DM Lecture 24-Saliva and Gastric Secretions

During acid secretion, gastric juice becomes high in H+, K+, and Cl-. This results in an acidic gastric juice.

The main stimuli that regulate gastric acid secretion are distension of the stomach by food and digestion of protein.

The total fluid input into the digestive system daily is 9.0 L, which includes 2.0 L from food and drink, 1.5 L from saliva, 0.5 L from bile, 2.0 L from gastric secretions, 1.5 L from pancreatic secretions, and 1.5 L from intestinal secretions.

Approximately 99% of luminal content is reabsorbed in the digestive system.

The regulation of digestive secretions is both neural and hormonal.

Saliva is composed of 99% water and 1% salts, enzymes (such as amylase and lipase), and mucins. It is also hypotonic.

The primary functions of saliva include:

1. Protection of oral tissues
2. Taste sensation
3. Lubrication and assistance in articulation
4. Digestion of food.

The control of salivation is mediated almost entirely by the nervous system, with both Sympathetic and Parasympathetic systems stimulating secretion.

The initial saliva produced by the acinus is isotonic and contains Na+, K+, Cl-, and HCO3-.

At low flow rates (basal), there is sufficient contact time for reabsorption of Na+ and Cl- and secretion of K+ and HCO3-, resulting in hypotonic saliva. At high flow rates (stimulated), saliva becomes more similar to acinar secretions.

During saliva modification, the ducts absorb Na+ and Cl- and secrete K+ and HCO3-.

Acinar cells secrete digestive enzymes, mucin, electrolytes, and water (isotonic NaCl).

Chloride (Cl-) is co-transported with sodium (Na+) into the cell basolaterally and then diffuses down its gradient into the lumen apically.

The extent of modification in acinar secretion depends on the flow rate of the secreted fluid.

Ductal cells are tight, exhibiting low water permeability, which allows for the modification of acinar secretion by actively transporting electrolytes. Specifically, they actively secrete K+ and HCO3-, while reabsorbing Na+ and Cl- through various transport mechanisms.

The Na-K ATPase located on the basolateral membrane of ductal cells drives the active reabsorption of Na+ and facilitates the secretion of K+. This mechanism is crucial for maintaining the electrolyte balance in the ductal system.

The anionic exchanger in ductal cells reabsorbs Cl- and actively secretes HCO3- via a Cl-/HCO3- exchange mechanism. This process is essential for modifying the ionic composition of the secretion as it passes through the duct.

As salivary flow rate increases, the concentration of Na+ in saliva starts low, increases rapidly, and eventually plateaus at around 100 mEq/L.

With increasing salivary flow rate, K+ secretion decreases, starting from around 20 mEq/L and declining as flow rate increases.

The concentration of HCO3- increases with salivary flow rate, but not as significantly as Na+, leveling off at around 60 mEq/L.

Factors that stimulate the salivary nucleus include:

1. Conditioned reflexes
2. Smell
3. Taste
4. Nausea

Inhibitory factors affecting the salivary nucleus include:

1. Sleep
2. Fear
3. Fatigue
4. Dehydration

The sympathetic pathway influences saliva production by:

• Originating from the superior cervical ganglion
• Releasing norepinephrine (NE) via beta receptors (β)
• Activating Calcium and cyclic AMP pathways, leading to increased secretion and vasodilation in the salivary gland.

The primary mechanisms of control for salivary secretion involve:

1. Parasympathetic stimulation:

   • Produces a secretion rich in electrolytes and salivary amylase (enzyme).

2. Sympathetic stimulation:

   • Produces a secretion rich in mucus.

3. Neurotransmitters involved:

   • Acetylcholine (Ach), Norepinephrine (NE), Vasoactive Intestinal Peptide (VIP), and Substance P.

In the resting state, salivary secretion is low at 30 ml/hr, with the submandibular glands contributing approximately 2/3 of the resting saliva. In contrast, stimulated glands can secrete up to 400 ml/hr, primarily from the parotid gland.

The parasympathetic component of the autonomic nervous system is more predominant in regulating salivary secretion compared to the sympathetic component.

Parietal cells secrete gastric acid (HCl) and intrinsic factor.

