in the vicinity of parietal cells, or indirectly, via the release of ACh that activate ECL cells, or GRP that activates G cells to release gastrin. These vago-vagal reflexes also transmit information downstream to ready more distal segments of the intestine to receive the meal. The gastric phase of secretion is also accompanied by a marked increase in gastric blood flow, which supplies the metabolic requirements of the actively secreting cell types.
Due to the combined influence of neurocrine and endocrine signals, further amplified by histamine release from ECL cells, secretory cells of the stomach are highly active during the gastric phase. Moreover, pepsinogen released by chief cells is rapidly cleaved to pepsin in an autocatalytic reaction that occurs optimally at pH 2, and this pepsin then acts on ingested protein to release short peptides and amino acids that further enhance gastrin release. Moreover, many dietary substances, including proteins, are highly effective buffers. Thus, while acid secretory rates remain high, the effective pH in the bulk of the lumen may rise to pH 5. This ensures that the rate of acid secretion during the gastric phase is not attenuated by an inhibition of gastrin release that would otherwise be mediated by somatostatin (when pH <=3).
As the meal moves out of the stomach into the duodenum, the buffering capacity of the lumen is reduced and the pH begins to fall. At a threshold of around pH 3, CGRP triggers somatostatin release from D cells in the gastric antrum, which acts on G cells to suppress gastrin release. Somatostatin released from D cells in the oxyntic mucosa, or from nerve endings, likely also acts directly to inhibit secretory function. This acid-sensing response is a neural pathway that involves the activation of chemoreceptors sensitive to pH, which in turn leads to the release of CGRP via an axon reflex. Other signals also limit the extent of gastric secretion when the meal has moved into the small intestine. For example, the presence of fat in the small intestine is associated with a reduction in gastric secretion. This feedback response is believed to involve several endocrine and paracrine factors, including GIP and CCK, the latter of which binds to CCK1 receptors on D cells.