away from the external wall when pressure is low.27,28,72,79,89,96,140

Evidence indicates that there is no direct opening of the hernia­ tions into the canal.27,28,79,89,96,140 The original study of the aqueous

valves illustrates, but does not emphasize, that the aqueous valves are always attached to the external wall of Schlemm’s canal and have a valve-like arrangement at the level of the external wall.140

One study interpreted the herniations as being the same struc­ tures as the aqueous valves and concluded that they could not carry aqueous to Schlemm’s canal.144 However, a salient feature of

the aqueous valves is their attachment to the external wall, thus suspending them within the canal.15,140 The study of the protru­

sions or herniations completely separated the walls of Schlemm’s canal, in the process disrupting the ‘tissue strands’144 or aqueous valves spanning the canal, and excluded the regions of disruption from observation.144 Although the study was valuable in further characterizing the herniations or protrusions,144 the study could

not address the appearance or function of the valves spanning

Schlemm’s canal.15,78,140,141,143,145

Collector channels, aqueous veins and episcleral veins

Schlemm’s canal is drained by a series of collector channels that in

turn drain into a complex system of intrascleral, episcleral, and sub­ conjunctival venous plexus.146–149 The collector channels arise from

the outer wall of Schlemm’s canal at irregular intervals (0.3–2.8 mm) that average 1.2 per mm150 creating a total of 20–30 collector channels.87 At the origin of some collector channels, torus or liplike openings are observed that are associated with septa.150 Septa at

collector channel ostia limit or prevent trabecular tissue from com­ pletely occluding the opening.27,150 A few (4–6) direct collector

channels ( 70 micron diameter) proceed directly from Schlemm’s canal through the sclera thus communicating directly with aque­ ous veins on the surface of the eye. Indirect collector channels are smaller ( 50 micron diameter), more numerous (15–20) and enter into the intrascleral drainage network. A few (4–6) intermediate types are present.150 Aqueous veins empty into episcleral and con­ junctival veins. Where aqueous and episcleral veins join, character­

istic laminar flow of aqueous humor and blood is seen on slit-lamp examination at the limbus.10,12,13,151–154 A number of manifestations

of pulsatile discharge of aqueous into the episcleral veins is also

seen.10,12,13,151–154

Resistance sites in the aqueous outflow system

Glaucoma results from an abnormality of the resistance charac­ teristics of the outflow system, but the actual nature of that resist­ ance remains controversial. The region of the trabecular beams is an unlikely source of significant resistance because of the large openings in the area and the lack of significant extracellular matrix material in the region. Investigators propose two very different models of the resistance location and mechanism. The first model envisions the main resistance localized to the juxtacanalicular space. The juxtacanalicular space acts as a syncytium of extracel­ lular matrix material and elastic-like fiber network that attaches to Schlemm’s canal endothelium.The syncytium must provide a suffi­ ciently stable geometry so that the extracellular matrix material can act as a passive filter regulating resistance. After passing through the juxtacanalicular resistance, aqueous passes through low-resistance pores in Schlemm’s canal endothelium.

The second model places the initial resistance to IOP-gener­ ated forces at Schlemm’s canal endothelium.The model necessitates redistribution of IOP-induced resistive forces at Schlemm’s canal endothelium to structural elements throughout a tensionally inte­ grated trabecular meshwork. The force redistribution takes place via cytoplasmic process attachments to Schlemm’s canal endothelium. A second component of the Schlemm’s canal endothelium/trabec­ ular meshwork resistance model is pressure-induced distention of Schlemm’s canal inner wall: such a distention leads to apposition between Schlemm’s canal walls. Schlemm’s canal wall apposition thus becomes a resistance element integral to the model.

Juxtacanalicular space resistance

The juxtacanalicular region is posited as a reasonable candidate for much of outflow resistance.71,85,155 Especially in non-pressurized

eyes, the space is narrower than the region of the trabecular lamella

and contains a greater concentration of extracellular and cellular elements than the rest of the meshwork.27–29,79,89,96,156,157 The jux­

tacanalicular space contains hyaluronic acid, other glycosaminogly­ cans (GAGs), other glycoproteins and fibronectin.66 An elastic-like fiber network along with cellular elements, fibrils, and structural proteins is described as creating a three-dimensional cellular sponge or syncytium. One may deduce that such a stable syncytium will be able to provide a resistance unit restricting flow.71

Glycosaminoglycans have been proposed as a key physiologic component of this resistance. The GAGs are found as components

of larger proteoglycans and generally function as a part of these larger molecules.155,158 The GAGs are heavily hydrated and able

to trap a large amount of water. Therefore GAGs are able to fill a very large hydrodynamic volume.158 Through hydration and fluid trapping mechanisms, the GAGs are proposed to reduce the func­

tional diameter of flow channels through the juxtacanalicular tis­ sues.155,158 A funneling mechanism dependent on the presence of

GAGs and Schlemm’s canal inner wall pores has been proposed to

alter effective resistance to flow,159 although two studies failed to find a correlation between outflow and pore density.66,122,125

The previously discussed evidence is indirect, but direct evidence is cited to indicate that the region accounts for about 75% of resist­ ance.160 Because the evidence is direct, it assumes special impor­ tance and warrants careful scrutiny. The investigators carefully pointed out that the micropipette used to cannulate Schlemm’s canal was 25 times the thickness of the highly compliant inner wall endothelium of Schlemm’s canal and that the actual location of the tip was not known at the time of measurements.160 They also referenced the previously identified compliance characteristics of the tissues as a possible cause of inaccurate interpretation of their results.27 Two other studies, involving Schlemm’s canal microcan­

nulation, did not find a high proportion of the resistance within the juxtacanalicular space.161,162

Alterations of extracellular matrix materials occur after laser trabeculoplasty.163 Upregulation of metalloproteinase synthesis also accompanies improvement of aqueous outflow following laser trabeculoplasty. This relationship between metalloproteinase upreg­ ulation and outflow improvement is offered as evidence that altera­

tions in the extracellular matrix distribution in the juxtacanalicular space contribute to outflow resistance.164–166 However, the response

to injury is complex as is illustrated by evidence of repopulation of trabecular meshwork cells following injury.167 Of interest, most of the extracellular matrix subject to remodeling responses is in the trabecular beams.