Blood circulation and fluid dynamics in the eye.

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REVIEWS Vol. 55, No. 3, July 1975 Printed in U.S.A.

Blood Circulation

and Fluid Dynamics in the Eye ANDERS

Department

of Physiology

and Medical

Biophysics,

BILL University

of Uppsala,

Uppsala,

I. Introduction ......................................................... II. Ocular Blood Flow ................................................... A. Methods for studies of ocular blood flow. ............................. B. Blood flow regulation. ............................................. III. Tissue Fluids and Barriers. ............................................ A. Blood-retinal barrier. .............................................. B. Blood-aqueous barrier. ............................................. C. Elimination of tissue fluid from the eye. .............................. IV. Aqueous Humor. ..................................................... A. General aspects .................................................... B. Methods to determine eye pressure and episcleral venous pressure. C. Determination of rate of aqueous humor formation. .................... D. Methods to determine outflow resistance. ............................. E. Secretion of aqueous humor. ........................................ F. Enrichment of aqueous humor. ...................................... G. Detoxification of aqueous humor. .................................... H. Factors influencing rate of aqueous humor formation. .................. I. Drainage of aqueous humor. ........................................ .......................................................... V. Summary.

I.

.......

Sweden 383 384 384 386 390 390 392 393 393 393 394 395 396 397 400 401 402 405 411

INTRODUCTION

The nutrition of the intraocular tissues, apart from being sufficient, has to occur with a minimum of blood interference with the transmission of light through the eye. During evolution this problem has been solved very efficiently, usually by the development of two systems of blood vessels-the retinal vessels and the uveal vessels-and by mechanisms for the formation of the aqueous humor. The uveal vessels are distributed within the choroid, the ciliary body, and the iris and supply these tissues. The outer parts of the retina including the layer of photoreceptors also are nourished by diffusion from the uveal vessels. The retinal vessels are distributed within the inner parts of the retina, but in both man and animals having a fovea this structure and the very periphery of the retina lack retinal vessels and are nourished mainly from the choroid. Blood vessels supplying the cornea and the lens in the embryo disappear before birth and the nutrition of these tissues from that time on is dependent on the flow of aqueous humor from the ciliary processes through the posterior and anterior chambers. Thus in primates part of the central vision is not disturbed by a single red cell-a remarkably elegant solution of one of the optical problems of the eye. Another problem, keeping the refracting surfaces in place, is solved also by the continuous formation of aqueous humor and its outflow through routes with a considerable resistance. 383

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The Aow of aqueous humor makes the pressure in the eye higher than in most other organs. In humans the eye pressure varies around 15 mmHg; monkeys usually have somewhat lower and cats and rabbits somewhat higher pressures. A great ri& of degenerative changes in the retina, glaucoma, and cataract may be part of the price that has been paid for the good optical properties of the eye. This review discusses recent studies on the circulation of blood in the different parts of the eye, the dynamics of the intraocular tissue fluids, and the formation and drainage of the aqueous humor. Previous reviews of the ocular circulation can be found in articles by Cole (61) and Weigelin (168) and in authoritative textbooks (40, 67, 71, 97, 174). For physiological studies aimed at relevance in humans, the diurnal monkey seems to be the ideal experimental animal. Such monkeys have an arrangement of the ocular blood vessels that is very similar to that in man (12, 13, 92). The iridocorneal-angle region where the outflow routes for aqueous humor are located also is very similar to that in man in having a well-developed canal of Schlemm and a close relationship between the ciliary muscle and the trabecular meshwork tissue separating the anterior chamber from the canal of Schlemm (101, 102, 141). If monkeys are not available, cats seem to be more useful in studies on the vascular aspects of retinal nutrition than rabbits since cats have a true system of retinal blood vessels (95). In rabbits the retinal vessels are distributed only within two wing-shaped areas with myelinated nerve fibers and represent an extension of the blood vessels of the optic nerve (139). Finally, when the formation of aqueous humor is to be studied, monkeys, cats, and rabbits may be just as useful although the composition of the aqueous humor varies among these species.

II.

OCULAR

BLOOD

FLOW

A. Methods for Studies of Ocular

Blood Flow

The large number of methods used in studies on ocular blood flow reflects the difficulties encountered in such studies. Over the last few years there have been important improvements in some of the previous techniques and new methods have been applied that permit studies on regional blood flow. Bulpitt and Dollery (56) have described how fluorescein angiography can be used to obtain semiquantitative measures of blood flow in the human retina. Serial photographs are taken after intravenous injection of the fluorescein, and the mean retinal circulation time and the vascular diameters are determined from the photographs. The blood flow can then be calculated in arbitrary units. In another recent modification of fluorescein angiography, fiber optics were used to obtain a continuous determination of the fluorescein concentration in the retinal vessels (127). For experimental investigations on retinal blood flow regulation in animals, there are two new methods that complement each other. One is the labeled-microsphere method, which has been used for several years to obtain flow measurements


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in the various tissues of the body. For flow studies in the retina this method is not quite ideal since the total retinal blood flow is very small and therefore large numbers of spheres have to be injected. Fortunately spheres as small as 15 pm seem to give reliable results and can be injected in large enough amounts without obviously adverse effects (3, 7). Results obtained with 350pm spheres are somewhat different from those obtained with 15-pm spheres. The reason is not a loss of small spheres from the tissue as one might fear but probably a skimming phenomenon at the origin of the central retinal artery. This results in relatively too few large spheres entering the retina (3). Skimming of course may affect also the 15-pm spheres and for that reason the flow values obtained with this method may be somewhat in error.’ The 50-pm spheres also have been used in studies on the ocular blood flow. The values obtained for segmental blood flow in the eye as a percentage of the total blood flow agree very well with the values obtained with 15-pm spheres (170). Other results that are discussed later differ, however, in a way that again suggests that the smaller spheres are more suitable for studies on ocular blood flow regulation. The other method that has proved to be very useful in studies on the retinal circulation is measurement of the close-retinal oxygen tension in the vitreous body (6, 157). An oxygen electrode is introduced from an opening in one part of the eye and pushed through the vitreous body to a position very close to the retina. The oxygen tension measured at this site is a measure of the average oxygen tension in the nearby part of the retina. The vitreous body itself can be assumed to have a negligible oxygen consumption. At a constant arterial POT and a constant oxygen consumption in the retina, the measured changes in PO* reflect the changes in blood flow. The labeled-microsphere method has shown that the total eye blood flow in monkeys is about 800 mg/min and that the flow distribution is approximately 1% to the iris, 4 % to the retina, 10 % to the ciliary body, and 85 % to the choroid. Absolute total flow values in cats (7), rabbits (46, 128), and dogs (104) are somewhat higher (1000-l 200 mg/min), but at least in cats and rabbits the flow distribution is rather similar. to that in monkeys with the exception that the retinal blood flow is an even smaller part of the total flow. The labeled-microsphere method has shed light on the validity of an interesting procedure used in previous studies on the blood circulation in the ciliary processes- the ascorbic acid-clearance technique of Linner (116). Ascorbic acid is transported very efficiently from the ciliary processes into the posterior chamber. In Linntr’s method it was assumed that there is a complete clearance of the ascorbic acid from the plasma passing through the ciliary processes. Plasma flow (FpI) could then be calculated from the ascorbic acid concentration in the arterial blood (Cp1) and in the aqueous humor (Cap) and the rate of flow of the aqueous humor (Faq) :

Fpl = Faq

l

C

The rate of aqueous formation of ascorbic acid in the aqueous

Gs

Pi

in rabbits is about 3 pl/min and the concentration humor is about 25 times that in the plasma ( 106).


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The plasma flow calculated from these values is about 75 pl/min. If clearance was incomplete the true values for the plasma flow would be higher. In rabbits the ciliary processes cannot be completely separated from the rest of the anterior uvea. The blood flow through the entire anterior uvea preparation measured with microspheres is about 125 mg/min (46). With a hematocrit of 0.35 the plasma flow through the whole anterior uvea is about 80 pl/min. Of course part of this flow does not reach the ciliary processes. It is clear then that the clearance of ascorbic acid from the blood perfusing the ciliary processes is practically complete. In vitro perfusion of isolated eyes is a new and promising technique for studies of ocular hemodynamics in a simpler system than under in vivo conditions (119). A problem is that if cell-free media are employed the nutrition of the ocular tissues is upset unless high perfusion rates are used (126). At such rates one can expect rather marked disturbances in the transcapillary fluid exchange. A further step toward simpler systems was taken by Dalske (66), who studied the effects of drugs on spiral strips cut from the isolated ciliary arteries. The results obtained showed good agreement with those from the in vivo experiments. B. Blood Flow Regulation 1. Perfusion pressure The pressure head for blood flow through the eye is equal to the difference between the pressure in the arteries entering the eye and that in the veins at the point where they leave the influence of the intraocular pressure (40). Under most conditions the latter pressure is practically equal to the eye pressure and the perfusion pressure can then be defined as the difference between the arterial blood pressure in the small arteries entering the eye and the intraocular pressure. The reference pressure of course has to be the same; both the arterial pressure and the eye pressure are preferably determined with the level of the eye as the zero point. The perfusion pressure can be reduced in two ways that are of clinical importance. One is to reduce the blood pressure and the other is to increase the intraocular pressure. Glaucomatous eyes with a high eye pressure thus have a low perfusion pressure. 2. Retinal

blood CfIow

Recent studies suggest that in cats about 20% of the oxygen supply to the retina comes from the retinal vessels and 80 % comes from the choroid (7). In monkeys the corresponding figures are 35 and 65 %, respectively (9). Unfortunately both sources of supply are necessary for the survival of the retina (55). In healthy experimental animals the retinal blood flow is affected remarkably little by changes in the perfusion pressure. In cats the oxygen tension close to the retina showed practically no change when the intraocular pressure was increased


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from normal levels to about 50-75 mmHg in animals with a mean arterial blood pressure of about 125 mmHg. At higher eye pressures the oxygen tension tended to fall (6). These results indicate that the blood flow in the innermost part of the retina is practically unaffected by moderate changes in the perfusion pressure. Experiments with labeled microspheres have shown that autoregulation of the blood flow in the whole retina is almost perfect in both cats and monkeys (7, 9). A recent study with fluorescein angiography indicates that this is true also in pigs (78). The mechanism for autoregulation of the retinal blood flow is not clear. It seems likely that myogenic factors are involved, since marked vasodilatation can be produced without much change in the chemical environment of the arterioles as judged from an almost constant close-retinal Pa. Metabolites such as COO are likely to play an important role in the regulation of the retinal blood flow. Studies on the oxygen tension close to the retina have shown that even small changes in the arterial PC% cause marked changes in the blood flow (157). Maximum vasodilatation was produced at a PC- of around 75 mmHg. Measurements with labeled microspheres in cats indicate that at such carbon dioxide tensions the retinal blood flow is about 50 mg/min, whereas at a PC@ of about 25 mmHg the flow is about 15 mg/min (7). It is well known that in premature babies as well as in very young animals high concentrations of oxygen in the arterial blood have very marked effects on the retinal vessels. The vessels contract and degenerate and when the oxygen tension in the arterial blood is normalized there is a rapid formation of new vessels with ingrowth into the vitreous body; the consequence is a very seriously damaged eye (14). Variations in the oxygen tension of the blood have effects also in adults. The retinal vessels tend to contract when the oxygen tension of blood is increased above the normal level and reductions in the oxygen tension seem to cause some vasodilatation. Part of the vasoconstriction at high oxygen tensions is probably due to an increase in the oxygen supply to the retina from the choroid (69). Stimulation of the cervical sympathetic nerves can be expected to have complex effects on the blood flow through the retina. The ophthalmic artery and the extraocular part of the central retinal artery have a rather rich sympathetic innervation but the intraocular part of the retinal vessels seems to lack sympathetic nerves completely (74, 114). Sympathetic stimulation produces a slight reduction in the close-retinal oxygen tension, which indicates that vasoconstriction outside the eye is strong enough to tend to reduce the blood flow in the innermost part of the retina (8). Experiments with labeled 15-pm microspheres have given very variable results suggesting that the effect of sympathetic stimulation, on the one hand, is a vasoconstriction of the extraocular arteries to the retina that tends to reduce the retinal blood flow and, on the other hand, that there is also a strong vasoconstriction within the choroid. Reduced nutrition via the choroid causes vasodilatation in the outer parts of the retinal vessels and the net effect on the total retinal blood flow may be a slight reduction in the flow, a slight increase, or no change at all (8). In a study with 50-pm labeled microspheres in cats, sympathetic stimulation caused a 40 % reduction in the retinal blood flow (171). It seems possible that this


