12 Do Prostaglandins Make Uveoscleral Outflow More Pressure Dependent? The question of pressure-dependency is important because it reflects the eye’s capacity to adjust aqueous drainage in response to changes in eye pressure. Under normal conditions, the uveoscleral outflow pathway likely can make only small magnitude adjustments in outflow in response to different eye pressures. Before addressing the question of whether prostaglandins make uveoscleral outflow more pressure dependent, one must first determine if uveoscleral outflow is pressure dependent at all. Some arguments are based on the belief that the driving force for uveoscleral flow is provided by the difference in pressure between the anterior chamber and the suprachoroidal space, which in the monkey is ~ 4 mm Hg. Within the intraocular pressure (IOP) range of ~ 10 to 40 mm Hg, a change in IOP is reflected by an equal change in pressure in the suprachoroidal space, thereby maintaining the pressure difference at a constant value.1 In contrast to the pressure-dependent flow from the anterior chamber across the trabecular meshwork into Schlemm’s canal, drainage via the uveoscleral pathway is virtually independent of pressure at IOP levels greater than 7 to 10 mm Hg.2 Under normal circumstances, uveoscleral facility2 in the monkey is ≤ 0.02 µL/min/mm Hg, and thus is a negligible component (< 6%) of trabecular outflow facility, which in the cited study was 0.307 µL/min/mm Hg. However, under certain conditions, other investigators found uveoscleral outflow to be more pressure-sensitive than described by Bill.2 Uveoscleral facility in monkeys has been shown to increase following the induction of inflammation by bovine serum injection into the vitreous cavity. Uveoscleral facility in control eyes ranged from 0.047 to 0.052 µL/min/mm Hg as determined from fluoresceinated dextran infusion at 15 mm Hg for 30 minutes. In inflamed eyes, uveoscleral facility increased two- to fivefold depending on the size of the tracer.3 Cyclodialysis was also shown to increase uveoscleral facility in monkeys from 0.01 µL/min/mm Hg in control eyes to 0.07 µL/min/mm Hg in cyclodialysis eyes. The latter studies utilized fluoresceinated dextrans of 70,000 mw (molecular weight) and pressures of either 4 mm Hg or 35 mm Hg for 30 minutes.4 Inflammation produced with both of these techniques likely resulted in the release of prostaglandins. Therefore, it is reasonable to hypothesize that uveoscleral outflow may become more sensitive to pressure following prostaglandin treatment. We conducted studies using the isotope dilution technique5 to measure uveoscleral outflow following unilateral topical prostaglandin F2 (PGF2α)-isopropylester (PGF2α-IE) treatment of 2 µg twice daily for 4 or 5 days in cynomolgus monkeys as confirmation that the technique could detect changes in uveoscleral outflow, as requested for another study.6 Because the IOP in most of the monkeys decreased below episcleral venous pressure during the isotope studies, a modification of the technique was made to also include data collection done with the pressure in both eyes elevated to ~ 16 mm Hg by flow from an external reservoir during the same experiment. These studies were not optimized for the determination of uveoscleral facility, but some suggestive results were derived from them. Given all of the assumptions, uveoscleral facility in PGF2α-IE–treated eyes was calculated to be 0.18 ± 0.04 µL/min/mm Hg (mean ± standard error of the mean) compared with control eye values of 0.04 ± 0.01 µL/min/mm Hg (ratio 5.88 ± 1.50, p < 0.02, n = 7). Trabecular facility was decreased in treated compared with control eyes (ratio 0.22 ± 0.03, n = 6, p < 0.001), whereas the total outflow facility was unchanged (Fig. 12.1). These data suggest that PGF2α-IE may increase uveoscleral facility and that more definitive studies are warranted. Also these data suggest that following PGF2α-IE treatment, more fluid can be removed from the eye via the uveoscleral pathway as compared with the trabecular pathway in response to pressure. The only study attempting to address this question has been that of Toris et al7 in cats following treatment with PGA2. In this study, PGA2 decreased IOP by increasing uveoscleral outflow (measured directly by the isotope accumulation techniques) and trabecular outflow facility but not uveoscleral facility or total facility. It is difficult to explain how total facility can remain unchanged while trabecular facility increases. Also, this increase in trabecular facility in cats after PGA2 is different from what has been found in monkeys after PGF2α-IE.8 In 2002–2003 there was renewed discussion about whether PGs can increase uveoscleral facility.9 Becker and Neufeld9 questioned how an increase in uveoscleral outflow can decrease IOP if uveoscleral outflow is pressure independent. They suggested modification of the Goldmann equation to contain a uveoscleral facility term: where F = flow; Ctrab = trabecular meshwork outflow facility; Cu = uveoscleral outflow facility; Pev = episcleral venous pressure; Peo = extraocular pressure. In a small way, with my contribution to the potential “phaco-like” transformation of glaucoma surgery, it is hoped the outlook and practice in this area will be less dismal. Kaufman10 agreed with Becker and Neufeld and went one step further to include a facility term for pseudofacility (Cps), the pressure-dependence of aqueous humor formation, so that Ctot = Ctrab + Cu + Cps Camras11 disagreed with Becker and Neufeld, arguing that the predominant mechanism of action of most prostaglandins in most species was through a pressure-independent mechanism. However, he acknowledged more work was needed. Yablonski12 also disagreed with Becker and Neufeld, stating his belief that the final pathway of uveoscleral flow is into the uveal blood rather than across the sclera. Also he believed that the flux of protein across the sclera reported in Bill’s13 studies was primarily by diffusion. However, our studies demonstrated that the proportion of tracer in the periocular tissue of primate eyes treated for 4 days with PGF2α-IE was so large compared with control eyes, that posteriorly draining aqueous must have exited the eye transsclerally rather than being reabsorbed by uveal blood vessels.14
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