• Gastric acid (HCl):

  • Stimulus for release: Acetylcholine, gastrin, histamine
  • Function: Activates pepsin; kills bacteria

• Intrinsic factor:

  • Stimulus for release: Acetylcholine, gastrin, histamine
  • Function: Complexes with vitamin B12 to permit absorption

D cells secrete somatostatin in response to acid in the stomach. The function of somatostatin is to inhibit gastric acid secretion, helping to regulate the acidity in the stomach.

Mucous neck cells secrete mucus and bicarbonate.

• Mucus:

  • Stimulus for release: Tonic secretion; with irritation of mucosa
  • Function: Physical barrier between lumen and epithelium

• Bicarbonate:

  • Secreted with mucus
  • Function: Buffers gastric acid to prevent damage to epithelium

Pernicious anemia is a type of megaloblastic anemia caused by autoimmune destruction of gastric parietal cells, leading to vitamin B12 deficiency.

Gastric parietal cell damage leads to:

1. Decreased intrinsic factor (IF), essential for vitamin B12 absorption.
2. Decreased gastric acid secretion (achlorhydria).

In pernicious anemia, vitamin B12 binds to intrinsic factor in the stomach, but due to the lack of intrinsic factor, vitamin B12 malabsorption occurs, leading to deficiency and impaired DNA synthesis.

The secretion of gastric acid varies during each GI event:

1. Cephalic Phase: Triggered by the sight, smell, or thought of food, leading to increased gastric secretion.
2. Gastric Phase: Occurs when food enters the stomach, further stimulating acid secretion through distension and chemical signals.
3. Intestinal Phase: Involves the release of hormones and feedback mechanisms that can either stimulate or inhibit gastric secretion based on the presence of food in the intestine.

The cellular mechanism of H+ secretion involves:

1. Parietal Cells: Located in the gastric mucosa, these cells are responsible for secreting H+ ions.
2. Proton Pump: The H+/K+ ATPase pump exchanges potassium ions for hydrogen ions, actively transporting H+ into the gastric lumen.
3. Regulatory Factors: Various factors, including gastrin, histamine, and acetylcholine, stimulate the proton pump, increasing H+ secretion during digestion.

As the secretory rate increases:

• The concentration of NaCl decreases.
• The concentration of HCl increases.

The concentrations of ions in oxyntic fluid vs non-oxyntic fluid are as follows:

The differences in gastric juice composition suggest:

• Oxyntic fluid is more acidic (higher H+ concentration), which is crucial for digestion and pathogen defense.
• Non-oxyntic fluid has higher concentrations of Na+ and HCO3-, indicating a role in buffering and maintaining pH balance in the stomach.

Carbonic anhydrase catalyzes the reaction:

CO2 + H2O → H+ + HCO3-

This reaction is crucial for producing hydrogen ions (H+) necessary for gastric acid secretion.

The three stimulants for parietal cells are:

1. Acetylcholine (ACh)
2. Gastrin
3. Histamine

These stimulants enhance the secretion of gastric acid.

The alkaline tide refers to the increase in venous blood pH following gastric acid secretion. This occurs due to the absorption of bicarbonate (HCO3-) into the bloodstream in exchange for chloride ions (Cl-), leading to a temporary rise in blood pH.

The overall effect of gastric acid secretion is that H+ enters the stomach lumen while HCO3- enters the venous blood, causing the pH of venous blood to rise, leading to an alkaline tide.

The production of gastric acid secretion is initiated by the stimulation of parietal cells.

• Stimuli: Thought of food, smell, taste, chewing, and swallowing
• Pathway: Vagus nerve to Parietal cells and G cells
• Stimulus to Parietal Cell: Ach and Gastrin (from G cells)

• Stimulus: Stomach distension by food
• Pathway: Local ENS reflexes and vagovagal reflexes to Parietal cells and G cells
• Stimulus to Parietal Cell: Ach and Gastrin

• Stimulus: Protein digestion products in duodenum and distension
• Pathway: Amino acids in blood stimulate intestinal endocrine cells
• Stimulus to Parietal Cell: Amino acids and Entero-oxyntin

The cephalic phase is initiated by food stimuli such as sight, smell, and taste, which activate the vagal nerve and lead to increased acid production.

D cells release somatostatin, which normally inhibits gastrin secretion. During the cephalic phase, the inhibition of somatostatin is necessary to allow for increased gastrin levels and subsequent acid production.

