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APOASE
AQUEOUS UMORS COMPOSITION
FORMATION AND SECRETION OF AQUEOUS HUMOR
Early in the twentieth century, aqueous humor was regarded as a stagnant
fluid.1 However, this misconception was revoked after a number of experiments
designed to investigate this were carried out, including Seidel's procedure, 2 in which
a cannula connected to a reservoir of indigo carmine dye was inserted into the
anterior chamber of the rabbit eye. The reservoir was raised, thus creating a
pressure of 15 mmHg, and the dye was seen to enter the anterior chamber and
subsequently the episcleral veins. From this, it was concluded that aqueous humor is
continuously formed and drained, and it is to a large extent from this historic work
that the modern study of aqueous humor dynamics has developed.
Other aspects of the anatomy and physiology of aqueous drainage were discovered
subsequently. Boerhaave3 first described the presence of the aqueous veins, and
Ascher4 observed a clear fluid in veins of the episclera and demonstrated by means
of external compression with a glass rod that these veins were interconnected with
veins containing blood. Goldmann5 demonstrated that these vessels contained
aqueous humor by injecting fluorescein intravenously and observing the dye enter
the anterior chamber and subsequently the aqueous veins. Ashton 6 identified an
aqueous vein in a living human eye, and postmortem examination showed that there
was a direct passage between the vessel and Schlemm's canal, using a neoprene
cast. Three physiologic processes are known to contribute to the formation and
chemical composition of the aqueous. These are diffusion, ultrafiltration (and the
related dialysis), and active secretion. The first two are passive and, therefore,
require no active cellular participation. Diffusion of solutes across cell membranes
occurs down a concentration gradient. Substances with high lipid solubility
coefficients that can easily penetrate biological membranes move readily in this way.
Ultrafiltration is the term used to describe the bulk flow of blood plasma across the
fenestrated ciliary capillary endothelia, into the ciliary stroma, which can be
increased by augmentation of the hydrostatic driving force. This process is
responsible for the formation of the reservoir of the plasma ultrafiltrate in the
stroma, from which the posterior chamber aqueous is derived, via active secretion
across the ciliary epithelium. Active secretion requires energy, normally provided via
the hydrolysis of adenosine triphosphate (ATP). The energy is used to secrete
substances against a concentration gradient.
Of these three processes, active secretion is believed to contribute the most to the
chemical composition and volume of the posterior chamber aqueous.
DIFFUSION
Diffusion arises from the fact that the molecules in a fluid are in constant, random
motion. The magnitude and rate of motion vary directly with the temperature. If the
molecules in a liquid or gas are not evenly distributed, then simply by the laws of
statistical probability the molecules will eventually reach a state of equilibrium
whereby they are redistributed equally. For example, if there is initially a cloud of
smoke particles on the right side of a closed room without air currents, more
particles will move from the right side to the left, than from left to right. This process
will continue until there is a relatively even distribution throughout the room, at
which time the number of particles going from right to left at any moment will be
equal to the number moving in the opposite direction.
A similar process occurs in single solutions and in situations in which two solutions
are separated by a membrane, as long as the membrane is permeable to at least
some of the constituents of the solution (semipermeable membrane). Most capillary
1
walls are permeable to water, dissolved gases, and many small molecules and ions.
In a stagnant system, substances of higher concentration on one side of a
semipermeable membrane show a net movement to the side of lower concentration
until the concentrations are equal on both sides. When equilibrium is reached,
movement across the membrane still occurs, but the number of particles going in
one direction equals the number going the other way, thus yielding
no net movement.
It should be noted that water (or another solvent) participates in this process. Net
movement of water is usually in the opposite direction of solute movement, since a
higher concentration of solute means, in effect, a lower concentration of solvent.
Fick's law describes quantitatively the net movement of a substance across a
semipermeable membrane where only diffusion is occurring:
The less permeable the membrane to the solute or solvent, the lower the
temperature, and the more viscous the fluid medium, then the longer will be the time
required for equilibration. Therefore, diffusion tends to occur more rapidly through
extracellular fluids than across cells. It should also be remembered that conditions
for diffusion are markedly altered in a dynamic system such as the ciliary processes,
in which blood is flowing rapidly, aqueous humor is constantly being formed and
carried away, and other processes occur, such as those described below.