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marked effect, compared with those observed with smaller spheres, may be explained by a marked constriction in the extraocular part of the arteries carrying the blood to the retina. If these arteries constrict, 50-pm spheres may be caught outside the retina-at least temporarilyand the retinal blood flow will be underestimated. Studies on the pharmacology of the retinal blood vessels (4) with close-retinal oxygen tension as an indicator for flow changes indicate that close-arterial injections of norepinephrine, angiotensin, and dihydroergotamine have no effects on the retinal arterioles. The vasodilatating substances isoproterenol, histamine, xanthinol niacinate, and nicotinic acid also failed to cause any retinal vasodilatation. Whether this is due to a lack of receptors in the smooth muscles or to impermeability of the vessels to the above substances was not clear. Papaverine, which has a high lipid solubility, invariably increased the retinal blood flow when given intra-arterially and this was an argument for lipid solubility being a factor of importance. This drug has been reported as causing dilatation of the minor arterioles of the retina (76). 3. Choroidal

blood flow

As mentioned above the outer layers of the retina are nourished from the choroid. However, this does not imply that choroidal blood flow regulation is similar to that in the retina. On the contrary, the choroidal blood vessels show no sign of autoregulation of the blood flow (7, 9) and they are under a strong influence from the sympathetic nerves (8). The oxygen content of the venous blood from the choroid is exceptionally high, about 95 % of that in the arterial blood (5). Reduced choroidal blood flow results in an increased oxygen extraction from each milliliter of blood passing and the total oxygen extraction from the choroid is very little changed until very low flow rates are reached. Carbon dioxide is a potent vasodilatator in the choroid of cats (7, 79). In rabbits the response is more variable, possibly as a result of the trauma involved in the measurements (153). One could expect that in a tissue where the arteries respond to CO2 there should also be some autoregulation of the blood flow. However, the apparent lack of autoregulation in the choroid can be explained easily. In this tissue even marked reductions in blood flow cause only small changes in the venous PC%. At minimal flow rates there may very well be some vasodilatation. Moderate variations in the arterial oxygen tension have no or small effects on the vascular resistance in the choroid (79). Sympathetic nerves to the choroid carry only vasoconstrictor fibers to the vessels (30). The effect of near-maximal sympathetic vasoconstriction on the choroidal blood flow in cats was a reduction by 60 % in experiments with 15-pm labeled microspheres (8) as well as in experiments with 50-pm spheres (171). Recent anatomical studies indicate that there are cholinergic fibers from the pterygopalatine ganglion to the choroidal arterioles ( 143). Since choroidal vessels dilate when acetylcholine is given intra-arterially (59) it seems likely that the


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choroidal nerves are vasodilating. So far, however, no studies have been reported on the effect of stimulation of these cholinergic nerves to the choroid on the choroidal blood flow. The choroidal blood vessels respond to many stimuli, including vasoactive drugs. Epinephrine and other adrenergic substances cause contraction, indicating that there are alpha-adrenergic receptors in the walls of the arteries and arterioles (59). No clear indications have been found for beta-adrenergic receptors in the living eye (30, 59) or in spiral strips from isolated ciliary arteries (66).

4. BZoodJIow in iris and diary

body

There is a very efficient autoregulation of the blood flow in the iris in both cats and monkeys (7). Excess carbon dioxide dilates the vessels. The arterioles respond to sympathetic stimulation by contraction mediated by the alpha-adrenergic receptors (30). There is no autoregulatory escape during sympathetic stimulation. The blood vessels of the ciliary processes seem to have less efficient autoregulation of the blood flow than the iris vessels (7, 29) but the responses to carbon dioxide and sympathetic stimulation are similar (7, 8). The vessels of both the iris and the ciliary body have muscarinic receptors and their stimulation causes vasodilatation (10). In rabbits autoregulation of the blood flow in the anterior uvea seems to be lacking or to be very inefficient for prolonged regulation. One day after carotid ligation on one side, the blood flow in the iris and the ciliary body was reduced to the same extent as in the choroid (46) . Prostaglandins E 1, &, and F4Q have very strong effects on the blood vessels of the eye, causing marked vasodilatation in the iris and the ciliary processes (64, 125, 172). The role played by the prostaglandins under normal conditions is not at all clear, but much of the inflammatory response of the eye in infections as well as after paracentesis seems to be caused by the release of prostaglandins from the tissues. Inhibition of prostaglandin synthesis by means of indomethacin (131) or aspirin (124) reduces the inflammatory responses considerably. Indomethacin also inhibits the ocular effects of the prostaglandin precursor arachidonic acid (135).

5. BZoodJlow

in optic nerue head

Both in glaucomatous eyes with high eye pressure and in eyes with low-tension glaucoma, there is a degeneration of the optic nerve head. It has been clear for a long time that the degeneration might be caused by an insufficient blood supply (70). Many studies have investigated this hypothesis, but they have been complicated by the fact that the optic nerve head has a dual blood supply. The innermost layer of the optic nerve head is nourished from recurrent arterioles from the central retinal artery (93). This part of the nerve head seems to have autoregulation of the blood flow (77). The deeper parts of the nerve head are nourished via arterioles entering the tissue from the choroid (93, 94, 96). In this part of the optic


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nerve head there seems to be poor or no autoregulation if the perfusion pressure is changed by changes in the eye pressure (9, 47). This peculiarity may be explained by two factors. I) The main resistance to flow through the deeper parts of the optic nerve head probably is located outside the nerve in the choroid and in the extraocular parts of the arteries. Metabolic autoregulation under such conditions is impaired because the metabolites cannot have a direct effect on the resistance vessels. 2) Myogenic autoregulation requires contact between the adjacent smooth muscle cells to be transmitted from the periphery (80). Many of the small vessels of the optic nerve head seem to be metarterioles in which such contact may be lacking, and thus myogenic autoregulation may also be deficient in case of a rise in the eye pressure. If the perfusion pressure for blood flow through the eye is reduced by a fall in the arterial blood pressure, the situation in regard to blood flow in the optic nerve head is quite different from that during a rise in the eye pressure. If the blood pressure falls the extraocular parts of the arteries will also experience a reduced transmural pressure difference that may result in a vasodilatation.

III.

TISSUE

FLUIDS

AND

BARRIERS

Recent studies have thrown much light on the old concepts of the bloodaqueous and the blood-retinal barriers. It is now clear that both these barriers have endothelial and epithelial parts and that both barriers have weak points. The barriers prevent almost all protein movement and they are effective even with respect to low-molecular-weight solutes, such as sucrose and fluorescein. Studies with horseradish peroxidase, mol wt 43,000, have localized the barrier to this substance at the tight junctions between the endothelial or the epithelial cells. There is no doubt that these junctions are also the barriers to the low-molecular-weight substances.

A. Blood-Retinal

Barrier

The endothelial part of the blood-retinal barrier is represented by the endothelial cells of the retinal capillaries. These cells are relatively thick, without fenestrations, and are attached to each other by tight junctions. Recent studies have confirmed and extended previous observations on the permeability of the vessels to horseradish peroxidase. When given intravenously, this material could not pass out of the capillaries of the retina and the optic nerve head; when injected into the vitreous body, it could not enter the capillaries. Both inward and outward movements of the horseradish peroxidase were stopped at the level of the tight junctions. After intravenous injection, the horseradish peroxidase was observed in pinocytotic vesicles both in the retinal and the optic nerve capillaries. However, the absence of the material outside the vessels even after 2 h indicates that in these vessels pinocytosis does not result in any appreciable outward transport (133, 134). The epithelial part of the blood-retinal barrier is represented by the pigment


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epithelium of the retina (150, 165). This part of the barrier separates the choroidal tissue fluid from the retinal tissue fluid and is important because choroidal tissue fluid is likely to be very similar to plasma. The endothelial cells of the choroidal capillaries are quite different from those in the retina. They are very thin, with numerous attenuations about 70 nm in diameter. There are narrow clefts between the endothelial cells and numerous pinocytotic vesicles seem to be involved in the transport of the plasma protein from the lumen of the vessels. After intravenous injection of horseradish peroxidase, this material passed rapidly out of the choroidal capillaries, through the membrane of Bruch, but was stopped from entering the retina at the level of the tight junctions between the pigmented epithelial cells (150). Horseradish peroxidase entering the pigmented epithelial cells by pinocytosis did not seem to be transported into the tissue fluid of the retina (I 34). The pigment epithelium thus seems to be as efficient as the retinal endothelial cells in excluding horseradish peroxidase from the retina. However, there is one weak point in the blood-retinal barrier. At the optic nerve head there are routes through which substances can pass from the choroid into the nerve (60, 85). One obvious consequence of a high permeability of the capillaries of the choroid is that all low-molecular-weight nutrients can pass very rapidly from the blood vessels to the pigmented epithelium, where one can expect mechanisms that facilitate their movement into the retina. The high protein permeability may be of great importance for the supply of vitamin A to the retina. This vitamin is transported in the plasma bound to a small globulin that in turn is bound to a prealbumin (132). This complex no doubt can pass through the functional pores that permit the albumin and the gamma globulin to pass (35). The complex thus can be expected to reach the pigmented cells, which may provide mechanisms for transfer of the vitamin to the photoreceptors. Another interesting consequence of the high protein permeability of the choroidal capillaries is the creation of a high oncotic pressure in the choroid that probably contributes to the movement of fluid out of the retina (Fig. 1). In rabbits the oncotic pressure of the tissue fluid in the choroid has been calculated to be about 12-l 4 mmHg (36). In the retina the colloid osmotic pressure is likely to be about zero, which gives a colloid osmotic pressure difference across the pigmented cells of about 12 mmHg. Fluid will then tend to be absorbed from the extracellular spaces of the retina into the choroid between and through the pigmented epithelial cells. This is probably a mechanism that normally helps to keep the retina attached to the choroid. It is not clear if there is also active transport through the pigmented epithelium that contributes to the movement of fluid out of the retina. Also studies with immunological techniques have shown that in the human eye the protein concentration in the choroid is very high (2). There is no barrier between the posterior chamber and the vitreous body and no barrier between the vitreous humor and the retina. Horseradish peroxidase and even Thorotrast particles can pass from the vitreous into the intercellular spaces of the retina (151). The movement of horseradish peroxidase is not stopped


