Gastric Secretion

Introduction Gastric secretion, commonly known as gastric juice, is a vital component of the digestive process, distinct from salivary secretion due to its acidic nature and diverse functions. The stomach, an organ divided functionally into the oxyntic gland area (proximal 80%, including fundus and body) and the pyloric gland area (distal 20%, or antrum), produces about 1 to 2 liters of gastric juice per day. Understanding its composition, formation, and regulation is crucial for comprehending gastrointestinal physiology and related pathologies.

I. Functions of Gastric Juice Gastric juice serves several critical functions, primarily in the initial stages of digestion and protection. The main functional constituents are acid, pepsin, intrinsic factor, mucus, and water.

• Hydrochloric Acid (HCl):

    ◦ Activates pepsin: Necessary for the conversion of inactive pepsinogen to active pepsin when the pH drops below 5, and pepsin itself can catalyze this conversion.

    ◦ Denatures proteins: Partially denatures dietary proteins, making them more accessible for enzymatic digestion.

    ◦ Kills microbes: Acts as a sterilizing agent, killing a large number of bacteria ingested with food, thereby reducing intestinal infections.

    ◦ Facilitates iron absorption: Converts ferric iron ($\text{Fe}^{3+}$) to ferrous iron ($\text{Fe}^{2+}$), which is more readily absorbed. This information is not explicitly in the sources provided but is a common physiological function.

    ◦ Stimulates hormone secretion: Stimulates the secretion of hormones that promote the flow of bile and pancreatic juice.

    ◦ Inactivates salivary enzymes: Stops the action of salivary amylase and lingual lipase.

• Pepsin:

    ◦ Begins the digestion of protein by cleaving internal peptide linkages, producing smaller peptides.

    ◦ While important, its absence does not cause significant digestion defects as pancreatic enzymes are sufficient.

• Intrinsic Factor (IF):

    ◦ A glycoprotein required for the efficient absorption of vitamin B12 (cobalamin) in the ileum. It is the only indispensable ingredient in gastric juice.

    ◦ Secreted by parietal cells in humans.

• Mucus:

    ◦ Lines the stomach wall, acting as a physical barrier and lubricant to protect the mucosa from physical injury and from digestion by acid and pepsin.

    ◦ Together with bicarbonate (HCO3-), it neutralizes acid and maintains the surface pH near neutrality, forming part of the gastric mucosal barrier.

• Water:

    ◦ Acts as the medium for the action of acid and enzymes.

    ◦ Solubilizes many of the constituents of a meal.

II. Composition of Gastric Juice Gastric juice is a unique fluid whose composition varies significantly with the rate of secretion.

• General Characteristics:

    ◦ Volume: Approximately 1 to 2 liters per day.

    ◦ Osmolality: Gastric juice and plasma are approximately isotonic at all secretory rates.

    ◦ Ionic Composition:

        ▪ Contains high concentrations of H+, K+, and Cl- compared to plasma.

        ▪ Contains a lower concentration of Na+ compared to plasma.

• Variations with Flow Rate (Two-Component Model):

    ◦ The composition of gastric juice is often conceptualized as a mixture of two components:

        ▪ Nonparietal Component: A basal alkaline secretion of constant and low volume. Its primary constituents are Na+ and Cl-, with K+ concentration similar to plasma. In the absence of H+ secretion, HCO3- (approximately 30 mEq/L) can be detected.

        ▪ Parietal Component: Secreted on top of the nonparietal background. It contains 150 to 160 mEq H+/L and 10 to 20 mEq K+/L, with Cl- as the only anion. It is slightly hyperosmotic.

    ◦ At low rates of secretion, the final juice is primarily a solution of NaCl with small amounts of H+ and K+.

    ◦ As the rate of secretion increases, the concentration of H+ increases and Na+ decreases, while Cl- and K+ concentrations rise slightly. At peak rates, gastric juice is primarily HCl.

    ◦ The pH of luminal contents also directly impacts the composition; when the pH drops below 3, gastrin release is inhibited, affecting secretion.

III. Mechanism of Secretion (Formation of Gastric Juice) Gastric juice is formed through the coordinated activity of specialized cells in the gastric mucosa.