DIALYSIS AND ULTRAFILTRATION
In most biological solutions, there exists a combination of salts, sugars, proteins, and
other large molecules. Most biological membranes are permeable to water, salt, and
some small organic molecules. However, these membranes are relatively
impermeable to larger molecules, such as proteins.
If a solution of protein and salt is separated from either water or a less concentrated
salt solution by a membrane permeable to the salt and water but not to the protein,
then there will be a net movement of water to the protein side by diffusion, and a
movement of salt away from the protein side. The protein, of course, cannot move
across the membrane. This process is called dialysis (Fig. 1) and is utilized, for
example, for removing unwanted salts and other toxic substances from the blood,
using the peritoneum as the membrane (peritoneal dialysis), or by using a synthetic
membrane such as that found in a dialysis machine (artificial kidney).
Fig. 1. Dialysis. The presence of protein molecules (large circles) induces a net
movement of water (small dots) across the semipermeable membrane to the protein
side. There is also a net movement of salt molecules (broken circles) away from the
protein side. With the exception of protein, movement of all molecules occurs in both
directions, but net movement is in the direction as indicated by the solid
arrows. (Courtesy of RL Stamper, MD)
By the addition of a hydrostatic pressure on the protein side of the system, the
exchange of salt and water can be accelerated. This process is called ultrafiltration
and differs from dialysis only because the hydrostatic pressure changes the rate of
movement of ions and slightly changes their final respective concentrations. The
fluid formed by the process of dialysis is called a dialysate, and that formed by
ultrafiltration is called an ultrafiltrate. Ultrafiltration is the process that occurs across
2
capillary walls due to the higher pressure and higher protein concentration in the
plasma as compared with the extracellular space (Fig. 2).
Fig. 2. Ultrafiltration. This process is similar to dialysis, but with the addition of a
hydrostatic pressure that increases the rate of net movement of water and salt
molecules across the semipermeable membrane. The final equilibrium
concentrations on either side of the membrane are the same as in dialysis. The
hydrostatic pressure merely increases the rate at which equilibrium is
achieved. (Courtesy of RL Stamper, MD)
GIBBS-DONNAN EQUILIBRIUM
The salt does not distribute itself equally on both sides of the membrane. Since the
protein carries an electrical charge (generally an overall negative charge at
physiologic pH), the positive ions in solution tend to be bound to the negatively
charged residues of the protein molecules. Thus, there is an excess of cations such
as Na+ or K+ on the protein side of the membrane.
This unequal distribution is called the Gibbs-Donnan effect, and the quantitative
relationships between the various ions (at least in simple systems) is predictable (Fig.
3). In order to maintain electrical balance, the total positive charges (e.g., number of
Na+ and K+ ions) on one side must equal the total negative charges (e.g., sum of
negative protein charges, Cl- ions, and any other negative ions). Furthermore, it has
been shown that the final equilibrium concentrations of Na + and Cl- on each side of
the membrane are related according to the following equation 7,8:
Fig. 3. Gibbs-Donnan effect. Because protein molecules carry an overall electrical
charge (usually negative) at physiological pH, the distribution of ions at equilibrium
is altered slightly to reflect the tendency of the protein molecules to attract
oppositely charged and repel like-charged ions. Therefore there is a higher
concentration of cations on the protein side and a higher concentration of anions on
the nonprotein side of the system. (Courtesy of RL Stamper, MD)
Thus, if the aqueous humor were like extracellular fluid in most capillary beds of
other parts of the body, we should expect to see a protein-free aqueous solution with
ionic concentrations like those on side 2 of a Gibbs-Donnan ultrafiltrate of plasma.
The Na+ and K+ concentrations should be less than plasma, and the Cl- and HCO 3concentrations should be slightly higher. Further, the actual values of the ratios of
the concentrations of each respective ion in aqueous to plasma would conform to the
values obtained experimentally when plasma is dialysed against its own ultrafiltrate.
In addition, no organic substance should be at higher concentration than in the
3
plasma, since diffusion and ultrafiltration can, at most, only equalize the
concentrations of organic substances. These processes cannot promote an excess
concentration on side 2 of the membrane.