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PHOTORECEPTORS

PIGMENT EPITHELIUM OOc3Om!JQ6’@Q I? -a-m ARTERIE&)--

CHORIOCAPILLARIES CHOROIDAL AND VEINS SUPRACHOROID SCLERA EPISCLERA

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1

An.12mmHg

1

APd2mmHg

FIO. 1. Outer part of retina, choroid, sclera, and episclera. Hydrostatic pressure in retinal tissue fluid and in choroid is probably about the same, but oncotic pressure of choroidal tissue fluid causes a gradient for fluid absorption from retina into choroid of about 12 mmHg. Hydrostatic pressure in suprachoroid is less than that in anterior chamber but is probably about 12 mmHg higher than that in episcleral tissue. Differences in oncotic pressure between suprachoroid and episcleral tissue are unlikely to have any effect on fluid transport since the sclera is permeable to plasma proteins.

until it reaches the tight junctions of the pigmented epithelium thus the blood-aqueous barrier that prevents movement of many the capillaries of the ciliary processes into the retina. B. Blood-Aqueous

(133, 134). It is substances from

Barrier

The capillaries of the ciliary processes are of the same type as those in the choroid (97) and these vessels also have a rather high protein permeability. The barrier that prevents the movement of intermediateand high-molecular-weight substances into the posterior chamber is constituted by the ciliary epithelium. This epithelium has two layers: one pigmented layer that faces the stroma of the processes and one nonpigmented layer that faces the posterior chamber. The ciliary epithelium is in fact a forward extension of the retina and one therefore could expect the pigmented layer to be the blood-aqueous barrier. This is not the case, however. The barrier is constituted by the nonpigmented cells. Some overlapping of the blood-retinal and blood-aqueous barriers seems to exist in the region of pars plana (179). The nonpigmented cells of the ciliary epithelium are attached to each other by tight junctions, and several studies have shown that penetration of horseradish peroxidase from the stroma of the processes into the posterior chamber is prevented by these junctions (147, 163). The epithelium, however, is not a perfect barrier. It was observed recently that small amounts of horseradish peroxidase could pass from the stroma of the processes into the posterior chamber by means of pinocytosis through the nonpigmented cells (152). It is likely that such transport accounts also for some protein movement from the ciliary processes into the posterior chamber. Protein can leave the ciliary processes also by moving through the bases


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of the processes into the rest of the anterior uvea. Interestingly, there is no barrier between the anterior uvea (iris and ciliary body) and the anterior chamber or between the anterior uvea and the sclera (44). This has consequences that are discussed later in section IV, H and I. Several studies on the ultrastructure of the blood vessels of the iris have shown that in primates there are tight junctions between the endothelial cells of the capillaries and that the permeability of these capillaries to macromolecules is very low. Horseradish peroxidase has been reported not to pass out of the capillaries (164). The endothelial cells of these vessels thus constitute part of the blood-aqueous barrier. C. Elimination

of Tissue Fluid from the Eye

Choroidal tissue fluid can leave the eye by passing via the perivascular spaces through the sclera and also through the scleral substance. Even protein can pass through the sclera without appreciable restriction (31, 43). Thus, as long as the fluid pressure in the suprachoroid is higher than that outside the eye, there will be a leakage of tissue Auid from the choroid through the suprachoroid and the sclera into the episcleral tissues. Figure 1 shows the situation schematically. The leakiness of the sclera is likely to cause complex pressure and flow conditions in the suprachoroid. Attempts to measure the pressure in this tissue space have been made (11). The pressure measured with a fine needle was a few millimeters of mercury lower than the intraocular pressure measured in the anterior chamber. The tissue pressure measured with needles in other tissues tends to be higher than the tissue fluid pressure measured by such techniques as Guyton’s capsules or Scholander’s wicks (89). It seems very likely that the same is true for the suprachoroid and that the fluid pressure here is considerably less than the pressure in the anterior chamber. Thus there probably is a wide safety margin in the drainage of fluid from the suprachoroid in the sense that the pressure required to drain the fluid entering the suprachoroid under normal conditions is much smaller than the intraocular pressure. If the pressure in the eye falls to very low values, there is no gradient for outflow from the suprachoroid. This no doubt contributes to the development of choroidal detachment, a complication often seen after eye surgery (146).* The drainage of tissue fluid from the ciliary processes is discussed in section IV.

IV.

AQUEOUS

HUMOR

A. General Aspects There is now general agreement that the aqueous humor is produced by the ciliary epithelium, flows from the posterior chamber into the anterior chamber, and leaves the anterior chamber in the iridocorneal angle. Many mechanisms are involved in the formation of aqueous humor. Some


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cause the movement of practically isotonic fluid into the posterior chamber, others add metabolically important molecules to the aqueous humor, and still other mechanisms transport certain substances from the posterior chamber into the ciliary processes. In primates most of the drainage of aqueous humor goes through narrow paths into the canal of Schlemm and from there into the intrascleral and episcleral veins. A smaller part is drained via uveoscleral routes through the interstitial tissue spaces of the ciliary muscle into the suprachoroid and out through the sclera. Whether there is also some movement of fluid from the posterior chamber into the vitreous body is not clear. Lower animals have no well-developed canal but a sinus structure has the same function. of Schlemm, The pressure in the recipient veins (P,,), the resistance in the outflow routes between the anterior chamber and the recipient veins (R), and the flow through these routes (F,) are the factors that normally determine the intraocular pressure (IOP) : IOP

= P, + F.4

Representative values in human eyes are: IOP, 16 mmHg; P,, 8 mmHg; R, 4 mmHg min &l; and F8, 2 ~1 min? Studies on the dynamics of the aqueous humor are complicated by the fact that changes in the IOP influence the other parameters of the equation. For example, if F8 is increased by infusion of fluid into the eye, IOP rises and both P, and R tend to change. Many methods have been tried to determine the intraocular pressure, the rate of aqueous formation, the outflow resistance, and the episcleral venous pressure. The interdependence of these parameters and the relationships between the eye pressure and the intraocular blood volume and the blood flow impose an important requirement on all such methods: that the parameter under investigation should be measured with a minimal change in the eye pressure. In many studies on the dynamics of the aqueous humor, the intraocular pressure and the outflow resistance were measured. The episcleral venous pressure was assumed to be a constant and the flow via Schlemm’s canal was calculated. Determinations of the outflow resistance have large errors and the episcleral venous pressure may be quite variable, as mentioned previously. The values for outflow via Schlemm’s canal thus may be greatly in error. l

l

B. Methods to Determine

l

Eye Pressure and Episcleral

Venous Pressure

Methods to determine the intraocular pressure by noninvasive techniques have been discussed recently (123). Of course, techniques involving cannulation of the anterior chamber give more reliable results but tend to cause irritation of the eye. This is the case especially in the rabbit eye, which tolerates very little trauma unless protected against prostaglandin release. Cannulation techniques were improved considerably by the construction of guns by means of which cannulas can be shot into the anterior chamber without any fixation of the eye (145).


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Since a recent comparison of the different methods for measurements of the episcleral venous pressure (53), a new technique has been developed for nontraumatic determinations (107). The pressure in a fine jet of air directed against an episcleral or conjunctival vein is increased progressively and observations are made of the pressure at which there is some indentation in the wall of the vein, the pressure at which the indentation is pronounced, and the pressure at which the vein is compressed completely. This method permits accurate determinations of changes in the venous pressure and possibly can also be calibrated to give absolute values. It was often assumed in studies on aqueous humor dynamics that the episcleral venous pressure is a very constant pa .rameter. The new nontraumatic method has already confirmed the observations made wi .th indirect methods that both pilocarpine and epinephrine tend to cause changes in the episcleral venous pressure. It has also shown that a small load on the eye tends to cause a considerable fall in the venous pressure (108, 171).

C. Determination of Rate of Aqueous Humor Formation There is no easy direct way to determine the rate of aqueous humor formation in vivo because the aqueous humor cannot be collected quantitatively from its outflow routes. Attempts have been made to determine the aqueous formation in monkeys by cannulating the anterior chamber and draining the fluid from the chamber at an intraocular pressure a little below the episcleral venous pressure (73). Under such conditions flow into the canal of Schlemm is inhibited. In ideal experiments one can get a measure of the flow that would have left the anterior chamber via Schlemm’s canal. Uveoscleral flow is very little influenced by a small reduction in the eye pressure and thus will be at its normal level and not included in the flow determinations. The great problem with the method is to find the right level for the intraocular pressure. If the pressure is too high, there will be outflow via the canal of Schlemm. If it is too low, there will be a risk of some backflow through the meshwork of plasma or blood and the fluid balance in other parts of the eye may also be upset. An ingenious way to determine the rate of aqueous humor formation was described by Holm (101). He found that if fluorescein is introduced into the anterior chamber, and mixed for some seconds with its contents, newly formed aqueous humor will appear at the pupil as a clear drop. The size of the drop can be determined by serial photographs and the flow calculated from the rate of increase in drop size. There are problems with this method too: one is that the pupil has to be rather small and another is that the fluid often appears discontinuously. Several methods now being used for aqueous flow determinations are based on the fact that molecules of the size of myoglobin and larger leave the anterior chamber almost exclusively by bulk flow- diffusion into the tissue playing practically no role (48). One simple way to determine flow is to inject a known amount of the labeled molecules into the anterior chamber and then later observe how much of the labeled substance has left the chamber (58). The rate of elimination


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is assumed to be exponential and the rate of aqueous humor formation is determined from the turnover rate constant and the volume of the anterior chamber. Continuous monitoring of the radioactivity of the anterior chamber makes it possible to verify the assumption concerning exponential elimination of the labeled material from this chamber. Another method for studying the rate of aqueous formation is to perfuse a radioactive fluid continuously through the anterior chamber into an outlet. The flow of aqueous humor can be determined from data for the infusion rate, the radioactivity of the infused fluid, and the radioactivity of the fluid leaving the eye (51). Mixing the contents of the anterior chamber is a problem in investigations of this type. Perfusion via the posterior chamber eliminates the problem but involves a great risk for eye irritation (82). To mix the anterior chamber contents a mechanical stirrer may be introduced into the anterior chamber (57). Another way to improve mixing is to incorporate an external circuit through which fluid is circulated from the anterior chamber through a constant volume and back. This solution to the stirring problem has the advantage that the radioactivity of a constant volume of the external circuit can be determined continuously (41). Even very small changes in radioactivity can be determined under such conditions. To analyze the distribution of the outflow via Schlemm’s canal and the uveoscleral routes rather laborious procedures have to be used (32, 43). The anterior chamber contents are mixed continuously with those of an external system having a constant volume and containing radioactive albumin. The radioactive contents of the anterior chamber flow via Schlemm’s canal to the blood circulation and via the uveoscleral routes into the ciliary muscle, the sclera, and the episcleral tissues. The flow into the blood can be determined from data for the radioactivity of the anterior chamber contents, the increase in the blood radioactivity, and the distribution volume for the albumin entering the general circulation. The flow into the uveoscleral routes can be calculated from the amounts of radioactivity recovered in the tissues mentioned after 1 h. At this time practically no albumin has left the uveoscleral routes and entered the conjunctival lymph vessels. Diffusion of labeled material into the uvea causes an unknown error. An interesting in vitro method for qualitative determinations of effects of different drugs on the rate of aqueous humor formation was described by Berggren (26). The ciliary processes are loaded with cold saline by in vivo perfusion. The iris-ciliary body preparation is then isolated and warmed. The rate of shrinkage of the processes is determined by serial photography and used as a measure of the rate of secretion of the aqueous humor. D. Methods

to Determine

Outflow

Resistance

Tonography is used clinically to measure outflow conductance or facility of outflow in ophthalmological literature; its many drawbacks are not discussed here. In experimental work the conductance is best measured with the method described by BBr&ny (16). The inflow into the anterior chamber from an external reservoir is measured at two different heights of the reservoir. The assumption is made that