The vagus nerve stimulates parietal cells to secrete HCl and G cells to release gastrin, which together enhance acid production in response to food stimuli.

The most important stimulus for gastric acid secretion is the direct release of acetylcholine (Ach) by nerve terminals on oxyntic cells.

Post-ganglionic vagal efferents release Gastrin Releasing Peptide (GRP) as a neurotransmitter, which stimulates gastrin secretion into the blood.

Somatostatin normally inhibits the release of gastrin via a paracrine mechanism. Cholinergic vagal efferents inhibit somatostatin secretion to allow gastrin release.

The gastric phase of acid production is initiated when food enters the stomach, which leads to a series of physiological responses.

When food enters the stomach, it neutralizes gastric acid, causing the pH to increase to around 6.

During the gastric phase, the restoration of gastrin secretion occurs, which subsequently increases acid production in the stomach.

The process begins with distension of the stomach due to food intake, which stimulates afferent signals.

ACh stimulates G cells to increase the production of gastrin, which in turn leads to an increase in acid secretion in the stomach.

The response involves long loop vagal reflexes and short enteric nervous system (ENS) reflexes that are triggered by the distension of the stomach.

The contributions to acid secretion in the stomach are as follows:

ACh, Gastrin, and Histamine stimulate acid secretion through the following mechanisms:

• ACh: Released from postganglionic cholinergic muscarinic nerves, it stimulates parietal cells directly.
• Gastrin: Secreted into the blood, it stimulates ECL cells, which in turn release Histamine.
• Histamine: Released from ECL cells, it further stimulates parietal cells to secrete acid.

The gastric phase is significant because it contributes the most (50%) to acid secretion. This phase is primarily triggered by the presence of food in the stomach, which stimulates the release of Gastrin and enhances the secretion of acid from parietal cells, facilitating digestion.

Local ENS reflexes and vagovagal reflex contribute to gastric acid secretion by leading to the release of acetylcholine and gastrin, which stimulate the ECL cells to produce histamine.

Histamine, produced by ECL cells, along with acetylcholine and gastrin, stimulates the parietal cells to secrete hydrochloric acid (H), which is essential for gastric acid secretion.

The cephalic phase accounts for approximately 30% of gastric secretion before food enters the stomach. It is triggered by neurogenic stimuli from the cerebral cortex and appetite centers, activating the vagus nerves, which release ACh to stimulate parietal cell H+ secretion and cause histamine release from ECL cells. Additionally, it promotes gastrin release from antral G cells and inhibits somatostatin production from antral D cells.

The gastric phase is responsible for 50-60% of total gastric secretion. It is initiated by food entering the stomach, which activates gastric acid secretion through mechanical stretch and the presence of partially digested proteins. This phase involves a vagovagal reflex and local enteric nervous system pathways, leading to gastrin release from antral G cells.

The intestinal phase contributes 5-10% of total gastric secretion. It is triggered by partially digested peptides and amino acids in the proximal small intestine, which activate duodenal G cells to produce gastrin. Additionally, distension of the small intestine stimulates acid secretion, likely through the release of the hormone entero-oxyntin from intestinal endocrine cells.

SST (Somatostatin) inhibits the release of gastrin from G cells and also inhibits the ECL cells that produce histamine, thereby reducing gastric acid secretion.

At low gastric pH (pH <3), G cells are inhibited by H+, leading to decreased gastrin secretion. Conversely, D cells produce SST, which further inhibits gastrin release.

Most gastric acid is released about 1 hour after a meal when the meal no longer buffers the stomach contents, causing gastric pH to fall.

1. Secretion of acid is only important during the digestion of food.
2. Excess acid causes mucosal damage.

Somatostatin inhibits gastric acid secretion through:

• Direct pathway: Binds directly to parietal cells.
• Indirect pathways:
  • In the corpus, it inhibits histamine release from ECL cells.
  • In the antrum, it inhibits gastrin release from G cells.

Stomach pH is the most sensitive regulator of acid secretion.

• A falling pH (<3) inhibits G cells directly and stimulates D cells to release somatostatin, which further inhibits gastrin and oxyntic cells.

Enterogastrones are enteric hormones that inhibit gastric acid secretion and decrease gastric motility. They include Secretin, GIP, and CCK, which are stimulated by the presence of acid, glucose, and protein/fat digestive products in the chyme.