• Functional Anatomy of Gastric Mucosa:

    ◦ Oxyntic Gland Area: Located in the fundus and body (proximal 80% of stomach). Contains:

        ▪ Parietal Cells (Oxyntic Cells): Secrete HCl and intrinsic factor.

        ▪ Chief Cells (Peptic Cells): Secrete pepsinogen and gastric lipase.

        ▪ Mucous Neck Cells: Found at the neck of the glands, they produce mucus and are stem cells for parietal cells and mucous cells.

        ▪ Enterochromaffin-like (ECL) Cells: Secrete histamine, a potent stimulant of acid secretion.

    ◦ Pyloric Gland Area (Antrum): Located in the distal 20% of the stomach. Contains:

        ▪ G Cells: Synthesize and release the hormone gastrin.

        ▪ Mucous Cells: Produce mucus and pepsinogen.

        ▪ D Cells: Secrete somatostatin, an inhibitory paracrine.

• HCl Secretion by Parietal Cells:

    ◦ A highly active process that consumes a large amount of ATP to concentrate H+ more than a million-fold.

    ◦ Resting State: Parietal cells have numerous tubulovesicles containing the H+,K+-ATPase (proton pump). An intracellular canaliculus is continuous with the gland lumen.

    ◦ Stimulated State: Tubulovesicles fuse with the apical membrane of the canaliculus, greatly increasing the surface area for secretion and the number of active proton pumps.

    ◦ Key Transport Processes (Figure 8-4, Figure 6.8):

        1. Water (H2O) enters the cell.

        2. Carbon Dioxide (CO2) diffuses into the cell from the blood.

        3. Carbonic Anhydrase (CA) catalyzes the reaction of CO2 + H2O → H2CO3, which then dissociates into H+ and HCO3-.

        4. The H+,K+-ATPase actively pumps H+ out into the secretory canaliculus in exchange for K+ (1:1 stoichiometry, electrically neutral). This pump is the target of proton pump inhibitors (e.g., omeprazole).

        5. K+ that enters the cell through the H+,K+-ATPase is then recycled back to the lumen through apical K+ channels.

        6. Cl- enters the cell from the plasma via a Cl-/HCO3- exchanger on the basolateral membrane (exchanging intracellular HCO3- for extracellular Cl-).

        7. Cl- exits the cell into the lumen through apical Cl- channels.

        8. Na+,K+-ATPase (Na+ pump) on the basolateral membrane maintains intracellular Na+ and K+ gradients.

        9. Water follows the secreted ions (H+ and Cl-) passively into the lumen to maintain isotonicity.

    ◦ The secretion of HCO3- into the blood by parietal cells contributes to the "alkaline tide" following a meal.

IV. Regulation of Gastric Secretion Gastric secretion is meticulously regulated by neural, hormonal, and paracrine mechanisms, often working in concert or in negative feedback loops.

• General Control:

    ◦ Neural Control: Dominated by the autonomic nervous system (ANS), particularly the vagus nerve (parasympathetic), which can directly stimulate parietal cells and G cells. Sympathetic activity usually depresses contractions and secretion.

    ◦ Hormonal Control: Primarily by gastrin. Other GI hormones (secretin, GIP, CCK) may inhibit secretion.

    ◦ Paracrine Control: Histamine (stimulatory) and somatostatin (inhibitory) are key paracrines.

• Stimulants of Acid Secretion:

    ◦ Histamine: The most potent stimulant of gastric acid secretion. Released from ECL cells. Acts on H2 receptors on parietal cells, increasing cAMP.

    ◦ Gastrin: Released from G cells. Its primary action is to stimulate HCl secretion. It does this primarily by causing histamine release from ECL cells, and also by direct action on parietal cells.

    ◦ Acetylcholine (ACh): Released from vagal and enteric neurons. Acts on muscarinic cholinergic receptors on parietal cells, ECL cells, and G cells, leading to increased intracellular Ca2+ and IP3.

