Uveoscleral outflow pathway better understood as more drugs target it

Researchers demonstrate the decrease in uveoscleral outflow may be age related.

ByBob Kronemyer

WAILEA, U.S.A. — Contrary to popular belief, the uveoscleral outflow pathway is a major component of human aqueous outflow, glaucoma experts now say. It is important to consider it to better understand glaucoma pharmacology and, in particular, prostaglandin effects on intraocular pressure (IOP).

“As residents, most ophthalmologists learned that the major component of aqueous outflow was through the trabecular meshwork,” said Robert N. Weinreb, MD, at Hawaii 2000, sponsored by Ocular Surgery News and the New England Eye Center. However, “there has been accumulating evidence over the past 15 years that the uveoscleral pathway is an important component and may even comprise more than 50% of outflow in many healthy human eyes.”

The mechanism of action of latanoprost (Xalatan; Pharmacia & Upjohn), the currently available prostaglandin analog, “is by increasing the uveoscleral outflow pathway,” said Dr. Weinreb, a professor of ophthalmology at the University of California, San Diego. “Because this pathway accounts for as much as 50% of the total outflow in healthy eyes, one can certainly understand why a prostaglandin can be such an effective pressure lowering agent.” Latanoprost, for example, has a minimal effect on inflow and trabecular meshwork outflow, and “it at least doubles the uveoscleral outflow pathway.” Other drugs, including brimonidine (Alphagan; Allergan) and epinephrine, also appear to have a major effect on the uveoscleral outflow pathway.

The uveoscleral pathway also may take on an increasingly important role as a person ages. “The uveoscleral pathway may even be more important as one ages,” Dr. Weinreb said. “There appears to be an age-related decrease in uveoscleral outflow, both in humans, as demonstrated by Drs. Carol Toris and Carl Camras, and in monkeys, as demonstrated by Dr. Paul Kaufman.”

Ciliary muscle prominent

The uveoscleral outflow pathway consists largely of the ciliary muscle, as well as the iris root and sclera.

The uveoscleral outflow pathway is important in many clinical settings, such as with choroidal effusions following glaucoma surgery. “A choroidal effusion is an accumulation of fluid within the suprachoroidal space,” Dr. Weinreb said. “In many instances, this is due to an enhanced outflow through the uveoscleral pathway.” Likewise, a cyclodialysis cleft is primarily a tear in the longitudinal ciliary muscle that also lowers IOP by increasing flow through the uveoscleral outflow pathway. “The ciliary muscle consists of an interstitial extracellular matrix and a basement membrane, which surrounds the muscle bundles within the ciliary muscle. In order to understand the mechanism of the action of drugs on the uveoscleral pathway, it is useful to understand what happens to the extracellular matrix.”

Altered extracellular matrix

Dr. Weinreb and his colleagues first became interested in the extracellular matrix when they observed the ciliary muscle in monkey eyes that had been treated with prostaglandins. Elke Lutjen Drecoll, PhD, had previously detected large spaces in the ciliary muscle of this animal. “That investigator postulated that prostaglandins might be washing out extracellular matrix that was accumulating within the ciliary muscle, but admittedly did not know the basis for this enlarged space,” Dr. Weinreb said. “With James Lindsey, PhD, a colleague at the University of California, San Diego, we hypothesized that the extracellular matrix might be altered by the prostaglandin, and that once it was altered, it would be washed out.”

Dr. Weinreb’s team treated some cultured ciliary muscle cells with prostaglandins. “When we looked at different extracellular matrix components — collagen I, collagen III, collagen IV — we found that in the groups that had been treated with prostaglandins, some extracellular matrix components were reduced,” Dr. Weinreb said.

To determine what was actually reducing the extracellular matrix when treated with prostaglandins, Dr. Weinreb’s team looked at a series of enzymes known as the metalloproteinases (collagenase for MMP-1 or gelatinase). “These are a family of proteases that degrade extracellular matrix. They are common in all tissue throughout the body,” Dr. Weinreb said. “Our hypothesis was that the prostaglandin was altering the extracellular matrix by increasing the amount of the MMPs.” By revisiting the cells, Dr. Weinreb found that the activity of MMP is increased when exposed to prostaglandin.

In-vivo testing

Dr. Weinreb tested his hypothesis in monkeys with Dr. Paul Kaufman at the University of Wisconsin. “We treated four monkeys with prostaglandin F2 alpha, and then we examined the ciliary muscle,” Dr. Weinreb said. “In the ciliary muscle, all the collagens were reduced in the treated group. This also was the case in the iris root and in the sclera,” he said. On the other hand, “the MMPs were increased. This supported our hypothesis.”

In summary, “it is not surprising to me that some prostaglandins are so effective at lowering IOP, as their effect appears to be on the uveoscleral outflow pathway,” Dr. Weinreb said. “Perhaps other drugs have a similar effect.” He also said that it is possible that prostaglandins have additional effects other than an alteration in the ciliary muscle, including reducing muscle tone.

For Your Information:

Robert N. Weinreb, MD, can be reached at Glaucoma Center, University of California–San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0946 U.S.A.; +(1) 858-534-8824; fax: +(1) 858-534-1625. Dr. Weinreb has no direct financial interest in any of the products mentioned in this article. He has received research support and honoraria from Pharmacia & Upjohn Co. and Allergan.