CCK (Cholecystokinin) decreases gastric motility, which is part of its role as an enterogastrone in regulating digestive processes.

The release of these enterogastrones is triggered by:

1. Acid in chyme → ↑ Secretin
2. Glucose → ↑ GIP
3. Protein and fat digestive products → ↑ CCK

1. H-K ATPase inhibitors (e.g., Omeprazole, Lanzoprazole)
2. Histamine receptor blockers (H2-blockers) (e.g., Cimetidine, Ranitidine)
3. Muscarinic antagonist (Atropine, not in clinical use)
4. Gastrin receptor blocker (Netazepide, experimental)

H-K ATPase inhibitors block the proton pump in parietal cells, which is responsible for secreting hydrogen ions (H+). This leads to a significant reduction in gastric acid production.

Acetylcholine (ACh), gastrin, and histamine stimulate acid secretion in parietal cells through various signaling pathways:

• ACh activates muscarinic receptors, increasing intracellular calcium (Ca++).
• Gastrin binds to its receptors on ECL cells, promoting histamine release.
• Histamine binds to H2 receptors on parietal cells, increasing cAMP levels, which enhances H+ secretion.

The Gastric Mucosal Barrier protects against damage from gastric acid by creating a negative potential in the lumen, facilitating H+ secretion, and trapping H+ ions in the lumen, which helps maintain the integrity of the gastric lining.

The barrier facilitates H+ secretion into the lumen by creating a lumen negative potential through the movement of Cl- ions via apical channels, which aids in the trapping of H+ ions and protects the gastric lining.

The effectiveness of the Gastric Mucosal Barrier is contributed by:

1. Cl- ion movement into the lumen via apical channels.
2. Creation of a lumen negative potential.
3. H+ secretion into the lumen.
4. Trapping H+ ions in the lumen to prevent damage to the gastric lining.

The mucus gel neutralization zone helps to neutralize gastric acid in the lumen by trapping HCO3-, which protects the underlying tissues from acid damage.

Tight junctions prevent the back diffusion of H+ ions, thereby protecting the oxyntic cells from high acidity levels in the stomach.

The HCO3- rich zone inactivates pepsinogen and maintains a low concentration of H+ (0.0001mM), which is crucial for protecting the gastric lining from damage.

Mucus forms a mucous gel barrier that prevents H+ ions from diffusing back through it, protecting the epithelial cells of the stomach lining.

HCO3- neutralizes any H+ ions that diffuse back from the lumen, and it also inactivates pepsinogen, preventing pepsin from digesting the gastric epithelial cells.

Prostaglandins stimulate the production of HCO3- by the gastric mucosa, which is essential for maintaining the integrity of the gastric mucosal barrier.

The protective factors include:

1. HCO3
2. Mucus
3. Blood flow
4. Growth factors
5. Cell Renewal
6. Prostaglandins
7. Increased blood flow

The damaging factors include:

1. H+
2. Pepsins
3. Ethanol
4. NSAIDs
5. Bile acids
6. Ischemia
7. Smoking
8. H. Pylori

An imbalance leads to the formation of ulcers, which occur when the digestive effects of acid exceed the ability of the gastric and duodenal mucosa to resist damage.

Prostaglandins stimulate HCO3 and mucous production, increase mucosal blood flow, and modify the local inflammatory reaction to acid.

Zollinger-Ellison syndrome is characterized by a gastrin-secreting tumor (gastrinoma) located in the pancreas or duodenum. This leads to acid hypersecretion, resulting in recurrent ulcers in the duodenum and jejunum.

Common symptoms of Zollinger-Ellison syndrome include:

1. Abdominal pain due to peptic ulcer disease and distal ulcers.
2. Diarrhea resulting from malabsorption.

The secretin stimulation test is significant in Zollinger-Ellison syndrome because it shows that gastrin levels remain elevated after administration of secretin, which normally inhibits gastrin release. This indicates the presence of gastrinoma.

MEN Type 1 is an autosomal dominant disorder caused by genetic mutations.

Zollinger-Ellison syndrome is characterized by gastrin-secreting tumors (gastrinomas) found in the pancreatic islet cells of patients with MEN Type 1. This condition leads to excessive gastric acid production, resulting in recurrent peptic ulcers.