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the venous pressure and the rate of aqueous humor formation are constant and that no change occurs in the intraocular blood or tissue fluid volume except within a few seconds after the change in the eye pressure. Under such conditions the rise in steady rate inflow from the reservoir (caused by the rise in pressure) divided by the pressure rise is a measure of the conductance. A reduction in the rate of aqueous formation and a progressive loss of tissue fluid from the eye are two of the factors that may make the outflow conductance measured include a pseudofacility component ( 17, 42). An interesting new method for outflow conductance measurements is to observe the rate of inflow from a reservoir at one level of artificially maintained eye pressure and two different venous pressures. The venous pressure is increased by means of a cuff or band placed around the neck (54). With this method problems with changing intraocular blood and ‘tissue fluid volumes are eliminated. To what extent new problems are introduced is not quite clear. On the assumption that these are small, the difference in conductance between the two methods is a measure of the pseudofacility.

E. Secretionof Aqueous Humor The formation of aqueous humor has long been regarded as being due both to ultrafiltration through the ciliary epithelium and to active transport through the epithelium. Cole (61) was the first to attempt estimations of the respective roles played by the two mechanisms. In experiments with perfusion of the chambers of the eye in rabbits he found that the active transport mechanism appeared to account for about 75 % of the observed rate of aqueous formation. The flow rate was about 6 pl/min, which is higher than the values obtained with other methods-a fact no doubt explained by irritation of the eye, which tends to cause leakage of tissue fluid from the processes into the posterior chamber. Normal flow rates are about 3 pl/min, which is even less than the part transported actively in More recently a number of publications (86, 129, 130, 169) Cole’s experiments. have indicated that about 70-80% of the rate of formation of aqueous humor is due to ultrafiltration, the rest being due to secretion. The evidence on which these conclusions are based is very indirect. Other indirect evidence discussed here indicates that, if anything, ultrafiltration through the ciliary epithelium is in the other direction-that is, tending to cause a reabsorption of the freshly secreted fluid (44). As mentioned previously the rate of plasma flow through the ciliary processes in rabbits is about 75 pl/min. The rate of formation of aqueous humor is about 3 pl/min. The net filtration of fluid from the capillaries of course has to correspond to the formation of the aqueous humor plus any loss of tissue fluid from the processes. The magnitude of such loss has been estimated to be between 0 and 0.2 pl/min, a small quantity compared to the rate of aqueous formation (35, 36). The net filtration of water and salts from the capillaries thus corresponds to about 4 % of the plasma flow (Fig. 2) l


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FIG. 2. Formation

of aqueous

sure, C,, : plasma concentration.

humor

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in rabbits.

P: hydrostatic

pressure,

II:

oncotic

pres-

See text.

Studies on the dynamics of the extravascular plasma proteins in the ciliary processes indicate that the outflow of albumin and gamma globulin corresponds to 0.13 and 0.08 ~1 plasma equivalent fluid/min for the two proteins, respectively (35). In the net filtrate from the capillaries the albumin concentration thus is about 4 % of that in the plasma and for gamma globulin the corresponding figure is about 3 %. The capillary wall thus is a considerable barrier for the plasma proteins, but the more important barrier is constituted by the ciliary epithelium. That this is true is indicated by the fact that the protein concentration in the tissue fluid is high (1, 2). In rabbits it is abopt 75 % of that in the plasma (36). The high protein concentration of the tissue fluid in the ciliary processes of course is of great importance for the filtration from the capillaries. It causes a high oncotic pressure in the tissue fluid and thereby reduces the transcapillary difference in the oncotic pressure. It is not clear what happens to the protein that passes out of the capillaries of the ciliary processes. Part of it probably is transported with pinocytosis into the posterior chamber, part may be metabolized, some may return into the capillaries with diffusion or pinocytosis, and some protein may leave the ciliary processes with a flow of the tissue fluid moving through the ciliary body into the supraciliary and suprachoroidal spaces. If all the protein leaking out of the capillaries were to be drained by a flow


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of tissue fluid from the processes through their bases, the flow would be about 0.2 pl/min. In rabbits the fluid might enter the anterior chamber, the space of Fontana, and the supraciliary space since there are no anatomical barriers even to protein between the stroma and the processes of these spaces. Obviously if the conductivity of these routes was known one could calculate the pressure gradient necessary to cause such a flow. Green and Pederson (86) made in vitro determinations of the conductivity between the anterior chamber side of the ciliary body-iris preparation and the posterior chamber side and found that the conductivity was 0.1-0.2 pl/min per mmHg pressure difference. The preparation studied included the ciliary epithelium, which was regarded as the main barrier. Obviously then the conductivity of the routes from the anterior chamber side up to the epithelium has to be considerably greater, and it should be about the same in both directions as long as the processes are filled with fluid. To cause a flow of tissue fluid through these routes from the processes toward the anterior chamber of 0.2 pl/min, the pressure gradient required clearly would be less than 2 mmHg. The difference in pressure between the stroma of the ciliary processes and the anterior chamber thus is likely to be O-2 mmHg and the same is true for the difference in the hydrostatic pressure over the ciliary epithelium. This difference in the hydrostatic pressure is much less than the difference in the oncotic pressure between the stroma of the processes and the aqueous humor in the posterior chamber. The effect of hydrostatic and oncotic pressure differences across the ciliary epithelium thus is a pressure of about 13 mmHg tending to move water into the processes from the posterior chamber. Since under normal conditions ultrafiltration through the ciliary epithelium is unlikely to contribute positively to the formation of the aqueous humor, secretion has to be of overall importance. It seems likely now that some solutes are moved actively through the nonpigmented cells into narrow clefts between these cells and into invaginations of the cells. Water is added as the secreted fluid moves toward the posterior chamber and consequently the fluid entering the posterior chamber is almost isotonic with plasma. This standing osmotic gradient model, first suggested by Ballintine (15), has been elaborated theoretically to explain the secretion of fluid in many organs (65, 68). Several ions seem to be actively transported into the clefts between and in the epithelial cells (105); the most important are probably sodium, chloride, and bicarbonate. Cole (62) has found very clear evidence for the transport of both sodium and chloride ions in rabbits in vitro, and sodium transport appeared to be the most important. Histochemical methods have shown that ouabain-sensitive Na-K-ATPase is located in the walls of the spaces in question (160). In cats Holland et al. (98, 99) have found chloride to be the ion transported efficiently. The discrepancy may be due to a true difference between the species; in fact it does not matter which ion is transported as long as the transport causes a net flow of water into the posterior chamber. The role of bicarbonate formation and transport in the forming of the aqueous humor is no doubt great but the mechanisms involved are not completely clear. Since Wistrand’s (175) demonstration of carbonic anhydrase in the ciliary


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processes it has been demonstrated that the enzyme is present in the nonpigmented cells and that inhibition of the enzyme reduces the rate of aqueous humor formation in all species investigated (23, 82, 164). This was surprising since high bicarbonate concentrations in the aqueous humor are found only in some species such as rabbits and cats whereas low concentrations are found in the primates. The interpretation of these facts has been discussed by Becker (22, 23) and Maren (121). In rabbits there may be a mechanism for bicarbonate transport into the clefts mentioned previously, the hydrogen ions being lost to the stroma, or the primary processes might be the exchange of hydrogen ions for sodium from the stroma, the resulting sodium and bicarbonate ions moving into the clefts by diffusion In both cases carbonic anhydrase would contribute toward providing the necessary ion. In primates the bicarbonate ions produced may be exchanged for chloride ions from the stroma, chloride entering the posterior chamber in excess of its concentration in the plasma. Obviously there must be a balance between the net filtration from the capillaries of the ciliary processes and the secretion of the aqueous humor and the losses of tissue fluid from the processes. The extravascular plasma protein can be expected to play an important role in the establishment of this balance. If for some reason blood flow is suddenly reduced by a fall in the arterial blood pressure or a rise in the eye pressure, the ultrafiltration from the capillaries may be lower than the secretion for a few seconds. This will make the processes shrink and the concentration of the extravascular plasma protein in the processes will then increase. This will tend to restore the net ultrafiltration from the capillaries. Such an increase, however, may tend to reduce the net formation of aqueous humor by increasing the tendency for reabsorption of the freshly secreted fluid. A sudden increase in the rate of filtration from the capillaries can be expected to have opposite effects. The processes probably tend to swell and the outflow of tissue fluid from the bases of the processes increases. As a consequence the protein concentration in the tissue fluid decreases and ultrafiltration from the capillaries is reduced until a new steady state is established. The secretion may appear to increase due to a reduced reabsorption of the freshly secreted fluid. A mutual dependence between secretion and ultrafiltration of the type discussed here of course is likely to exist in all secreting tissues and a similar situation probably exists also in the reabsorbing tissues. In enucleated cat eyes perfused with cell- and protein-free perfusate the rate of aqueous formation is almost proportional to the perfusion pressure, indicating that ultrafiltration is important in the production of the aqueous humor under such conditions (12 1). This is not surprising in view of the proposed role of the plasma proteins. In the absence of protein in the perfusate one can expect outward filtration through the ciliary epithelium.

