April 25, 2005
Salivary and Gastric Secretion
Ron Lynch, PhD
626-2472
SALIVARY GLANDS
Objectives: Salivary Secretion (1200 ml/day)
1. What are the primary functions of saliva and the basic constituents which
provide these functions.
2. How is salivary secretion regulated:
What are the primary activators of salivary secretion?
What role does blood flow play in elevating secretion of saliva?
I, Functional Anatomy. There are many saliva secreting glands within the oral cavity, however,
three sets of principal glands secrete greater than 99% of all fluid. The largest are the bilateral pair
of Parotid glands. Secretions from the parotids have a high water content (serous secretion) which
generally accounts for 60% of all saliva. The other two primary pairs are Submaxillary glands and
the Sublingual glands.
II. General Glandular Structure
The primary salivary glands resemble grapes on a stem. The bolbus portion is called the acinus, and
fluid moving from the acini of the gland is collected into a series of enlarging ducts. The functional
properties and permeability of the cells in these two regions are quite different. The acinus is very
permeable to water, and acts in filtering water and ionic components from blood. The acinus is
highly vascularized so flow of blood around this region can increase dramatically upon activation.
In contrast to acinar cells, ductal cells are very impermeant to water.
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April 25, 2005
Salivary and Gastric Secretion
Ron Lynch, PhD
626-2472
III. Composition of saliva. The components that confer function to saliva include water, ionic and
organic factors. The primary ionic components contained in saliva include Na+, K+, Cl- and
HCO3- . In addition, small amounts of Ca2+, I-, H2PO4- , F- and SCN- are present. The primary
organic components of saliva include the enzymes -amylase, lysozyme and lingual lipase. Also
present at a relatively high concentration are mucopolysaccharides and glycoproteins (mucus).
IV. Function of Saliva: Saliva performs two specific functions in the oral cavity: Digestive, and
Protective which includes Lubrication.
A. Digestive: -amylase acts to begin starch digestion, and lipase fat digestion. The pH
optima of amylase is 7.0 while that of ligual lipase is 4.0. Thus, amylase is active only
before its environment becomes acidified. Since the proximal stomach stores food with
limited mixing, the interior of a bolus of food can remain non-acidified for a variable
period within the stomach. Depending on the bulk of a meal, amylase can assist in initial
starch breakdown, although in general it's role normally is not significant relative to that
played by the pancreatic and intestinal (brush border) enzymes.
B. Protective: F-, SCN-, immunoglobulin A, lysozyme and lactoferrin all act to kill bacteria
or retard bacterial growth in the mouth; secreted HCO3 buffers pH. The mucus secretion
acts to coat the interior of the mouth to prevent abrasion and to coat the food to aid in
swallowing. Saliva also acts as a solvent and aids in taste sensation.
V.
Mechanism of Secretion: The acinus is the site where secretion of fluid and organic
components takes place in the salivary glands. The acinus produces saliva by filtration of
plasma from blood coupled with Ca2+ activated anion (HCO3- / Cl-) and protein secretion.
A. Filtration: Filtration through acinar cells is primarily passive. Net fluid movement is
accomplished by regulating blood flow to the acinus. Blood flow to the acinus is elevated
in association with secretory stimuli, leading to increased blood pressure around the
acinus. The elevation in interstitial pressure drives filtration through the acinar cells,
thereby elevating net fluid flux into the lumen. The large fluid flux carries ions as well as
some plasma protein into the lumen by solvent drag.
B. Organic components: Specific proteins are produced and secreted from acinar cells upon
activation (e.g., amylase, mucopolysaccharides), while others are simply filtered (IgG).
The mucopolysacchadies are stored within granules which are released when intracellular
Ca2+ concentration increases.
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April 25, 2005
Salivary and Gastric Secretion
Ron Lynch, PhD
626-2472
Ionic components: Bicarbonate secretion is under control of Ca2+. An anion channel in the apical
membrane of acinar cells is more selective for HCO3 than Cl- and is opened by elevated intracellular Ca2+. Thus, when Ca2+ becomes elevated, the Ca2+ activated anion channel resident in the
acinar cell apical membrane opens and HCO3 selectively flows with water into the lumen.