Although aqueous humor resembles a dialysate of plasma in many ways, as will be
seen, the ionic concentrations do not quite fit the Gibbs-Donnan predictions, and
some nonionic substances have higher concentrations in aqueous than in plasma
(Table 1). Such a condition can only occur in the presence of some active metabolic
process.9
TABLE ONE. Aqueous Versus Dialysate
Concentration Ratio
Concentration Ratio
Substance
(aqueous/plasma)
(dialysate/plasma)
Na+
0.96
0.945
K+
0.955
0.96
0.58
0.65
Mg2+
0.78
0.80
Cl-
1.015
1.04
HCO3-
1.26
1.04
H2CO3
1.29
1.00
Glucose
0.86
0.97
Urea
0.87
1.00
Ca
2+
Values are for the rabbit eye. Although the chemical composition of aqueous humor
bears some similarities to a plasma dialysate, the small differences are significant.
These differences can only be accounted for theoretically by an active secretory
mechanism.
(Adapted from Davson H: The Aqueous Humor and the Intraocular Pressure. In:
Physiology of the Eye, 5th ed, pp 395. New York, Pergamon Press, 1990.)
SECRETION
Secretion implies an active process that selectively transports some substances
across the cell membrane. Since energy is consumed, substances can be moved
across a concentration gradient in a direction opposite to that which would be
expected by passive mechanisms alone. One example of this is the ability of the
thyroid gland to accumulate iodide at up to 40 times the circulating plasma
level.10 One would expect the iodide concentration in the plasma and the thyroid
gland to be similar if only diffusion and ultrafiltration were operating. Aqueous humor
exhibits increased ascorbate, lactate, and certain amino acid concentrations as
compared with plasma, as a consequence of active secretion.
Another way of testing for the presence of an active metabolic process is to apply
specific metabolic inhibitors to the ciliary body and observe the effect on aqueous
secretion. Ultrafiltration of fluid from the plasma to the posterior aqueous has been
suggested to be responsible for approximately 70% of aqueous formation. 11
15
However, the results of experiments where metabolic inhibitors have been used
have shown conclusively that this is not the case. For example, systemic 16 or
intravitreal injection17 of ouabain (an inhibitor of the enzyme sodium-potassium
activated adenosine triphosphatase--Na + /K+ ATPase) results in a decrease of up to
70% in aqueous formation, in a variety of species. The topical administration of
vanadate (also a Na+ /K+ATPase inhibitor) lowers aqueous secretion in rabbits 18,19 and
monkeys.20 If the greatest proportion of aqueous secretion was attributable to
4
ultrafiltration, then this could not occur. In addition, Bill 11 noted that the hydrostatic
and oncotic forces that exist across the ciliary epithelium-posterior aqueous interface
would favor resorption, not secretion, of aqueous humor. The ciliary process stroma
has an oncotic pressure of approximately 14 mmHg, because of its protein content.
Since IOP in the healthy eye is maintained at approximately 15 mmHg, a capillary
hydrostatic pressure of greater than 29 mmHg would be required to drive an
ultrafiltrate. Capillary hydrostatic pressure in the ciliary stroma has been estimated
to be 25 to 33 mmHg and 27 to 28 mmHg. 2It has been calculated14 that a capillary
pressure of greater than 50 mmHg would be necessary to promote ultrafiltration as
the major mechanism for the secretion of aqueous. The values of capillary
hydrostatic pressure in the ciliary processes and a consideration of the hydrostatic
and oncotic forces involved do not favor ultrafiltration as an important mechanism
for aqueous humor secretion. Acetazolamide, and other specific inhibitors of the
enzyme carbonic anhydrase, decrease the formation of aqueous by 40% to 60%. 21
24
A reduction in temperature, which inhibits most active metabolic processes, also
results in a decrease in aqueous formation, to a greater extent than would be
expected if only diffusion were operating.24
Active transport systems usually exhibit a limit beyond which an increase in
substrate concentration produces no further increase in transport. When this limit is
reached, the system is said to be saturated. Thus, the fact that a transport
mechanism for a substance can be saturated provides evidence of an active system.