F. Enrichment of Aqueous Humor The weight

blood-aqueous barrier is remarkably efficient even to low-molecularsubstances. Therefore amino acids and glucose could be expected to pass


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through the barrier rather poorly if moving only by diffusion between the epithelial cells. Reddy et al. (138) have demonstrated that in rabbits the concentration of most amino acids in the aqueous humor is higher than in the plasma. There seem to be at least three carrier systems involved in the transport-one each for basic, acidic, and neutral compounds. In other species, including primates, the concentration of most amino acids in the aqueous humor is lower than in the plasma. Reddy (137) has suggested that in rabbits there is an active transport of the amino acids by the ciliary epithelium and that in other species the amino acid transport also involves a carrier-mediated mechanism. The concentration of amino acids in the vitreous humor is much less than that in the aqueous humor, which indicates that the amino acids are lost into the retina from the vitreous. The concentration difference gives a continuous net movement of amino acids from the posterior chamber into the vitreous body. The supply of amino acids to the retina via this route is probably much more important in rabbits, which have no true retinal blood vessels, than in species with a well-developed system of retinal vessels. This may be a teleological background for the more efficient transport of amino acids into the posterior chamber in rabbits than in rats, cats, and primates. It is not clear, however, whether all the amino acids entering the retina are utilized by the retinal cells. Reddy (137) has found that the nonmetabolized amino acid cycloleucine also has a low steady-state concentration in the vitreous humor compared with that in the plasma and the aqueous humor. He suggested that this was due to an active transport of the cycloleucine through the retina into the blood vessels. Uptake of cycloleucine into the retinal cells and loss with the axoplasmic flow might be an alternative explanation for Reddy’s results. Hanna and Sanchez (90) recently reported that if aqueous humor formation is reduced by acetazolamide the concentration of amino acids in the aqueous humor in human eyes increases by about 50 %. The increase was about the same for all amino acids and for several of them the concentration reached levels similar to those in the plasma. Acetazolamide thus inhibits one of the mechanisms contributing to the formation of aqueous humor without causing a parallel effect on involved in enrichment the mechanisms of the aqueous humor. Glucose concentrations in the posterior aqueous humor are not much lower than in the plasma, suggesting that there may be a facilitated diffusion of glucose through the ciliary epithelium (106). In rabbits practically all the ascorbic acid that enters the ciliary processes with the blood seems to be transported through the ciliary epithelium into the posterior chamber, as mentioned previously. The same seems to be true in primates. The importance of the high concentration of ascorbic acid in the aqueous humor is not clear. In cats the concentration is little above that in the plasma without harmful effects. any obviously G. DetoxrjTcation

tend

of Aqueous Humor

There are several systems for active transport to move substances from the posterior chamber

in the ciliary epithelium that into the stroma. One of these


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systems transports iodide (25), another transports such organic anions as iodopyracet and hippurate (24, 166), and a third system seems to transport metabolites destined for excretion by the liver (19). A mechanism exists also for prostaglandin transport from the posterior chamber into the ciliary processes (52, 75). The importance of these systems is probably to protect the lens, the cornea, and the chamber-angle tissue from noxious substances. H

Factors Zn@en&g

Rate of Aqueous Humor Formation

1. Central regulation As mentioned in the introduction (sect. I) the formation of aqueous humor is important for the maintenance of the comparatively high pressure in the eye required for good optical properties. It is also important for the nutrition of the lens, the cornea, and the chamber-angle tissue. The nutritional requirements can be expected to be almost constant and the pressure also should preferably be at an almost constant level. There is thus no obvious need for a mechanism regulating the rate of formation of the aqueous humor in accordance with varying metabolic needs or needs for varying pressure. However, it would be advantageous of course to have a regulating mechanism that could maintain the eye pressure within normal limits if for some reason one of the factors influencing the eye pressure was changed. There has been much speculation about a center in the diencephalon that could adjust the rate of aqueous formation according to information from intraocular receptors sensing eye pressure but the question is far from settled (165). It was observed long ago that electrical stimulation of loci in the diencephalon in cats may cause alterations in the intraocular pressure without concomitant changes in the blood pressure or pupil size (83, 144). An efferent pathway involved in the regulation of the intraocular pressure thus might originate in this area or pass through it. Lele and Grimes (115) found in cats that a rise in eye pressure elicits impulses in the afferent nerves from the eye. Efferent activity recorded from the long and short ciliary nerves could not be modulated by- pressure changes, however, a result that made it seem very doubtful that regulation of the intraocular pressure involves a center in the central nervous system. A regulating mechanism most probably would have to in&de unexpected efferent pathways. Evidence suggesting that such pathways may exist after all has appeared recently. Krupin et al. (109) have shown that when a hypertonic solution is injected into the third ventricle there is no change in eye pressure if the optic nerve has been transected but with the intact nerve there is a fall in eye pressure. Hypotonic solutions give diametrically opposite results in eyes with a normal optic nerve and no effects in eyes with a transected nerve. Whether the changes in eye pressure were due to changes in the rate of aqueous humor formation or to another of the parameters influencing eye pressure was not clear. In a recent study Krakau and Wilke (108, 173) observed in humans that


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loading the eye with a weight causes a fall in the episcleral venous pressure both in the loaded eye and in the contralateral eye and that this drop makes the eye pressure fall. The nervous pathways involved in these responses are not clear but it was observed that eyes with optic nerve atrophy did not react or reacted less to both ipsilateral and contralateral loading. This observation raised the question whether there are centripetal fibers in the optic nerve that cause changes in the eye pressure by influencing the episcleral venous pressure. Of course the possibility exists that there is a central influence on the rate of aqueous formation that is triggered by some parameter other than the intraocular pressure. One could expect the autonomic nerves to the eye to be involved in such a regulating mechanism. It therefore is of interest that stimulation of the autonomic nerves in fact has effects on the rate of aqueous formation. These effects, however, are small and vary among the different species. The effects of drugs that interfere with the autonomic nervous system are also small. In monkeys stimulation of the sympathetic nerves to the eye tends to cause a slight increase in the rate of aqueous humor formation (39) and the parasympathomimetic drug pilocarpine tends to decrease the rate of aqueous formation. In rabbits, on the other hand, strong sympathetic stimulation causes a reduction in the rate of aqueous humor formation (112) and parasympathetic stimulation has been reported to increase the rate of aqueous humor formation (159). Parasympathomimetic drugs, however, have no effects on the aqueous flow in rabbits (158). It seems very likely that the effects on the aqueous humor formation caused by stimulation of the autonomic nerves in fact are secondary, due to overflow of transmitter, and that they are not involved in a regulating mechanism. The difference in effect of sympathetic stimulation between monkeys and rabbits can easily be explained. In monkeys sympathetic stimulation has a moderate effect on the blood flow through the anterior uvea (Alm, personal communication) but in rabbits the vasoconstriction is marked (30). A slight stimulating effect on the epithelium in monkeys by the norepinephrine released might thus overcome any effect of vasoconstriction, whereas in rabbits the opposite might be true. 2. Blood pressure and aqueous humor formation Effects of an acute reduction in blood pressure on the rate of aqueous humor formation have been investigated in two ways. Linner (116) has demonstrated that in rabbits occlusion of the common carotid artery reduces the blood flow through the uvea by about 20 % and produces a similar fall in the concentration of ascorbic acid in the aqueous humor. On the assumption of a complete clearance of the ascorbic acid in the ciliary processes this result could be expected if the rate of aqueous humor formation was unchanged and the blood flow through the ciliary processes was reduced by 20%. More recently experiments in monkeys with a continuous determination of the rate of aqueous formation have shown that there is very little. effect on the formation rate for moderate reductions in the blood pressure. Marked reductions in the aqueous formation were seen only at mean blood pressures below 50 mmHg.


ANDERS At such pressures the blood flow through mittent or have stopped completely (41).

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be inter-

3. Eye pressure and aqueous humor formation The effects of increments in intraocular pressure on the rate of aqueous formation have been very much discussed since the introduction of tonography for measurements of the conductivity of the outflow routes. In this method the pressure in the eye is raised artificially and the extra outflow caused by the rise in pressure (in pl/min per mmHg) is determined. It is assumed in the calculations that the rate of aqueous humor formation is not influenced by the pressure rise. Experiments in monkeys indicate that at least in this species the assumption is not altogether justified and that measurements of outflow conductance include a pseudofacility (17) component. This is probably caused both by a reduced net formation of aqueous humor and a loss of tissue fluid from the eye. In monkeys the long-term reduction in the rate of aqueous humor formation caused by a rise in eye pressure of 20-25 mmHg is quite small-about 0.02 pl/min per mmHg pressure rise (42). Immediately after a pressure rise, the loss of tissue fluid from the eye seems to be more important (42). Tissue fluid may be reabsorbed into the blood vessels especially in the choroid, where there is no autoregulation, and there may also be a loss of tissue fluid from the suprachoroid and choraid through the sclera. At high intraocular pressures the blood flow through the ciliary processes is compromised and there is a more marked reduction in the rate of aqueous humor formation. 4. Pharmacology

of aqueous humor formation

Difficulties in measuring the rate of aqueous humor formation have caused a great deal of confusion regarding the effects of drugs. There is general agreement about the effect of one agent, acetazolamide. In all species investigated this drug causes a very marked fall in the rate of aqueous formation, more than 50 % (23, 82, 167). Ouabain, systemically as well as topically, reduced the rate of aqueous humor formation in cats probably by inhibiting the active Na and/or Cl transporting mechanisms in the eye (26, 82). The effect has been observed also in experiments with rabbit eyes in vitro (26). Pilocarpine causes a reduced rate of pumping in isolated ciliary processes from rabbits (27) and causes a reduction in the rate of aqueous humor formation in monkeys (51) and man (1 10). In living monkeys neostigmine has no apparent (44). Atropine effect on the rate of aqueous humor formation under in vitro conditions tends to decrease the pumping of isolated ciliary processes (27) ; in vivo it sometimes causes some increase in the rate of aqueous formation (38). It is possible that there is a parasympathetic tone in vivo that tends to decrease the rate of aqueous formation and that this tone is abolished by the drug, which would result in an apparent increase in secretion rate.


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Adrenergic agents have very complex effects in the eye. Numerous studies indicate that there may be considerable species variations and also that the effects of adrenergic agents depend on the mode of administration. Anterior chamber perfusion of the monkey eye with isoproterenol has been reported to cause a rise in the formation of aqueous humor (39). When given topically in man, however, it has been reported to reduce the intraocular pressure in a way suggesting a fall in the rate of aqueous humor formation (81, 111). In rabbits intravitreous administration of the agent produces a fall in eye pressure that also has been interpreted as being due to a reduced rate of aqueous formation (72). In monkey eyes, topical epinephrine (37) as well as norepinephrine perfused through the anterior chamber produced no significant change in the rate of aqueous humor formation (39). In humans, topical epinephrine has been reported to reduce the rate of aqueous flow, but norepinephrine seemed to increase the aqueous flow (82). In isolated ciliary processes, epinephrine reduces the rate of shrinkage, reflecting a fall in the rate of aqueous humor secretion (27). Anesthetics also may affect the formation of aqueous humor. A recent study (58) indicates that pentobarbital causes a marked reduction in the rate of aqueous humor formation in monkeys compared with urethan and phencyclidine hydrochloride. A strange effect of mercurial diuretics on isolated ciliary processes is that not only is the rate of shrinkage of the processes reduced but there is even a swelling (28). This might be a case of ultrafiltration into the stroma revealed after complete inhibition of the secreting mechanism. I. Drainage

of Aqueous Humor

The aqueous humor that enters the anterior chamber via the pupil is in close contact with the blood vessels of the iris. This might cause net fluxes of water and such fluxes might exist also between the anterior chamber fluid and the cornea. Recent studies have shown, however, that any such fluxes are small and negligible compared with the outflow of aqueous humor known to occur in the chamberangle tissue. In the iris the pores through the capillary walls have a hydrodynamic conductivity too low to permit significant ultrafiltration into or out of the vessels (45). In the cornea the endothelial cells facing the anterior chamber cause an active transport of ions into the anterior chamber. This causes a fluid movement that seems to balance a small outward leakage from the anterior chamber (122). The processes by which the aqueous humor leaves the anterior chamber in the chamber angle have been debated for a long time (Fig. 3). There are two routes: one via Schlemm’s canal and another via the ciliary muscle, the suprachoroid, and out through the sclera. In the chamber angle the aqueous humor can pass into a peculiar meshwork tissue. Part of the fluid then moves through the meshwork tissue and the inner wall of Schlemm’s canal into the canal and is then drained by collector channels into the intra- and episcleral veins. Another part of the fluid entering the meshwork or the anterior surface of the ciliary body