C. Role for Carbonic Anhydrase (CA) in "activated" bicarbonate secretion:
+
A recurrent theme in cells which secrete either H or HCO3- is the presence of the enzyme
carbonic anhydrase. In the presence of CO2 CA forms carbonic acid that dissociates into H
+
+
and HCO 3  . Generally the H and HCO3 are transported in opposite directions. CA recently
has been found in salivary acinar cells, and is important for the increase in cellular HCO3content during active salivation. It appears CA activity is increased by mass action; i.e., during
cell depolarization energy utilization is increased which stimulates mitochondrial respiration.
The subsequent increase in CO2 drives the CA mediated production of carbonic acid; the
dissociated bicarbonate enters the lumen via an apical Ca
+
+
crosses basolateral membranes via Na /H
2+
activated anion channel. H
+
exchange. Inhibition of CA by drugs
(acetozolamide) decreases cytosolic HCO3 levels and increases Cl- in saliva under activated
2+
conditions, because Cl- can move through the Ca activated anion channel when cytosolic
HCO3 levels are not elevated. This accounts for the fact that acetozolamide blocks CA and
salivary HCO3 production without a changing fluid or protein flux.
VI.
Regulation of Secretion:
Since the active components of salivary secretion are
expressed in the acinus, this is where the regulators of salivation act. Sympathetic stimulation
through -adrenergic receptors elevates protein secretion. However, through -adrenergic
receptors on vascular smooth muscle cells, sympathetic stimuli also can elicit vasoconstriction. Since increases in blood flow are required to increase salivary flow rate,
sympathetic stimulation by itself leads to secretion of a very viscus saliva. This is observed in
coincidence with the "fight or flight" and other stressful sympathetic mechanisms. Parasympathetic stimuli on the other hand, activate HCO3- and protein secretion at the level of the
acinar cells, and fluid flux by elevating blood flow via relaxation of vascular smooth muscle.
Acetylcholine activates the acinar cell while Substance P appears to be the vasodilatory
transmitter thereby acting by elevating blood flow. No hormones have significant influence
on salivary secretion rate, or composition.
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April 25, 2005
Salivary and Gastric Secretion
Ron Lynch, PhD
626-2472
GASTRIC SECRETIONS: (2000 ml/day)
Objectives:
1. Determine the components of gastric secretions, the cells from which
the specific components arise, and the function of each component.
2. Identify the basic constituents that provide the digestive and protective
functions of gastric secretions.
3. What is the basic cellular mechanisms by which HCl is produced and
secreted from the oxyntic cell?
a. What are the key transport and enzymatic processes required for
activated HCl secretion, and where in the cell are they located?
4. Determine how HCl secretion is regulated at the cellular level:
a. What are the primary secretagogues for activating HCl
secretion?
b. What are the second messenger pathways through which the
activators of HCl secretion operate?
I.
Functional Anatomy - The secretory glands in the stomach can be delineated into 3 regional
divisions. Cardiac glands are mucus secreting glands found primarily in proximal stomach.
Gastric (or Oxyntic) glands are located in the central 3/4 of the stomach. These glands
penetrate into the submucosa and secrete primarily hydrochloric acid (HCl), and Pepsinogen.
There are also mucus secreting cells at the regions of the gland nearest the stomach lining. The
third type of gland is smaller in size and located in the terminal Antral region. These Pyloric
glands secrete mucus into stomach and gastrin into the blood.
