The major constituents of saliva are water, electrolytes, and a few enzymes. The unique properties of this GI juice are (1) its large volume relative to the mass of glands that secrete saliva, (2) its low osmolality, (3) its high K+ concen- tration, and (4) the specific organic materials it contains.
Inorganic Composition
Compared with other secretory organs of the GI tract, the salivary glands elaborate a remarkably large volume of juice per gram (g) of tissue. Thus, for example, an entire pancreas may reach a maximal rate of secretion of 1 mil- liliter (mL)/minute, whereas at the highest rates of secre- tion in some animals, a tiny submaxillary gland can secrete 1 mL/g/minute, a 50-fold higher rate. In humans, the sali- vary glands secrete at rates severalfold higher than other GI organs per unit weight of tissue.
The osmolality of saliva is significantly lower than that of plasma at all but the highest rates of secretion, when the saliva becomes isotonic with plasma. As the secretory rate of the salivon increases, the osmolality of its saliva also increases.
The concentrations of electrolytes in saliva vary with the rate of secretion (Fig. 7.3). The K+ concentration of saliva is 2 to 30 times that of the plasma, depending on the rate of secretion, the nature of the stimulus, the plasma K+ concentration, and the level of mineralocorticoids in the circulation. Saliva has the highest K+ concentration of any digestive juice; maximal concentration values approach those within cells. These remarkable levels of salivary K+ imply the existence of an energy-dependent transport mechanism within the salivon. In most species the concen- tration of Na+ in saliva is always less than that in plasma, and, as the secretory rate increases, the Na+ concentration also increases. In general, Cl− concentrations parallel those of Na+. These findings suggest that Na+ and Cl− are secreted and then reabsorbed as the saliva passes through the ducts.
The concentration of HCO3−in saliva is higher than that in plasma, except at low flow rates. This also accounts for the changes in the pH of saliva. At basal rates of flow the pH is slightly acidic but rapidly rises to approximately 8 as flow is stimulated. The relationships between ion concentrations and flow rates (shown in Fig. 7.3) vary somewhat, depend- ing on the stimulus.
The relationships shown in Fig. 7.3 are explained by two basic types of studies that indicate how the final saliva is produced. First, fluid collected by micropuncture of the intercalated ducts contains Na+, K+, Cl−, and HCO3−in
55 CHAPTER 7 Salivary Secretion
Medulla
Facial nerve
Inferior salivatory nucleus
Glossopharyngeal
nerve Parasympathetic
innervation Tympanic
plexus
Submandibular ganglion
Sublingual gland
Parotid gland Submandibular
gland
Arterial blood
supply Sympathetic
innervation
Thoracic spinal nerves T1
T3 Sympathetic
chain Superior
cervical ganglion
Auriculotemporal branch
of trigeminal nerve
Jacobson’s nerve
Oticganglion
Fig. 7.2 Autonomic nervous distribution to the major salivary glands.
56 CHAPTER 7 Salivary Secretion
concentrations approximately equal to their plasma con- centrations. This fluid also is isotonic to plasma. Second, if one perfuses a salivary gland duct with fluid containing ions in concentrations similar to those of plasma, Na+ and Cl− concentrations are decreased and K+ and HCO3− con- centrations are increased when the fluid is collected at the duct opening. The fluid also becomes hypotonic, and the longer the fluid remains in the duct (i.e., the slower the rate of perfusion), the greater are the changes. These data indi- cate, first, that the acini secrete a fluid similar to plasma in its concentration of ions; and second, that as the fluid moves down the duct, Na+ and Cl− are reabsorbed and K+ and HCO3− are secreted into the saliva. The higher the flow of saliva, the less time is available for modification, and the final saliva more closely resembles plasma in its ionic
makeup (see Fig. 7.3). At low flow rates K+ increases con- siderably, and Na+ and Cl− decrease. Because most salivary agonists stimulate HCO3−secretion, the HCO3−concentra- tion remains relatively high, even at high rates of secretion.
Some K+ and HCO3−are reabsorbed in exchange for Na+ and Cl−, but much more Na+ and Cl− leave the duct, thus causing the saliva to become hypotonic. Because the duct epithelium is relatively impermeable to water, the final product remains hypotonic. These processes are depicted in Fig. 7.4.
Current evidence indicates that Cl− is the primary ion that is actively secreted by the acinar cells (Fig. 7.5).
No evidence exists for direct active secretion of Na+. The secretory mechanism for Cl− is inhibited by ouabain, a finding indicating that it depends on the Na+/K+ pump 20
60 100 140
Concentration mEq/L
Saliva
10 20 30 40
Plasma Na
Cl
K HCO3
Flow mL/min
Na
Cl K HCO3
Fig. 7.3 Concentrations of major ions in the saliva as a function of the rate of salivary secretion. Values in plasma are shown for comparison. Cl−, Chloride; HCO3–, bicarbonate; K+, potassium; Na+, sodium.
