Effect of Prosfaglandin F2a on Aqueous Humor
`Dynamics of Rabbit, Cat, and Monkey
`
`Ping-yu Lee, Steven M. Podos, and Colette Severin
`
`Topical administration of prostaglandin F2a (PGF2a) produced a reduction in intraocular pressure in
`eyes of rabbits, cats, and cynomolgus monkeys. In rabbit eyes at 5 or 6 hr, 50 ng, 100 ng, or 250 ng
`of PGF2a caused a significant intraocular pressure reduction with a small miotic effect. Treatment with
`500 ng, 750 fig, or 1000 ng of PGF2a lowered intraocular pressure significantly in cat eyes for at least
`24 hr with the development of profound pupillary constriction. Administration of 500 ng, 750 ng, or
`1000 ng of PGF2a produced a significant reduction of intraocular pressure in monkey eyes lasting at
`least 24 hr, with an initial hypertensive phase and a small decrease in pupillary diameter in the treated
`eyes. Tonography revealed an increased facility of outflow simultaneous with the reduction of intraocular
`pressure in the eyes of cats and monkeys. These increases of outflow facility could not explain completely
`the reductions in intraocular pressure. The aqueous humor flow measured by fluorophotometry was
`unaltered in both species, and possible reasons for this finding are discussed. Anterior chamber aqueous
`humor protein was significantly higher in cat eyes topically treated with 750 ng of PGF2o than in the
`diluent-treated fellow eyes. Invest Ophthalmol Vis Sci 25:1087-1093, 1984
`
`Early studies of the effect of prostaglandins (PGs)
`on intraocular pressure led to the general conclusion
`that PGs, administered topically or systemically, ele-
`vated intraocular pressure in rabbits, cats, and mon-
`keys.1"5 More recently, some studies have shown that
`topical application of either PGE2 or PGF2a effectively
`reduced the intraocular pressure in rabbits, cats, and
`monkeys.6"8 Those studies suggested that PGs, espe-
`cially PGF2« and/or its analogues, may provide a new
`therapeutic approach to the clinical control of intra-
`ocular pressure and the treatment of glaucoma.
`The present study was designed to investigate further
`the mechanism of the hypotensive effect of PGF 2a on
`rabbit, cat, and monkey eyes.
`
`Materials and Methods
`
`Adult, albino, unanesthetized rabbits, 2-3 kg, were
`restrained. Eleven adult cats, 2.5-3.5 kg, and eight,
`adult, cynomolgus monkeys, 4-5 kg, were lightly tran-
`quilized with 5-10 mg/kg of ketamine. The cats were
`restrained, and the monkeys were kept in primate
`chairs throughout each experiment.
`
`From the Department of Ophthalmology, Mount Sinai School of
`Medicine of the City University of New York.
`Supported in part by grants EY-03651 and EY-01867 from the
`National Eye Institute, Bethesda, Maryland, and an unrestricted
`grant from Research to Prevent Blindness, Inc., New York, New
`York.
`Submitted for publication: June 2, 1983.
`Reprint requests: Steven M. Podos, MD, Mount Sinai School of
`Medicine, One Gustave L. Levy Place, New York, NY 10029.
`
`Intraocular pressure was measured under 0.5% top-
`ical proparacaine hydrochloride anesthesia using a
`manometrically calibrated Alcon pneumatonometer.
`New animals were acclimated to the tonometer by
`undergoing several readings the day before they were
`to be used in an experiment. Two sets of baseline
`readings were taken each day before 9 AM.
`Pupillary diameters were measured with a millimeter
`ruler in normal room light. In cats, the horizontal
`(shorter) diameter always was recorded.
`The aqueous flare and cellular response in the an-
`terior chamber were assessed by slit-lamp examination
`and rated from 0 to 3 (aqueous flare: 0 = no Tyndall
`effect; 1+ = slight Tyndall effect; 2+ = moderate to
`dense Tyndall effect; 3+ = dense Tyndall effect with
`fibrin clots; cellular response: 0 = no cells apparent;
`1+ = few cells; 2+ = many cells; 3+ = cell clumps).