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April 25, 2005
Salivary and Gastric Secretion
Ron Lynch, PhD
626-2472
II. Cellular Properties and Functions of the Oxyntic Glands.
Gastric Lumen
Gastric
Pits
Columnar
Epithelium
Lamina
Propria
Mucosa
Gastric
Gland
SubMucosa
Lymph
Node
Lymphatics
Mucularis
Serosa
Gastric or Oxyntic glands are protrusions into the lining of the stomach. In the non-activated state,
the density of the glands make the surface of the stomach look demarcated by cracks or pits. Lining
the opening of the gastric pits near the epithelial surface are mucus and HCO3- secreting cells. The
cells within the oxyntic gland and stomach epithelia are connected by tight junctions making them
highly impermeant. This feature together with secretion of mucus and HCO3- provide the stomach
surface with a protective barrier. Anything that alters the coupling between cells causes defects in
the barrier and subsequent ulceration in the prescence of HCl. Similar cells are found lining cardiac
and pyloric glands. Further down the gastric pits are multi-potential cells (mucus neck cells) which
can migrate to the surface, or differentiate into secretory cells that remain within the gland. There
are two types of secretory cells within the gland. These are the oxyntic (or parietal) cells and the
peptic (or chief) cells. Parietal cells secrete HCl and the vitamin B12 binding protein intrinsic
factor. Intrinsic factor is a glycoprotein which is essential for normal absorption of Vitamin B12 in
the intestine. Peptic cells secrete pepsinogen. Pepsin is a proteolytic enzyme secreted in an inactive
form (pepsinogen) and converted by stomach acidity or by autocatalysis to pepsin. Pepsin expresses
maximal activity at pH < 5.0.
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April 25, 2005
Salivary and Gastric Secretion
Ron Lynch, PhD
626-2472
Basal (non-activated) secretion of HCl is relatively low, but significant. Resting stomach pH can
be as low as 2.0. With maximal stimulation, lumenal pH can reach 1.0 or lower. Thus, the
gradient between cell (pH 7.0) and lumen can be as high as 106. The HCl secreted by oxyntic
cells produces an acid environment in the stomach lumen which helps to kill bacteria and to
activate pepsin. However, the primary digestive role for HCl is to solubilize connective tissue
and dissociate ionic bonds between molecules.
III. Mechanism of Hydrochloric Acid Secretion: Oxyntic cell.
Upon activation of the oxyntic cell, mitochondial metabolism is elevated producing CO2.
CO2 produced by cellular metabolism or entering the cell from the blood reacts with H2O
under the influence of carbonic anhydrase to form carbonic acid which then dissociates into
+
+
H+ and HCO3- . H+ are actively secreted into the lumen in exchange for K+ by the H -K
ATPase while the HCO3- diffuses out of the cell into the blood in exchange for C1- via a
HCO3-/Cl- antiporter. The release of HCO3 to the blood raises venous pH. The rise in venous
pH that accompanies luminal H+ secretion is called the "alkaline tide".
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April 25, 2005
Salivary and Gastric Secretion
Ron Lynch, PhD
626-2472
+
Electroneutality must be maintained as the cell secretes H to the lumen and HCO3- to the blood.
+
During activation, Cl-/HCO3- antiport and Na /Cl- cotransport in the basolateral membrane assure
+
that cell Cl- levels are elevated. C1- is then secreted into the lumen through co-transport with K .
+
+
+
+
Since the H ATPase exchanges H for K , and equi-molar Cl- is secreted with K , there is no net
+
K flux under activated (active secretion) conditions rather net HCl secretion.
Regulation of HCl Secretion: HCl from oxyntic cells is increased by Ach (parasympathetic),
gastrin (endocrine) and histamine (paracine). Gastrin release from G cells is stimulated by
gastrin releasing peptide (neural; submucosal plexus), and inhibited by somatostatin (paracrine).
Mechanisms whereby secretagogues elicit acid secretion from the parietal cells. The actions of blocking agents
are shown: atropine (A), cimetidine (CM), lanthanum ion (La2+), and protaglandin E2 (PGE2). (from Johnson
LR. editor: Physiology of the gastrointestinal tract, New York, 1981, Raven Press.)
Nerves whose cell bodies originate in the submucosal plexus release Ach that opens voltage
+
dependent Ca2 channels after binding to oxyntic cells. Blockers of the voltage dependent
channels block the neuronal mediated response. Gastrin is the most potent stimulus for HCl
secretion. Gastrin release into the blood from G cells (in pyloric glands) is stimulated by
peptides in the lumen and by the release of gastrin releasing peptide (GRP) from nerves whose
cell bodies reside in the sub-mucosal plexus. Gastrin from the blood binds to specific receptors
2+
2+
on the oxyntic cells, and leads to an elevation of cell Ca by releasing Ca from intracellular stores.