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FIG 3. In iridocorneal angle most of aqueous humor passes through meshwork tissue into canal of Schlemm. A smaller part passes from meshwork along muscle bundles of ciliary muscle into supraciliary and suprachoroidal spaces and then out through the sclera. Aqueous humor also can pass directly into ciliary muscle. Some tissue fluid probably passes from ciliary processes into ciliary muscle, where it mixes with locally produced fluid and aqueous humor seeping toward the sclera. SC, Schlemm’s canal; SS, scleral spur; ScS, supraciliary space; CP, ciliary processes; CM, longitudinal part of ciliary muscle.

flows through the interstitial spaces of the ciliary muscle into the suprachoroidal space and leaves this space by movement through the scleral substance or through the perivascular spaces. The importance of these uveoscleral routes varies greatly among the different species. 1. Drainage

via Schlemm’s canal

The structure of the tissue between the anterior chamber and the canal of Schlemm is very complicated, and in spite of much recent work the function of the different parts of the tissue is not quite clear (101, 102, 154). There are three layers of meshwork between the anterior chamber and the inner wall of Schlemm’s canal (Fig. 4). The first layer of the meshwork that the aqueous humor has to pass through on its way out of the eye is the uveal meshwork, which is a forward extension of the ciliary muscle inserting in the cornea. The openings in this meshwork are large and overlap to such an extent that it seems precluded that this layer can normally offer any significant resistance to the outflow (50). The second layer of the meshwork is constituted by several perforated sheets of connective tissue extending between the scleral spur and the cornea. These openings are smaller than those in the uveal meshwork and overlapping of open-


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FIG. 4. Schematic

representation

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of a section

through

chamber-angle

tissue.

ings in the sheets seems to be rare. The resistance of this layer to outflow probably is considerable, not so much because of the smaller size of the openings in the sheets but because of the long and tortuous paths created between the meshwork sheets. These are connected to each other by many tissue strands and endothelial cells. The third layer of the meshwork, the endothelial meshwork, lies between the corneoscleral meshwork and the inner wall endothelium of Schlemm’s canal. It is a kind of loose connective tissue containing collagen and elastic fibers, a ground substance, and cells that are regarded as endothelial cells. The paths through this tissue seem to be very narrow and irregular and probably shift from time to time. The inner wall endothelium of Schlemm’s canal is very thin. There is normally a pressure gradient for flow from the outside of the canal toward its inside. In sections of the inner wall endothelium there seem to be vacuoles in the endothelial cells but all these vacuoles are in fact invaginations from the trabecular side into the cells (102). The mechanism responsible for the creation of these invaginations has been debated but it seems very likely now that the main factor is the pressure from the anterior chamber side. If the normal pressure difference is increased there seems to be an increase in the number of vacuoles and invaginations. If the pressure difference is reduced to zero or made negative by infusion of fluid into the canal of Schlemm the vacuoles disappear (88, 162). These effects are not dependent on the metabolic activity of the cells since they can be obtained also at 4°C. In some invaginations the endothelial wall is very thin, and at such places


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one can find not only membrane-covered fenestrations similar to those found in the capillary endothelial cells but also actual pores ranging in diameter from about 50 nm to 3 pm ( 101, 102). These pores are scattered in a very irregular manner in the inner wall of Schlemm’s canal. In human eyes their number has been estimated to be around 15,000~ZO,OOO/eye. A reasonable hypothesis for the creation of the pores is the following (102). Pinocytosis occurs in all parts of the endothelial cells. At places where the cells are very thin the creation of a pinocytotic vesicle may result in a fenestrated small pore; the pressure gradient over the pore may then make its membrane burst and thus open up a connection between the invagination and the canal of Schlemm. If for some reason the flow through the invagination into the canal of Schlemm stops it is possible that the pore disappears. At present, however, nothing is known about the lifetime of the pores. Most pores seem to exist in the walls of the invaginations but there are exceptions. Pores also have been found in other very thin parts of the endothelial cells (102). Often the pores do not overlap with the openings into the endothelial cells from the meshwork side and this results in a valvelike action. If the pressure in the canal increases above that in the anterior chamber, the invaginations collapse and probably disappear within a short time. For that reason there is either none or very little backflow from the canal toward the anterior chamber-if for some reason there is a local increase in the intrascleral venous pressure, blood would flow into the canal of Schlemm. A reversal of the normal pressure gradient across the meshwork also causes a widening of the canal of Schlemm and a compression of the meshwork tissue (88). The endothelial cells that cover the uveal and corneoscleral meshwork and also those of the endothelial meshwork are phagocytotic (87, 142). Foreign material entering the meshwork with the aqueous humor thus can be degraded by the cells. Rohen and van der Zypen (142) have shown that even such nondigestible material as gold particles can be eliminated from the meshwork by the endothelial cells. The particles were ingested, and the cells then detached and moved out of the tissue into the canal of Schlemm. The picture that emerges is that of a selfcleaning composite filter with rectifying properties. Large pieces of debris entering the chamber-angle tissue are caught by the uveal meshwork and degraded. Smaller fragments may pass as far as the corneoscleral meshwork to be caught and degraded. Finally, very fine material around 1-2 pm may enter the endothelial meshwork, where it tends to become degraded. Particles small enough to pass through the endothelial meshwork also can pass through the endothelial cells of the inner wall of Schlemm’s canal. Insufficient self-cleaning of the meshwork tissue can be expected to lead to an accumulation in the meshwork of foreign material and a rise in the outflow resistance. There might be two reasons for insufficiency: one is an increased inflow of debris; the other is a reduced phagocytotic capacity of the endothelial cells. It seems likely that one of these alternatives or both may contribute to the development of open-angle glaucoma. Accumulation of an unknown substance in the juxtacanalicular tissue in fact has been reported in glaucomatous eyes (140). There is no complete agreement on the ultrastructure of the inner wall endo-


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thelium and the way in which the aqueous humor moves through the endothelium. In several studies on the ultrastructure no pores were observed in the inner wall (149). Investigators finding no pores in the inner wall of Schlemm’s canal had to suggest some hypothesis for the drainage of aqueous humor into the canal. Movement between the endothelial cells into the canal of course was one obvious possibility. Most investigators have reported that the endothelial cells are attached to each other by tight junctions but in a recent study it was suggested that there is a narrow cleft between the cells (149). However, simple calculations show that if a maximum number of 8-nm pores in the junctions between the endothelial cells is assumed such pores could account for only about 1 % of the total conductivity of the inner wall of Schlemm’s canal. The cells of the inner wall of Schlemm’s canal were considered to be unique for a long time. Recently, however, Tripathi and Tripathi (156) discovered similar cells in the sinus structures that are analogous to the canal of Schlemm in lower animals and the same type of cells was also observed by Tripathi (155) in the arachnoid matter through which the cerebrospinal fluid enters the superior saggital sinus. 2. Uveossleral drainage There is no complete endothelial layer covering the anterior surface of the cifiary body, which faces the anterior chamber between the cornea and the iris. There also is no delimitation of the spaces between the trabecular sheets and the spaces between the muscle bundles of the ciliary muscle. Fluid thus can pass from the chamber angle into the tissue spaces within the ciliary muscle. These spaces in turn open into the suprachoroid from which fluid can pass through the scleral substance or through the perivascular spaces into the episcleral tissues. The pressure in the suprachoroid, as mentioned previously, is lower than that in the anterior chamber, the difference being at least a few millimeters of Hg under normal conditions. These are the conditions resulting in a very peculiar type of drainage of the aqueous humor. The fluid enters the ciliary muscle via its anterior surface directly in the iridocorneal angle or it passes into the muscle via the intertrabecular spaces. It then flows through the interstitial spaces of the muscle into the suprachoroid and out through the sclera. On its way through the muscle, the fluid mixes with tissue fluid from the muscle and probably also with tissue fluid from the ciliary processes that is seeping out of the processes. The routes through which the modified aqueous passes backward are so wide that even latex particles with a diameter of 1 pm can be recovered at the posterior pole of the eye within a few hours after their administration into the anterior chamber (103). In subhuman primates uveoscleral flow is considerable-around 30-50% of the total drainage in animals under general anesthesia (43). The importance of uveoscleral flow in humans has been investigated only in old patients with ocular tumors, making enucleation necessary. In such eyes the uveoscleral flow was about 5-20 % of the total drainage (148). It may very well be larger in younger


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persons in whom the ciliary muscle is not partly degenerated. In cats, which also have a well-developed ciliary muscle, uveoscleral flow is present (33) but its relative role in aqueous humor drainage is smaller than in the primates. Finally, in rabbits the ciliary muscle is very poor and practically no fluid moves from the anterior chamber into the suprachoroid (31). A small amount of fluid, however, moves through the sclera near the limbus directly through the scleral substance and also through the perivascular spaces. It has been shown that in primates the uveoscleral flow decreases at very low intraocular pressures. However, moderate increments in the eye pressure above the normal level caused by infusion of fluid into the anterior chamber do not increase the uveoscleral flow significantly (34). Of course it is not surprising that the uveoscleral flow decreases at low intraocular pressures. At such pressures the gradient for flow is reduced. It is less clear why the uveoscleral flow does not increase significantly at pressures above 7-10 mmHg. Since many parts of the uveoscleral routes are within the soft intraocular tissues, one can expect, however, that there are very complex pressure and resistance conditions in these routes.

3. OutJlow resistance Grant (84) has shown that if the tissue between the anterior chamber and the canal of Schlemm is removed the outflow resistance in the eye is reduced by 75 %. Only a small part of the resistance to outflow thus lies within the routes through the sclera. The resistance in the pathways through the endothelial cells of the inner wall of Schlemm’s canal has been calculated by use of data for pore sizes and pore frequencies obtained with scanning electron microscopy (50). The results indicated that in this layer also the resistance to flow is low. The main resistance to outflow thus seems to be located in the narrow parts of the corneoscleral meshwork and in the endothelial meshwork close to the inner wall of Schlemm’s canal. The latter tissue may be the more important: Ltitjen-Drecoll (118) in a recent study in monkeys found a negative correlation between the outflow resistance and the volume of the routes close to the inner wall of Schlemm’s canal. Accommodation is known to reduce the outflow resistance and drugs causing contraction of the ciliary muscle also tend to cause reduction. Drugs relaxing the ciliary muscle tend to increase the resistance (18). Another effect of contraction of the ciliary muscle is to decrease uveoscleral flow, whereas relaxation increases the flow (51). The explanation for these effects seems to be that contraction of the ciliary muscle causes a tighter packing of the muscle bundles and makes the muscle thicker in the limbus region (20, 14 1). The latter effect causes separation of the lamellae in the uveal meshwork, which can be expected to reduce the resistance in this part of the meshwork (Fig. 5). Tissue strands between the uveal meshwork and the corneoscleral meshwork may cause some separation also of the corneoscleral lamellae and a reduction in the resistance in this region and possibly also in the endothelial meshwork. It is not surprising of course that the flow through the interstitial tissue spaces of the ciliary muscle is very much reduced if the volume of these spaces is reduced by contraction of the muscle.