    ◦ Potentiation: These three stimulants (histamine, gastrin, ACh) exhibit potentiation, meaning their combined effect is greater than the sum of their individual effects. Histamine potentiates the effects of both gastrin and ACh.

• Phases of Gastric Secretion:

    ◦ 1. Cephalic Phase:

        ▪ Initiated by the sight, smell, taste, chewing, and even thought of food.

        ▪ Mediated entirely by the vagus nerve.

        ▪ Vagus nerve stimulates:

            • Parietal cells directly via ACh release.

            • G cells to release gastrin via Gastrin-Releasing Peptide (GRP) or bombesin (not ACh, explaining why atropine does not block vagally-mediated gastrin release).

        ▪ Accounts for approximately 30% of the total acid response to a meal.

    ◦ 2. Gastric Phase:

        ▪ Begins when food enters the stomach.

        ▪ Accounts for at least 50% of the acid response.

        ▪ Stimuli:

            • Distention of the stomach wall: Activates mechanoreceptors, initiating both long vagovagal reflexes (afferent and efferent signals via vagus nerve) and short intramural reflexes. These are primarily cholinergic and stimulate both parietal cells and G cells.

            • Chemical stimulation by digested protein products (peptides and amino acids) in the lumen of the stomach: Directly stimulate G cells to release gastrin. Aromatic amino acids are most potent.

        ▪ Rise in pH (due to food buffering existing acid) permits gastrin release to be effective, as gastrin release is inhibited below pH 3.

    ◦ 3. Intestinal Phase:

        ▪ Begins when chyme enters the duodenum.

        ▪ Accounts for a small portion (approximately 5%) of the acid response.

        ▪ Primarily involves inhibition of gastric acid secretion and emptying, but absorbed amino acids can cause some stimulation.

• Inhibition of Acid Secretion:

    ◦ Low Luminal pH: The most important inhibitory mechanism. As gastric contents become acidic (pH below 3), gastrin release is inhibited.

    ◦ Somatostatin: Released from D cells (in both antrum and oxyntic gland area) by low intragastric pH. It acts as a paracrine to:

        ▪ Directly inhibit parietal cells.

        ▪ Inhibit histamine release from ECL cells.

        ▪ Inhibit gastrin release from G cells.

        ▪ Vagal stimulation inhibits somatostatin release.

    ◦ Enterogastrones: Hormones released from duodenal mucosa by acid, fatty acids, or hyperosmotic solutions entering the small intestine. They inhibit both gastric acid secretion and gastric emptying. Examples include:

        ▪ Gastric Inhibitory Peptide (GIP): Released by fatty acids and glucose, inhibits acid secretion, but its physiological significance for acid inhibition is doubtful.

        ▪ Secretin: Released by H+ and fatty acids in the duodenum (when pH drops below 4.5), inhibits gastric acid secretion. Its physiological importance for acid inhibition in humans is debated.

        ▪ Cholecystokinin (CCK): Released by fatty acids and protein digestion products, inhibits gastric emptying. While primarily stimulating pancreatic and gallbladder functions, it can inhibit gastric acid secretion, though its physiological role in this is less clear.

    ◦ Prostaglandins: Inhibit gastric H+ secretion by decreasing cAMP levels, and also maintain the mucosal barrier by stimulating HCO3- secretion.

• Regulation of Pepsinogen Secretion:

    ◦ Stimulated by vagal activation and ACh.

    ◦ Also stimulated by acid in the lumen of the stomach.

    ◦ Gastrin may be a weak pepsigogue in humans, but its primary effect on pepsin is indirect through stimulating acid secretion and the acid-sensitive reflex mechanism. Secretin can also promote pepsinogen secretion, but its physiological role is doubted due to small amounts released normally.

• Trophic Effects:

    ◦ Gastrin is an important regulator of the growth of the oxyntic gland mucosa, and also stimulates growth of the small intestine, colon, and exocrine pancreas.

    ◦ Hypergastrinemia (e.g., in Zollinger-Ellison syndrome) leads to increased parietal cell mass and ECL cell hyperplasia.

    ◦ G-Gly (glycine-extended gastrin) also has trophic effects, working in concert with gastrin to regulate gut development.