Histamine also can stimulate HCl secretion, but it is not known if the secretion of histamine itself is
regulated. The histamine containing cells (also known as Enterochromaffin cells, ECL) are located
in the gastric pits, and appear to secrete continuously. The released histamine diffuses through the
extracellular space binding to specific receptors (H2 subtype) on the oxyntic cell elevating cAMP
concentration, which weakly activates the oxyntic cell. Histimine likely drives basal HCl secretion.
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April 25, 2005
V.
Salivary and Gastric Secretion
Ron Lynch, PhD
626-2472
Major Mechanisms for Stimulation of Gastric Acid Secretion: Secretion from all
gastro-intestinal glands can be delineated into 3 phases: Cephalic, Gastric and
Intestinal. The cephalic phase is initiated by central anticipatory signals like smell of
food or time of day. The Gastric phase begins as food reaches the stomach eliciting
distension and elevating the luminal pH by buffering its contents. Strong stimulation
of HCl secretion is initiated by stomach distension which elicits local reflexes
(release of Ach on oxyntic cells; GRP on G-cells). Also, buffering of lumenal pH
inhibits somatostatin release removing a break on gastrin secretion, and nutrients in
the stomach lumen (amino acids) directly stimulate G cells to secrete. The Intestinal
phase is driven by mild activation of stretch, osmo- and nutrient receptors in the
intestinal lumen though again these stimuli are minor relative to the Gastric stimuli.
For Cephalic stimuli, reflexes of central origin elicit initial responses coordinated
within the neural plexi, but without local stimuli (gastric distension, lumenal amino
acids), the secretory response is relatively weak amounting to usually 10% of the
maximal HCl output. Conversely, gastric signals are generated within the canal. For
example, amino acids act directly on the G-cell and local pH buffering reduces G-cell
inhibition, thereby providing strong signals for gastrin release with gastrin being the
strongest activator of HCl secretion. Moreover, local distension in the stomach
provides rapid and intense input to the neural plexi leading to strong activation of
oxyntic cell secretion (release of Ach), as well as coordinated increases in stomach
motility.
Major Mechanisms for Stimulation of Gastric Acid Secretion
Phase
Stimulus
Pathway
Cephalic
Chewing, swallowing, etc.
Vagus nerve to Plexi
1. Parietal cells
2. G cells
Local and vagovagal reflexes to
1. Parietal cells
2. G cells
1. Intestinal endocrine cells
Gastric
Gastric distension
Intestinal
Protein digestion products in duodenum:
weak stimulants
InterDigestive
Basal Release
ECL Cells- paracrine
Stimulus to
Parietal Cell
Acetylcholine
Gastrin, Histamine
Acetylcholine
Gastrin
Enterooxyntin
Histamine
Modified from Johnson LR: Gastrointestinal physiology, ed 3, St. Louis, 1985, The CV Mosby Co. from MI Grossman.
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VI.
Salivary and Gastric Secretion
Ron Lynch, PhD
626-2472
Inhibition of Gastric Secretion: Signals originating from duodenum. There are several primary
enteric mechanisms which can act to inhibit gastric secretion. These mechanisms are most effective
when chyme pH < 3. Acid (pH < 5.0), stretch and protein products in the intestine generate short
and long enterogastric reflexes which inhibit acid production in the stomach, and also can inhibit
gastrin release leading to reduced acid secretion. In addition, pH < 2.0 in the stomach promotes
somatostatin release, which decreases gastrin secretion. It is clear that the level of acid in the
duodenum and pyloris are the primary signals for feedback regulation of oxyntic secretion.
However, several other parameters may also contribute to the feedback. For example, hyperosmotic
solutions in the duodenum will lower acid secretion apparently by releasing a hormone from the
intestinal wall that feeds back to the oxyntic cells (i.e., the candidate hormone: enterogastrone). The
other signals are identical to those previously discussed for the regulation of gastric emptying.
Body
ECL
Antrum
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