It has been demonstrated that by increasing the ascorbate concentration in plasma,
a level of plasma ascorbate is reached above which no further increase in aqueous
ascorbate concentration will occur.36 This provides evidence that the ascorbate
transport system in the eye is saturable.
Several membrane active transport systems have been identified in the ciliary
epithelium that are known to pump various substances against a concentration
gradient, including Na+ /K+ ATPase and amino acid membrane transporters (Fig.
4).There are also passive transport proteins specific for HCO 3- and Cl-. Membrane
bound Na+ /K+ ATPase is one important system involved in Na +and K+ transport and is
present mainly along the lateral cellular interdigitations of the nonpigmented ciliary
epithelium.16,26-32 The transmembrane Na+ /K+ transport protein is energized by the
Gibbs free energy of hydrolysis of ATP, mediated by the ATPase enzyme intimately
associated with it in the membrane. The ATP required for this process is derived
predominantly from oxidative metabolism of glucose via the Krebs' citric acid cycle.
It is most likely that Na+ is pumped across the cell membrane and Cl)- is passively
carried with it in order to maintain electrical neutrality, although the relative rate of
transport of Cl- is unclear.33 The Na+ pump induces a potential difference across the
ciliary body, ranging from 6 to 10 mV. Measurements of the potential difference
across the ciliary epithelia indicate that the aqueous is positive with respect to the
stroma. The magnitude of this potential difference is reduced after poisoning with
ouabain.34These data are consistent with the hypothesis that Na + is the primary
mover. Active transport of Cl- is probably small in comparison to that of
Na+ .35 Interspecies differences in the aqueous-plasma ratios of Cl- (e.g., high in
human, low in rabbits) might be explained by the relative proportions of Cl- actively
transported.36 Transepithelial electrical measurements in the isolated rabbit irisciliary body indicate that Na+ /K+ ATPase and HCO3- are required for active ion
transport.37
Fig. 4. Diagram of possible secretory pathways in the ciliary processes. AA, ascorbic
acid; CA, carbonic anhydrase. (Adapted from Wiederholt M, Helbig H, Korbmacher C:
Ion transport across the ciliary epithelium: Lessons from cultured cells and proposed
role of the carbonic anhydrase. In: Carbonic Anhydrase, pp 232244. Basel, VerlagChemie, 1991)
monkeys.64 Further, inhibition of carbonic anhydrase lowers the aqueous Clconcentration in primates and the HCO 3- concentration in rabbits.65,66 The mechanism
bywhich carbonic anhydrase activity is coupled to Na + and HCO3- movement into the
posterior chamber is still subject to much study. However, it is now known that the
primary reaction, which occurs within the cytosol of the nonpigmented ciliary
epithelial cells, is the proteolysis of water to yield OH- and H + ions (Fig. 5). The
hydroxide ions so formed react with CO 2 catalytically (or noncatalytically when the
enzyme is inhibited) to form HCO 3-, which is passively transported to the aqueous
humor, simultaneously with the active transport of Na+ . The protons liberated from
water pass into the blood circulation where they are buffered by proteins. The
theoretical rates of flow of HCO 3-, based on known constants and some assumptions
regarding cell volume and pH of the secretory region, are shown at the bottom
of Figure 5. The catalytic rate (i.e., when active carbonic anhydrase is present) is 7
mol/min, and the uncatalyzed is 0.07
Fig. 5. Model for HCO3- formation and its linkage to Na+ transport in the ciliary
processes. Observed rates are for monkey. Chemical rate constants (37C) taken
from the work of Maren. (Adapted with permission, from The Annual Review of
Physiology 50:695. Copyright 1988,
by Annual Reviews Inc)A
varying rates, but all are slower than their transit across capillary walls. Generally,
the greater the lipid solubility coefficient of a substance, the greater its ability to
penetrate the blood-aqueous barrier and pass to the posterior aqueous chamber. 8082
In addition, regional differences of permeability in the ciliary body have been
noted. For instance, the epithelia of the anterior portions of the ciliary processes of
the rabbit are less permeable than the epithelia of the pars plana. 78
Substances such as mannitol are used clinically to reduce IOP. They function as
hyperosmotic agents, by exploitation of the fact that they penetrate the bloodaqueous barrier only poorly but are distributed widely within the extracellular spaces
of the body. Water is drawn from cells and the ocular fluids, balancing the high
osmotic pressure induced in the extracellular space via the high concentrations of
mannitol. The resulting loss of water from the eye leads to a reduction in the IOP. The
effect of hyperosmotic agents is most pronounced in eyes exhibiting pathologically
elevated IOP.83
Other examples of hyperosmotic agents include glycerin, urea, isosorbide, and
ethanol. Urea was the first substance to be used for this purpose; however, it will
slowly penetrate the blood-aqueous barrier, and hence the hyperosmotic effect of
urea on the eye is shorter lived than that of mannitol. Ethanol is not used clinically as
it penetrates the eye even more rapidly than urea and in the required doses has
undesirable effects on the sensorium.