Cl
HCO3
Na
K H2O HCO3
K
Cl Na
H2O
Fig. 7.4 Movements of ions and water (H2O) in the acinus and duct of the salivon. Cl−, Chloride; HCO3–, bicarbonate; K+, potassium; Na+, sodium.
57 CHAPTER 7 Salivary Secretion
in the basolateral membrane. The active pumping of Na+ out of the cell creates a diffusion gradient for Na+ to enter across the basolateral membrane. Two main ion transport pathways exploit this Na+ gradient to accumu- late Cl− above its equilibrium potential. In the first (see Fig. 7.5, cell 1), 2Cl− are cotransported with Na+ and K+ into the cell to preserve electrical neutrality. This process increases the electrochemical potential of Cl− within the cell, and Cl− diffuses down this gradient into the lumen via an electrogenic ion channel that may also allow HCO3−to enter the lumen. Inhibition of the Na+/K+/2Cl− cotrans- porter decreases salivary secretion by 65%. In the second
(see Fig. 7.5, cell 2), Na+ enters in exchange for hydrogen (H+), which alkalinizes the cell promoting the intracellular accumulation of HCO3−, which then is exchanged for Cl−. Removal of HCO3−from the perfusate or inhibition of the Na+/H+ exchanger by amiloride reduces secretion by 30%.
In both cases Na+ moves paracellularly through the tight junctions and into the lumen, thus preserving electroneu- trality; water follows down its osmotic gradient. Evidence indicates that water also moves into the saliva transcellu- larly through the aquaporin 5 apical water channel. There may also be a Ca2+-activated K+ channel in the basolateral membrane. Exodus of K+ increases the electronegativity of
Lumen Acinus
1
2
Blood
K K,
K
K K
H Na
Na Na
Na Na
Na,
Na Cl
Cl
Cl
Cl Cl
Cl Cl
H2O
H2O H2O
H2O
H2O
H2O CO
2
K
HCO3
HCO3
Passive conductance Exchange mechanism Primary active transport
Fig. 7.5 Intracellular mechanisms for the movement of ions in the acinar cells of the salivary glands. Cl−, Chloride; HCO3–, bicarbonate; H2O, water; K+, potassium; Na+, sodium.
58 CHAPTER 7 Salivary Secretion
the cytosol and thereby increases the driving force for the entry of Cl− and HCO3−into the lumen. Agents that stimu- late salivary secretion increase the activity of all these chan- nels and transport processes.
Within the ducts, Na+ and Cl− are actively absorbed, and K+ and HCO3−are actively secreted (Fig. 7.6). These processes are also inhibited by ouabain and depend on the Na+ gradient created by the Na+, K+-adenosine triphos- phatase (ATPase) in the basolateral membrane. The apical membrane contains a Na+ channel, and its movement into the cell supports the electrogenic movement of Cl− into the cell through Cl− channels. The Na/K-ATPase pumps Na+ out while a Cl− channel in the basolateral membrane transports it out of the cell. Cl− reabsorption also occurs via the paracellular pathway. K+ is secreted through apical channels into the saliva. To secrete HCO3−into the lumen, HCO3−must be concentrated within the cell. This occurs via an Na/HCO3− transporter in the basolateral mem- brane, which is driven by the Na+ gradient. HCO3−leaves the cell either through the apical cyclic adenosine mono- phosphate (cAMP)-activated CFTR (cystic fibrosis trans- membrane regulator) Cl− channel or via the Cl−/HCO3− exchanger at the apical membrane. The tight junctions of the ductule epithelium are relatively impermeable to water
compared with those of the acini. The net results are a decrease in Na+ and Cl− concentrations and an increase in K+ and HCO3−concentrations, as well as pH, as the saliva moves down the duct. More ions leave than water (H2O), and the saliva becomes hypotonic. Aldosterone acts at the luminal membrane to increase the absorption of Na+ and the secretion of K+ by increasing the numbers of their channels.
Organic Composition
Some organic materials produced and secreted by the sal- ivary glands are mentioned earlier in the section on the functions of saliva. These materials include the enzymes α-amylase (ptyalin) and lingual lipase, mucus, glycopro- teins, lysozymes, and lactoferrin. Another enzyme pro- duced by salivary glands is kallikrein, which converts a plasma protein into the potent vasodilator bradykinin.
Kallikrein is released when the metabolism of the salivary glands increases; it is responsible in part for increased blood flow to the secreting glands. Saliva also contains the blood group substances A, B, AB, and O.
The synthesis of salivary gland enzymes, their storage, and their release are similar to the same processes in the pancreas (detailed in Chapter 9). The protein concentra- tion of saliva is approximately one tenth the concentration of proteins in the plasma.