Characterization of uveoscleral outflow in enucleated porcine eyes perfused under constant pressure.

Glaucoma is the leading cause of irreversible blindness in the United States. Blindness in those affected by the disease appears to be caused in most cases by compression of retinal ganglion cell axons in the optic nerve, due to elevated intraocular pressure (IOP). IOP increases over time because of impaired aqueous humor outflow. Many pharmaceuticals that lower IOP target aqueous secretion. Recently, prostaglandin and prostamide compounds have been introduced. They lower IOP primarily by increasing aqueous outflow through the unconventional, or uveoscleral, route. The precise molecular mechanisms by which these compounds lessen resistance in the outflow pathways to lower IOP are currently unknown. Aqueous humor is actively secreted into the posterior chamber by the ciliary processes. The fluid then passes through the pupil and can be drained in two ways at the iridocorneoscleral angle. Aqueous humor exiting through the conventional pathway crosses the trabecular meshwork and flows through Schlemm’s canal into large collector channels that reach to the surface of the sclera, at which point they join episcleral vessels. Aqueous humor, following the unconventional or uveoscleral pathway, passes through the ciliary muscle bundles into the supraciliary and suprachoroidal spaces. The fluid then leaves through the sclera. Whether it can also be drained by the posterior choroid into the vortex veins remains a subject of controversy. Although, in tracer studies in the rhesus monkey, evidence of outflow through vortex veins has been found,1–3 no significant amount of tracer was detected in the posterior choroid in human and mouse eyes.4,5 It is possible that drainage through the choroid occurs in some species but not in others. The uveoscleral pathway was first described by Bill,6 who reported that in the cynomolgus monkey, about half of the aqueous humor exits through the ciliary muscle. Bill and Phillips7 then observed this behavior in humans and found that the percentage of total aqueous outflow attributed to the uveoscleral pathway was approximately 10% to 20%. Later indirect calculations have produced values of approximately 35% in young adults and 3% in elderly persons over the age of 60.8,9 As reviewed by Nilsson,10 the relative importance of the unconventional pathway varies significantly with age and from species to species. In cats and rabbits, the uveoscleral outflow constitutes only 3% to 8% of the total drainage. It has been suggested10 that the prostaglandin-induced increase in uveoscleral outflow is caused by two mechanisms: an initial relaxation of the ciliary muscle, and a subsequent decrease in the resistance of the pathway due to changes in the extracellular matrix. After multiple doses of prostaglandin F2α (PGF2α) the ciliary muscles bundles in cynomolgus monkey eyes are widened and a loss of type 1 and III collagen fibers from the connective tissues in these spaces is observed.11,12 Other studies have shown that prostaglandin F2α and latanoprost induce increased secretion of prometalloproteinases (MMPs) which results in a rearrangement of the extracellular matrix of the ciliary muscle with a reduction in the amount of collagen.13–15 The corresponding increase in spaces between the ciliary muscle fibers may greatly reduce the hydraulic resistance of the uveoscleral pathway.16 In this study, we developed a new technique to measure directly the uveoscleral outflow in porcine eyes and to examine whether there is any outflow through the choroid into the vortex veins. After having measured total outflow during constant-pressure perfusion, we blocked the episcleral vessels with cyanoacrylate to eliminate outflow through the conventional pathway. After isolation, we then blocked the vortex veins to assess the amount of choroidal drainage.