`Following these baseline observations, a 5 mg per
`ml solution of PGF2rt (each ml of this solution contains
`prostaglandin F 2a tromethamine salt equivalent to 5
`mg prostaglandin F 2 a, and benzyl alcohol, 9.45 mg,
`added as a preservative. The Upjohn Co. (Kalamazoo,
`MI), diluted with normal saline to various concentra-
`tions, was applied topically to one eye of each animal.
`As topical application of an aqueous solution con-
`taining 9.45 mg per ml of benzyl alcohol did not alter
`the intraocular pressure in our trials with cynomolgus
`monkeys, we used an equal volume of normal saline
`applied to the contralateral eye as the control. All the
`drugs were made up just prior to their administration.
`The following amounts of PGF 2a were applied: rab-
`bits— 1 /tig in 1 n\, 5 /tig in 1 jul, 25 ng in 5 /xl, 50 fig
`
`1087
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`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

`1088
`
`INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / September 1984
`
`Vol. 25
`
`I 1 I I I I I I I I I I I I
`
`N = 8
`
`0
`-4
`
`+ 8
`+ 4
`0
`-4
`
`-4
`
`: t lOOjig
`
`i
`
`i i i i i i i i i i i i i
`
`+12
`+ 8
`+ 4
`0
`-4
`-8
`
`i i i i i i
`i i
`0 1 2 3 4 5 6
`HOURS
`Fig. 1. Effects of topical application of 1-250 jug of PGF2o on the
`intraocular pressure of rabbits. Points represent the mean pressure
`values. The greatest SE was ±2.1 mmHg.
`
`24
`
`in 50 n\, 100 Mg in 50 MI and 250 /xg in 50 /zl; cats
`and monkeys—250 ng, 500 ng, 750 ng, 1000 ng as
`250 ng in 50 /A given one, two, three, or four times,
`respectively, 3-5 min apart. Repeat, intraocular pres-
`sure measurements were made at 0.5, 1, 1.5, 2, 3, 4,
`5, 6, and 24 hr after instillation of PGF 2 a.
`Tonography was performed with an electronic to-
`nometer (Alcon EDT-103) in 21 cats and 20 monkeys.
`Baseline outflow facility was determined at 8:30 A M-
`9 AM. PGF2« (750 ixg in cats and 500 fig in monkeys)
`was applied randomly to one eye and an equal volume
`of normal saline to the contralateral eye 2 hr after
`baseline measurements. The tonography results were
`
`obtained at 2 hr (cats) or 4 hr (monkeys) after instil-
`lation of PGF2«. Tonography values were approxi-
`mated*from the 1955 Friedenwald tables.
`Aqueous humor flow was estimated using a fluo-
`rophotometric technique9 on 14 cats and 10 monkeys.
`The fluorescein iontophoresis was done at 4 PM and
`fluorescence measurements were made from 9 A M -2
`PM on the following day. The iontophoresis was carried
`out in the central 4 mm of the cornea with an electrode
`of 10% fluorescein in 2% agar. A current of 200 fiA
`was used for 5 min. Fluorophotometric measurements
`of the cornea and anterior chamber were repeated at
`about 60-min intervals. Five to six such measurements
`were made. Following these baseline measurements,
`on another day, PGF 2a (750 ng in cats and 500 ^g in
`monkeys) was topically applied to one eye of each
`animal at about 8:30 AM. An equal volume of normal
`saline was applied to the control eye. The iontophoresis
`was carried out at 4 PM on the preceding day as de-
`scribed above. Fluorophotometric measurements were
`taken from 1-6 hr after instillation of PGF 2 a. The
`cornea and anterior chamber readings were divided
`by the reference filter reading and the ratio (F) was
`recorded. For each animal, the natural logarithm of
`F was plotted versus time. The lines of best fit and
`their slopes were calculated by the
`least-squares
`method.
`
`The value of aqueous flow was calculated by the
`mathematical assumptions of Yablonski and co-work-
`ers.10 The value of A used for each eye was midway
`between the absolute values of the slopes of the anterior
`chamber and cornea lines of best fit. The value of Fc/
`Fa was determined from the corresponding lines of
`best fit at 2 hr (cats) or 4 hr (monkeys) after PGF 2a
`administration. Values of 853 n\ for anterior chamber
`volume" and 296 fi\ for cornea volume 12 in cats were
`used in the calculations. Values of 106 ^il13 for anterior
`chamber volume and 50 i*\ (unpublished data, M. E.
