There is a constant flow of aqueous humor through the anterior segment of the eye. The aqueous is formed by the ciliary process and flows from the posterior chamber to anterior chamber through the pupil and exits the eye at the angle. The secretion of aqueous humor generates the intraocular pressure required for an optically efficient globe. The flow of aqueous provides nutrition for the avascular ocular tissues that it bathes, the posterior surface of the cornea, trabecular meshwork, crystalline lens and anterior vitreous.The volume of the aqueous in the anterior chamber turns over approximately once every 100 minutes.This constant flow of aqueous replenishes nutrients that have been taken up by the avasculat tissues and carries away their metabolic wastes.The factors that determine the the IOP is given by the Goldmann equation.
Where P0 is the IOP, F is the rate of aqueous humor formation in (l/min, C is the facility of outflow in (l/min/mmHg and Pv is the episcleral venous pressure in mmHg
SITE OF FORMATION OF AQUEOUS HUMOR
The precise location of aqueous humor production appears to be predominantly in the anterior portion of the pars plicata along the tips or crests of the ciliary processes, since this region has been shown to have
a).increased basal and lateral interdigitations, mitochondria and rough endoplasmic reticulum in the non-pigmented ciliary epithelium
b).more numerous fenestrations in the capillary endothelium
c).thinner layer of capillary stroma and
d).an increase in all organelles and gap junctions between pigmented and non-pigmented epithelia
When Sodium fluroscein is administered systemically and the ciliary body is absorbed with a special gonioprism, fluroscein stained aqueous is seen
primarily at the tips of the ciliary process.
The site of active transport is considered to be the non-pigmented epithelial cells, especially in the cell membrane of the lateral interdigitations. Since this area has
a) abundant Na+ K+ activated AT Pase and Carbonic anhydrase
b) higher specific activity for glycolytic enzymes
Blood Aqueous Barrier
The blood aqueous barrier consists of all of the barriers to the movement of substances from the plasma to the aqueous humor.In ciliary body the barrier include: vascular endothelium, basementmembrane, stroma, Pigmented epithelium, Tight junction between nonpigmented epithelial cells. In iris the nonfenestrated iris vessels contribute to blood aqueous barrier. Destabilization of the blood aqueous barrier with leakage of plasma proteins into the anterior chamber has important clinical consequences.
Breakdown of the blood aqueous barrier occurs after paracentesis of the anterior chamber with subsequent leakage of plasma protein into the aqueous. This inflow of plasma like or “plasmoid” aqueous is also called as “Secondary Aqueous”.
MECHANISM OF AQUEOUS HUMOR FORMATION
It is the movement of a substance across a membrane along its concentration gradient. As the aqueous humor passes from the posterior chamber to Schlemm’s canal, it is in contact with the ciliary body, iris, lens, vitreous, cornea and trabecular meshwork. There is sufficient diffusional exchange with the surrounding tissues that the anterior chamber aqueous humor resembles plasma more closely than does the posterior chamber aqueous humor. Aqueous humor provides glucose, amino acids, oxygen and potassium to surrounding tissues and removes carbondioxide, lactate and pyruvate.
It refers to the movement of substances along a pressure gradient that is dialysis under applied pressure. In the case of the ciliary body, fluid movement is favored by the hydrostatic pressure difference between the capillary pressure and IOP and resisted by the difference between the oncotic pressure of plasma and the aqueous humor. The ciliary process stroma has an oncotic pressure of approximately 14 mm of Hg, because of its protein content. If one assumes an intraocular pressure of 15 mm of Hg, a capillary hydrostatic pressure in excess of 29 mm of Hg would be required to drive an ultrafiltrate. Values for capillary hydrostatic pressure in the ciliary process have been estimated to be 27 to 33 mm of Hg. Thus hydrostatic and oncotic forces involved do not favour ultra filtration as an important mechanism of aqueous humor formation.
Active transport (secretion) is an energy dependant process that selectively moves a substance against its electrochemical gradient across a membrane. It is postulated that the majority of aqueous humor formation depends on an ion or ions being actively secreted into the intercellular clefts of the non-pigmented ciliary epithelium beyond the tight junctions. In these confined spaces the ion or ions create sufficient osmotic forces to attract water. By the time the newly secreted fluid reaches he posterior chamber, the osmotic driving force has been nearly dissipated.
A number of investigations postulate that the active transport of the sodium ion is the key process in aqueous humor formation. This theory is supported by the observation that the membrane bound Ouabain-sensitive Na+K+ ATPase (the enzyme that facilitates transport of potassium into and sodium out of the cells). Furthermore, Ouabain inhibition of Na+K+ ATPase decreases aqueous humor formation by 70% to 80%.
Active transport of chloride may also occur, although the magnitude of this transport is small compared with that of Na+. and is affected by concentration of Na+.
Carbonic anhydrase type II (isoenzyme C) is present in the cell membrane and cytoplasm of the non pigmented and pigmented epithelium of the ciliary body. This enzyme catalyses the following reaction.