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meshwork Aqueous interstitial meshwork appeared.

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DYNAMICS

5. A:ciliary muscle is relaxed, spaces between lamellae of uveal and corneoscleral are narrow, and interstitial spaces between muscle bundles of ciliary muscle are wide. humor leaves the anterior chamber by routes via Schlemm’s canal and by routes via spaces of ciliary muscle. B: ciliary muscle is contracted, spaces in different parts of are relatively wide, and interstitial spaces between muscle bundles have almost disAqueous humor leaves the eye almost entirely by routes via Schlemm’s canal.

Adrenergic drugs have unexpected effects on outflow resistance. Such agents tend to relax the ciliary muscle and increase the uveoscleral flow but at the same time they tend to reduce the outflow resistance in the routes via Schlemm’s canal. The mechanism behind the action of the adrenergic drugs on the outflow resistance is not at all clear. It seems likely that there is some change in the tissue between the anterior chamber and the canal of Schlemm (39). Changes in the blood flow through the routes in the sclera draining both the aqueous humor and the blood also have been suggested as contributing to these results (111). In monkeys the effects on the outflow conductance are caused mainly by stimulation of beta receptors (39). In rabbits mainly alpha receptors seem to be involved (113). There are nerves and nerve endings in the chamber-angle tissue that might be involved in a regulating mechanism, but it seems very doubtful that such a mechanism involving a regulating center exists. However, there may be a local mechanism in the sense that an increaied flow tends to wash out some material from the chamber-angle tissue and a reduced flow may lead to increased amounts of ground substance in the tissue. The increase in conductance in the outflow routes often seen in extended experiments-in which the eye pressure is slightly elevated by infusion of fluid (16, ,39) into the anterior chamber-is one piece of evidence supporting such a hypothesis. The evidence against this hypothesis is the observation in a rather large number of monkeys that there was no correlation between the outflow resistance and the outflow via Schlemm’s canal (43). V.

SUMMARY

The nutrition of the intraocular tissues is accomplished the uveal vessels, and by the aqueous humor.

by the retinal

vessels,


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Both morphologically and physiologically the retinal vessels are similar to those in the brain. The endothelial cells of the capillaries are attached to each other by tight junctions, the resistance vessels respond poorly to a large number of drugs, and the blood flow through the retina is autoregulated and very little affected by the sympathetic nervous system. The blood vessels of the iris also have morphological and permeability characteristics similar to those in the brain but they are under a strong influence from the sympathetic nerves and react to many drugs. The blood flow is autoregulated. The blood vessels of the choroid and the ciliary processes are similar to those in the small intestine and in the kidney. The endothelial cells of the capillaries are fenestrated; the vessels respond to sympathetic nervous stimulation and to a large number of vasoactive drugs. Autoregulation of the blood flow is intermediate in the ciliary body and very poor or absent in the choroid. The aqueous humor is secreted by the two-layered epithelium of the ciliary processes. A standing osmotic gradient model involving active transport of Na+, Cl-, and possibly HCOB- seems to fit the available data. Ultrafiltration through the ciliary epithelium is unlikely to contribute positively to the formation of the aqueous humor. Mechanisms exist for the enrichment of the aqueous humor by ascorbic acid, amino acids, and possibly glucose. Other mechanisms transporting iodide, organic anions, and metabolites destined for excretion by the liver seem to be involved in the detoxification of the aqueous humor. Aqueous humor formation appears to be under very little or no central control. The aqueous humor is drained from the eye by two routes: I) via Schlemm’s canal (or its equivalents in lower animals) into the episcleral and the conjunctival veins and 2) through uveoscleral routes from the anterior chamber through the ciliary muscle into the suprachoroid and out through the sclera. The blood-retinal barrier has two parts: one is the endothelium of the retinal capillaries; the other is constituted by the pigment epithelium of the retina. The blood-aqueous barrier also has two anatomical parts: one is represented by the layer of nonpigmented cells in the ciliary epithelium; the other is constituted by the endothelial cells of the iris capillaries. A functional barrier preventing movement of locally produced tissue fluid from the uvea into the anterior chamber is created by the uveoscleral flow of the aqueous humor moving in the opposite direction. The eye has no lymph vessels. A high protein concentration in the tissue fluid of the choroid causes a high oncotic pressure in this fluid that contributes to the movement of water from the retina into the choroid. The sclera is permeable even to proteins and tissue fluid thus can pass from the choroid through the sclera into the episcleral tissues. The arrangement of the mechanisms involved in ocular nutrition contributes to the very good optical properties of the eye but involves hazards. Glaucoma, cataract, and macular degeneration are some diseases that may have their basis in the “risky” arrangement of the nutritional apparatus of the eye. Investigations from the author’s laboratory discussed in this review were supported in part by Public Health Service Grant EY 00475 fkom the National Eye Institute and by Grant B7414X-147 from the Swedish Medical Research Council.


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REFERENCES 1. ALLANSMITH, M., L. NEWMAN, AND C. WHITNEY. The distribution of immunoglobulin in the rabbit eye. Ad. OphzhdmoZ. 86 : 60-64, 1971. 2. ALLANSMITH, M. R., C. R. WHITNEY, B. H. MCCLELLAN, AND L. P. NEWMAN. Immunoglobulins in the human eye. Arch. Ojhthdmol. 89: 3645, 1973. 3. ALM, A. Aspects of physiological and pharmacological regulation of blood flow through retina and uvea. A study in cats and monkcys. Acta Univ. U’j+ s&&z. 137: l-28, 1972. 4. ALM, A. Effects of norepinephrine, angiotensin, dihydroergotamine, papaverine, isoproterenol, histamine, nicotinic acid and xanthinol nicotinate on retinal oxygen tension in cats. Acta OphthuZmol. 50: 707-719, 1972. 5. ALM, A., AND A. BILL. Blood flow and oxygen extraction in the cat uvea at normal and high intraocular pressures. Acta Physiol. &and. 80 : 19-28, 1970. 6. ALM, A., AND A. BILL. The oxygen supply to the retina, I. Effects of changes in intraocular and arterial blood pressures, and in arterial Po2 and Pcor on the oxygen tension in the vitreous body of the cat. Acta Physid. Scud 84 : 261-274, 1972. 7. ALM, A., AND A. BILL. The oxygen supply to the retina, II. Effects of high intraocular pressure and of increased arterial carbon dioxide tension on uveal and retinal blood flow in cats. Acto Physiol. Scud. 84 : 306-319, 1972. 8. ALM, A., AND A. BILL. The effect of stimulation of the cervical sympathetic chain on retinal oxygen tension and on uveal, retinal and cerebral blood flow in cats. Acta Physiol. Scat&. 88 : 84-94, 1973. 9. ALM, A., AND A. BILL. Ocular and optic nerve blood flow at normal and increased intraocular pressures in monkeys (Mucuca inns) : a study with radioactively labclled microspheres including flow determinations in brain and some other tissues. ExptZ. Eye Res. 15 : 1S-29, 1973. 10. ALM, A., A. BILL, AND F. A. YOUNG. The effects of pilocarpine and neostigmine on the blood flow through the anterior uvea in monkeys. A study with radioactively labelled microspheres. ExptZ. Eye Res. 15: 31-36, 1973. 11. ALPHEN, G. W. VAN. On cmmetropia and ametropia. Oplithafmdogicu 142, Suppl. : I-92, 1961. 12. ANDERSON, D. R. Vascular supply to the optic nerve of primates. Am. J. Ojhthalmol. 70: 341-351, 1970. 13. ANDERSON, D. R. The retinal capillary bed at the posterior pole of primate eyes. Am. J. Ophthdmvl. 71 : 815818, 1971. 14. ASHTON, N. Some aspects of the comparative pathology of oxygen toxicity in the retina. &it. J. OPhthdmol. 52 : 505531, 1968. 15. BALLINTINE, E. J. Glaucoma. In: Trunsoctions of the Second Confrrencc. Princeton, N.J.: Josiah Macy, Jr. Found., 1956, p. 118. 16. BARANY, E. H. Simultaneous measurements of changing intraocular pressure and outflow facility in the vervet monkey by constant pressure infusion. Invest. Ophthalmd. 3 : 135-143, 1964. 17. BAR&Y, E. H. A mathematical formu1ation of intraocular pressure as dependent on secretion, ultrafiltration, bulk outflow and osmotic reabsorption of fluid. Znorst. OphthalmoZ. 2: 584-590, 1963.

18. BARANY, E. H. Relative importance of autonomic nervous tone and structure as determinants of outflow resistance in normal monkey eyes (CcrcopitAccus ethiops and Macaca irus). In : The Structure of the Eye. 22. Symposium, edited by J. W. Rohen. Stuttgart: Schattauer-Verlag, 1965, p. 223-236. 19. BARANY, E. H. The liver-like anion transport systern in rabbit kidney, uvea and choroid plexus. I. Selectivity of some inhibitors, direction of transport, possible physiological substrates. Acta Physid. Scud. 88 : 412429, 1973. 20. B&ANY, E. H., AND J. W. ROHEN. Localized contraction and relaxation within the ciliary muscle of the vervet monkey CercopirAecus etAiops. In: The Structure of the Eye. ZZ. Symjosium, edited by J. W. Rohen. Stuttgart : Scha ttauer-Verlag, 1965, p. 287311. 21, BARFORT, P., AND D. MAURICE. Electrical potential and fluid transport across the cornea1 endothe1ium. Ex#rl. Eye Res. 19: 11-19, 1974. 22. BECKER, B. The effects of the carbonic anhydrase inhibitor, acetazolamide, on the composition of the aqueous humor. Am. J. Ophthalmol. 40, Part 2 : 129136, 1955. 23. BECKER, B. Carbonic anhydrasc and the formation of aqueous humor. Am. J. Ophthalmof. 47, Part 2: 342-36 1, 1959. 24. BECKER, B. The transport of organic anions by the rabbit eye. Am. J. OpAthuZmd. 50: 862-867, 1960. 25. BECKER, B. Iodide transport by the rabbit eye. Am. J. Physiol. 200: 804-806, 1961. 26. BERGGREN, L. Effect of composition of medium and of metabolic inhibitors on secretion in vitro by the ciliary processes of the rabbit eye. Invest. Ophthdmol. 4: 83-90, 1965. 27. BERGGREN, L. Effect of parasympathomimetic and sympathomimetic drugs on secretion in vitro by the ciliary processes of the rabbit eye. Invest. Ofihthulmol. 4: 91-97, 1965 28. BERGGREN, L. Effect of a mucurial diuretic, mersalyl, on in vitro secretory activity of the rabbit eye ciliary processes. Acta OphthaZmoZ. 48: 275-283, 1970. 29. BEST, M., D. GERSTEIN, N. WALD, A. 2. RABINOVITZ, AND G. H. HILLER. Autoregulation of ocular blood flow. Arch. Ophthufmol. 89: 143148, 1973. 30. BILL, A. Autonomic nervous control of uveal blood flow. Actu Physiol. Scud 56 : 70-81, 1962. 31. BILL, A. The routes for bulk drainage of aqueous humor in rabbits with and without cy~lodialysir. DOG. Ophthdmol. 20 : 157-169, 1966. 32. BILL, A. Conventional and uveo-scleral drainage of aqueous humor in the cynomolgus monkey (Mucucu inns) at normal and high intraocular pressures. Ex@. Eye Res. 5 : 45-54, 1966. 33. BILL, A. Formation and drainage of aqueous humor in cats. Exjtl. Eye Res. 5 : 185-190, 1966. 34. BILL, A. Further studies on the influence of the intraocular pressure on aqueous humor dynamics in cynomolgus monkeys. Invest. Ojhthdmd. 6: 364-372, 1967. 35. BILL, A. Capillary permeability to and extravascular dynamics of myoglobin, albumin and gammaglobulin in the uvca. Acta Physid. Scand. 73 : 204-219, 1968. 36. BILL, A. A method to determine osmotically effec-