Certain antibiotics (e.g. chloramphenicol, cephalothin, and ampicillin) are known to
penetrate the blood-aqueous barrier well, whereas others do so only poorly
(e.g., penicillin, methicillin, erythromycin, and gentamicin).
A similar barrier to the passage of solutes exists in the retinal pigment epithelium,
thus forming a blood-vitreous barrier between the vitreous and the blood capillaries
of the choroid. Blood capillaries with tight junctions in their endothelia form further
physiologic barriers (functionally similar to the blood-brain barrier) in the iris and
retina.
SECONDARY AQUEOUS
The blood-aqueous barrier is fragile and may bedisturbed by a variety of noxious
stimuli. A corneal abrasion, paracentesis (withdrawal of a small volume of aqueous
via a needle inserted into the anterior chamber), 8488 intraocular infection, uveal
inflammation, intraocular surgery, and certain drugs, applied topically (such as
nitrogen
mustard
or
an
anticholinesterase, e.g.,echothiopate,
diisopropyl
flurophosphate [DFP], demecarium, neostigmine, or physostigmine), or delivered by
intracarotid infusion, such as hyperosmotic agents (causing separation of the ciliary
epithelial layers, opening of the blood-aqueous barrier, and severe, permanent
damage to the pigmented epithelial cells 89), are all capable of breaking down the
blood-aqueous barrier and inducing changes in the aqueous humor composition
(Table 2). Disruption of the blood-aqueous barrier has also been reported in the
contralateral eyes of patients who have had cataract extraction and lens
implantation surgery,90 and after argon laser trabeculoplasty. 91 Severe damage to the
blood-aqueous barrier occurs with cyclodestructive procedures used to treat
advanced glaucoma and is evidenced by the prolonged or chronic presence of flare
(the scattering of light upon slit-lamp examination by increased levels of protein in
the anterior chamber).
TABLE TWO. Factors Interrupting the Blood-Aqueous Barrier
I.
Traumatic
A.
Mechanical
1.
Paracentesis
2.
Corneal abrasion
3.
Blunt trauma
4.
Intraocular surgery
5.
Stroking of the iris
9
II.
B.
Physical
1.
X-ray
2.
Nuclear radiation
C.
Chemical
1.
Alkali
2.
Irritants (e.g., nitrogen mustard)
Pathophysiologic
A.
Vasodilation
1.
Histamine
2.
Sympathectomy
B.
C.
D.
E.
III.
Pharmacologic
A.
Melanocyte-stimulating hormone
B.
Nitrogen mustard
C.
Cholinergic drugs, especially cholinesterase inhibitors
D.
Plasma hyperosmolality
Rabbit
Total
protein
0.013
7.5
0.050
5.6
Globulin
0.003
2.5
0.025
2.5
Albumin
0.010
0.025
3.1
(g/100
(Adapted from Davson H: The Eye. In: Vegetative Physiology and Biochemistry,Vol 1,
2nd ed, New York, Academic Press, 1969; and Duke-Elder S: The Aqueous Humour.
The Physiology of the Eye and of Vision, Vol 4, pp 104200. In Duke-Elder S (ed):
System of Ophthalmology. St. Louis, CV Mosby, 1968)
There are also trace quantities of several components of the fibrinolytic and
coagulation system present in the aqueous, with the exception of plasminogen and
plasminogen proactivator, which are present at more significant concentration. Only
11
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17
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