CO2 + H2O HCO3- + H+
HCO3- thus formed is secreted into the aqueous along with the Cl- ions. The active transport of the sodium, chloride and bicarbonate ions is linked in some unknown fashion.
Cole’s hypothesis of fluid production
A standing gradient osmotic flow system consists of a long narrow channel with a restriction at the apical end (tight junction) solute pumps lines the walls of the channel and solute is continuously and actively transported from the cells into the inter cellular channels. This makes the
channel fluid hyperosmotic. As water flows along the path of least resistance towards the open end of the channel more water enters across the walls because of the osmotic differential. In the steady state standing gradient is maintained. The relative osmolarity reduces from the tight junction towards the open end of the channel and the volume flow is directed towards the open end of the channel.
Chemical Composition of Aqueous humor
The entry of various substances into the eye depends on number of factors including molecular size, electrical charge, & lipid solubility. Large molecules like proteins penetrate the eye poorly. The capillaries of the ciliary body are permeable to proteins but the non-pigmented ciliary epithelium and capillaries of the iris are not. The concentration of protein in the aqueous humor of the human eye is approximately .02% while protein concentration in plasma is 7%. The smaller proteins such as albumin are present in higher concentration than the large proteins.
Smaller water soluble molecular are not restricted by the capillaries of the ciliary body but are somewhat limited by the non-pigmented ciliary epithelium the entry of these molecules is inversely related to their size and electrical charge.
Lipid soluble molecules pass readily through the NPE. Thus lipid soluble substances move primarily by diffusion, whereas water soluble molecules move by ultrafiltration and secretion.
Composition of Aqueous humor in relation to plasma
1. Slightly hypertonic
3. Marked excess of ascorbate
4. Marked deficit of protein
5. Slight excess of a. Chloride b. Lactic acid
6. Slight deficit of a. Sodium b. Bicorbonate c. Carbondioxide d. Glucose.
Rate of aqueous humor formation and measurement technique
Rate of secretion: 2-3(l/min
Complete turnover occurs in 1½ hours
The technique for measuring aqueous humor formation can be divided into two major categories
1.Pressure dependent methods that utilizes volumetric analysis of the eye
b) Suction cup
2.Tracer methods that monitor that rate of
appearanceanddisappearance of various
substances from the eye.
▪ Radiolabelled isotopes
▪ Flurosceinated dextrans
Factors affecting aqueous humor formation
1.Blood flow to the ciliary body: A modest reduction of plasma flow to the ciliary processes does not reduce aqueous humor production substantially. However, a profound vasoconstriction does diminish the rate of aqueous flow. Acute experimental carotid artery occlusion in rabbits and monkeys reduces aqueous humor production, however, this effect is transient and aqueous production raises to near normal levels in few weeks. In humans with unilateral carotid artery occlusion, aqueous humor production is normal and equal in both eyes. 2.Age & Sex: Aqueous humor formation appears to be similar in males and females. There is a reduction in aqueous formation with age particularly after age of 60. Age appears to have less effect on aqueous humor production than it does on intraocular pressure and anterior chamber volume.
3.Diurnal Variation: Intraocular pressure fluctuates over the course of the day. The most common diurnal variation has the maximum pressure in the morning and most authorities attribute the diurnal fluctuation of IOP to diurnal variation in aqueous humor formation. It has been postulated that the reduction was the result of decreased stimulation of the ciliary epithelium by circulating catecholamines on (adrenergic receptors). 4.Feedback control of aqueous humor formation /psuedofacility. Many investigators have postulated a feedback mechanism whereby aqueous humor-formation increases or decreases to compensate for changes in Intraocular pressure.
One proposed example of this phenomenon is the apparent decrease in aqueous formation that occurs during tonography. This decrease could be misinterpreted as an increase in outflow facility so this phenomenon is termed as psuedofacility. In addition, prolonged alterations of IOP do not seem to affect aqueous humor formation. For example, when topical corticosteroids are administered to sensitive patients for several weeks, IOP rises but there is no corresponding fall in aqueous humor formation. Conversely laser trabeculoplasty lowers IOP in glaucomatous eyes with out a concomitant increase in aqueous formation.
1) Carbonic anhydrase inhibition: Acetazolamide is a potent inhibitor of carbonic anhydrase, and decreased the rate of Na+ and HCO3- transport into the posterior chamber by equimolar amounts, suggesting a linkage of the accession of these two solutes into the posterior chamber. Several hypothesis could explain the decrease of active transport of sodium by the NPE 1.Inhibition of carbonic anhydrase causes a decrease in Hco3 available for movement with Na+ to aqueous to maintain electroneutrality 2.Change in the intracellular pH may inhibit Na+K+. ATPase &
3.Decrease availability of H+ produced by the reaction catalyzed by carbonic anhydrase decreases H+ /Na+ exchange and reduces the availability of intracellular sodium for transport into the intercellular channel.
The beta-adrenergic antagonists are also known to reduce aqueous humor formation by blocking the (2 receptors on NPE of the ciliary body and thus inhibiting the secretion of aqueous humor.