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ANDERS tive albumin and gammaglobulin concentrations in tissue fluids, its application to the uvea and a note on the effects of capillary “leaks” on tissue fluid dynamics. A& Physiof. Scond. 73 : 51 l-522, 1968. BILL, A. Early effects of epinephrine on aqueous humor dynamics in vervet monkeys. ExptZ. Eye Res. 8: 35-43, 1969. BILL, A. Effects of atropine on aqueous humor dynamics in the vervet monkey, Cercopithccus ethiops. Exprl. Eye Res. 8 : 284-291, 1969. BILL, A. Effects of norepinephrine, isoproterenol and sympathetic stimulation on aqueous humor dynamics in vervet monkeys. Exptf. Eye Res. IO : 3146, 1970. BILL, A. Ocular circulation. In: Physiology of the Eye, edited by R. Moses. St. Louis, MO.: Mosby, 1970, p. 278-296. BILL, A. The effect of changes in arterial blood pressure on the rate of aqueous humor formation in a primate (Cercopithecus ethiops). Ophthalmol. Res. 1 : 193-200, 1970. BILL, A. Effects of longstanding stepwise increments in eye pressure on the rate of aqueous humor formation in a primate (Cercopirhecus cthiops). Exptl. Eye Res. 12: 184-193, 1971. BILL, A. Aqueous humor dynamics in monkeys (Macaca irus and Cercopithecus ethiops). Expel. Eye Res. 195-206, 1971. BILL, A. The role of ciliary blood flow and ultrafiltration in aqueous humor formation. Exptl. Eye Res. 16 : 287-298, 1973. BILL, A. The role of the iris vessels in aqueous humor dynamics. Japan. J. Ophthafmol. 18 : 30-36, 1974. BILL, A. Effects of acetazolamide and carotid occlusion on the ocular blood flow in unanaesthetised rabbits. Invest. Ophthalmof. 13: 954-958, 1974. BILL, A., AND A. ALM. Physiological aspects on the circulation in the optic nerve head. In: The Zntemationaf Gfaucoma Symposium, Alibi 1974, edited by R. Etienne. Marseille : Diffusion Litteraire et Scientifique, 1975. BILL, A., AND K. HELLSING. Production and drainage of aqueous humor in the cynomolgus monkey (Macaca irus). Invest. Ophthalmoi. 4: 920-926, 1965. BILL, A., AND C. I. PHILLIPS. Uveoscleral drainage of aqueous humor in human eyes. Exptf. Eye Res. 12: 275-281, 1971. BILL, A., AND B. SVEDBERGH. Scanning electron microscopic studies of the trabecular meshwork and the canal of Schlemm-an attempt to localize the main resistance to outflow of aqueous humor in man. Acta Ophthaimol. 50 : 295-320, 1972. BILL, A., AND P.-E. WAHLINDER. The effects of pilocarpine on the dynamics of aqueous humor in a primate (Macuca irus). Invest. Ophtholmol. 5: 178-175, 1966. BITO, L. 2. Accumulation and apparent active transport of prostaglandins by some rabbit tissues in vitro. J. Physiol., London 221 : 371-387, 1972. BRUBAKER, R. F. Determination of episcleral venous pressure in the eye. A comparison of three methods. Arch. Ophthulmol. 77: 1IO-I 14, 1967. BRUBAKER, R. F. The measurement of pseudofacility and true facility by constant pressure perfusion in the normal rhesus monkey eye. Invest. Ophthulmol. 9: 42-52, 1970.

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55. BUETTNER, H., R.MACHEMER, S. CHARLES, AND D. R. ANDERSON. Experimental derivation of choroidal blood flow. Retinal morphology, early receptor potential, and electroretinography. Am. J. Ophthalmol. 75 : 943-952, 1973. 56. BULPITT, C., AND C. T. DOLLERY. Estimation of retinal blood flow by measurement of the mean circulation time. Cardiovascular Res. 5: 406412, 1971. 57. CEVARIO, S. J. A leakproof needle useful for anterior chamber mixing or for multiple injections in acute experiments. Invest. Ophthulmol. 12 : 464465, 1973. 58. CEVARIO, S. J., AND F. J. MACRI. The inhibitory effect of pentobarbital Na on aqueous humor formation. Invest. Ophthalmol. 13: 384-386, 1974. 59. CHANDRA, S. R., AND E. FRIEDMAN. Choroidal blood flow, II. The effects of autonomic agents. Arch. OphthaImoZ. 87 : 67-69, 1972. 60. COHEN, A. I. Is there a potential defect in the blood-retinal barrier at the choroidal level of the optic nerve canal. Invest. Ophthufmof. 12 : 513-519, 1973. 61. COLE, D. F. Aqueous humor formation. Dot. Ophthulmol. 2 1 : 116-I 38, 1966. 62. COLE, D. F. Evidence for active transport of chloride in ciliary epithelium of the rabbit. Exptl. Eye Res. 8: 5-15, 1969. 63. COLE, D. F., AND R. RUMBLE. Responses of iris blood flow to stimulation of the cervical sympathetic in the rabbit. Exptl. Eye Res. IO: 183-191, 1970. 64. COLE, D. F., AND W. G. UNGER. Prostaglandinr aa mediators for the responses of the eye to trauma. Exptl. Eye Res. 17 : 357-368, 1973. 65. CURRAN, P. F., AND J. R. MACINTOSH. A model system for biological water transport. Nuture 193 : 347-348, 1962. 66. DALSKE, H. F. Pharmacological reactivity of isolated ciliary arteries. Znrrcst. Ophthalmol. 13 : 389-392, 1974. 67. DAVSON, H. The intraocular fluids. In: The Eye, edited by H. Davson. New York: Academic, 1969, p. 67-186. 68. DIAMOND, J. M., AND W. H. BOSSERT. Standing-gradient osmotic flow. J. Gen. Physiol. 50 : 20612083, 1967. 69. DOLLERY, C. T., C. J. BULPITT, AND E. M. KOHNER. Oxygen supply to the retina from the retinal and choroidal circulations at normal and increased arterial oxygen tensions. Invest. Ophthuimof. 8 : 588-594, 1969. 70. DRANCE, S. M., V. P. SWEENEY, R. W. MORGAN, AND F. FELDMAN. Studies of factors involved in the production of low tension glaucoma. Arch. Ophthalmol. 89 : 457465, 1973. 71. DUKE-ELDER, S. System of Ophthulmofogy. London: Henry Kimpton 1968, vol. 4. 72. EAKINS, K. E. The effect of intravitreous injections of norepinephrine, epinephrine and isoproterenol on the intraocular pressure and aqueous humor dynamics of rabbit eyes. J. Pharmacol. Expel. Therap. 140 : 79-84, 1963. 73. EDWARDS, J., V. L. HALLMAN, AND E. S. PERKINS. Perfusion studies on the monkey eye. Exptl. Eye Res. 6: 316-326, 1967. 74. EHINGER, B. Adrenergic nerves to the eye and to related structures in man and in the cynomolgur monkey. Invest. Ophthalmol. 5 : 42-52, 1966.


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B. Localization of the uptake of proataEl in the eye. Exptl. Eye Res. 17: 4347, AND

I. C. MICHAELSON.

Assessment of pharmacologic effects on the retinal circulation of hypertensive subjects by a quantitative method. Microvascular Rcs. 4 : 374-383, 1972. ERNEST, J. T. Autoregulation of optic-disk oxygen tension. Invest. Ophthalmof. 13: 101-106, 1974. FFYTCHE, T. J., C. J. BULPITT, E. M. KOHNER, D. ARCHER, AND C. T. DOLLERY. Effect of changes in intraocular pressure on the retinal microcirculation. J. Ophthalmof. 58 : 514-522, 1974. FRIEDMAN, E., AND S. R. CHANDRA. Choroidal blood flow, III. Effects of oxygen and carbon dioxide. Arch. Ophthdmol. 87: 70-71, 1972. FOLKOW, B., AND E. NEIL. Circulafion. London1 Oxford Univ. Press, 1971. GAASTERLAND, D., C. KUPFER, K. ROSS, AND H. L. GABELNICK. Studies of aqueous humor dynamics in man III. Measurements in young normal subjects using norepinephrine and isoproterenol. Invest. Ophthalmof. 12: 267-279, 1973. GARG, L. C., AND W. W. OPPELT. The effect of ouabain and acetazolamide on transport of sodium and chloride from plasma to aqueous humor. J. Pharmacd. Exptl. Therap. 175 : 237-247, 1970. GLOSTER, J. Response of the intraocular pressure to diencephalic stimulation. &it. J. Ophthalmol. 44:

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aqueous perfusion in eyes. Arch. Ophthalmol. 69 : 783-801,

85. GRAYSON, M. C., AND A. M. LATIES. Ocular localization of sodium fluorescein. Arch. Ophthalmol. 85 : 600-609, 1971. 86. GREEN, K., AND J. E. PEDERSON. Contribution of recretion and filtration to aqueous humor formation. Am. J. Physiof. 222 : 1218-l 226, 1972. 87. GRIERSON, I., AND W. R. LEE. Erythrocyte phagocytosis in the human trabecular meshwork. Bit. J. Ophthalmof. 57 : 400415, 1973. I., AND W. R. LEE. Changes in the 88. GRIERSON, monkey outflow apparatus at graded levels of intraanalysis by light miocular pressure : a qualitative croscopy and scanning electron microscopy. Exptl. Eye Res. 19: 21-33, 1974. 89. GUYTON, A. C., H. J. GRANGER, AND A. TAYLOR. Interstitial fluid pressure. Physiof. Rev. 51 : 527-563, 197 1. 90. HANNA, C., AND J. SANCHEZ. Effects of acetazolamide on concentration of free amino acids in aqueous humor. Ophthalmic Res. 3 : 283-288, 1972. H. P. J. Histochemical demonstration 91. HANSSON, of carbonic anhydrase activity in some epithelia noted for active transport. Acta Physiol. Sand. 73: 427434, 1968. 92. HAYREH, S. S. The orbital vessels of rhesus monkeys, Exptf. Eye Rcs. 3 : 16-30, 1964. 93. HAYREH, S. S. Blood supply of the optic nerve head and its role in optic atrophy, glaucoma, and oedema of the optic disc. &it. J. Ophthalmol. 53:

721-748, 1969. S. S. Pathogenesis 94. HAYREH,

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