`Yablonski and J. B. Serle) for cornea volume in mon-
`keys were used in the calculations.
`Seven hundred fifty micrograms of PGF 2a were in-
`stilled in one eye of awake, restrained cats, control
`solution in the other eye. Two hours later, under ke-
`tamine anesthesia, a 25-gauge needle was inserted
`through clear cornea and aqueous humor withdrawn.
`Care was taken to avoid the iris and lens. Aqueous
`humor protein concentrations were measured by the
`method of Lowry and co-workers.14
`These experiments adhered to the ARVO resolution
`on the use of experimental animals in research.
`
`Results
`
`Intraocular Pressure
`Rabbits. PGF2a administered topically to rabbit eyes
`often induced a biphasic intraocular pressure response:
`
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`Micro Labs Exhibit 1044-2
`
`

`

`No. 9
`
`PGF2a AND AQUEOUS HUMOR DYNAMICS / Lee er ol.
`
`1089
`
`N =7
`
`+2
`O
`-2
`-4
`
`+ 4
`+ 2
`0
`
`+ 4
`+ 2
`1 *2
`2 0
`-2
`-4
`
`-/L
`
`-t
`
`5 O O M5
`~l I I I I I I I I T I I I I
`
`- t
`
`_750ng
`I I I I I I I I I I I I I I
`
`a relatively short, initial, hypertensive phase followed
`by prolonged hypotony. Dose-response relationships
`could be demonstrated (Fig. 1). Topical application of
`100 fig or 250 fig of PGF2« produced a significant (P
`< 0.01) initial increase in intraocular pressure. Topical
`application of all doses of PGF2a produced a significant
`(P < 0.05) ocular hypotony at 5 or 6 hr. The greatest
`hypotensive response was observed in eyes given 250
`ng of PGF2«.
`Cats. Topical application of 500-1000 ng PGF2« to
`the eyes of cats produced a significant (P < 0.05) de-
`crease in intraocular pressure, as compared with the
`pressure of the control eyes, occurring between 30 min-
`24 hr after PGF2a administration. The greatest hy-
`potensive response was observed in eyes given 750 ng
`of PGF2a at 2 hr (P < 0.001). There was no transient
`ocular hypertensive response in cats. Dose-response
`relationships could be shown (Fig. 2).
`Monkeys. Topical application of 250 fig, 500 fig,
`750 ng, or 1000 fig of PGF2a to one eye of monkeys
`resulted in a biphasic intraocular pressure response: a
`relatively short initial hypertensive phase followed by
`a prolonged hypotony (Fig. 3). The maximum rise of
`
`0
`-2
`-4
`-6
`
`0
`-2
`£ -4
`I -6
`
`X
`
`k 0
`.2
`-2
`S -4
`~ -6
`-8
`
`0
`-2
`-4
`-6
`
`V" V
`
`Onq
`^•—•^/
`I I I I I I I I I I I I I I
`
`N = II
`
`-/A-
`
`750 |jg
`^r
`onei
`I I I I I I I I I I I I I I
`
`N =10
`
`N=9
`
`0 12 3 4 5 6
`HOURS
`Fig. 2. Effects of topical application of 250-1000 ng of PGF2a on
`the intraocular pressure of cats. Points represent the mean pressure
`values. The greatest SE was ±1.7 mmHg.
`
`24
`
`+ 4
`+ 2
`O
`_ p
`-4
`
`-/A
`
`V.-
`IOOO nq
`I I I I I I I I I I I I I I
`0 1 2 3 4 5 6
`HOURS
`Fig. 3. Effects of topical application of 250-1000 jig of PGF 2o on
`the intraocular pressure of monkeys. Points represent the mean pres-
`sure values. The greatest SE was ±1.7 mmHg.
`
`N =8
`
`24
`
`the pressure occurred at 30 min. The intraocular pres-
`sure then rapidly decreased. The maximum ocular hy-
`potensive response occurred after topical application
`of 500 Mg of PGF2a, with a significant (P < 0.001)
`decrease in intraocular pressure of 4 mmHg at 4 hr,
`as compared with the pressure of the control eyes. The
`intraocular pressure was significantly (P < 0.05) re-
`duced up to 24 hr by 500-1000 ng PGF 2«.
`
`Miotic Response
`
`Rabbits. Topical application of 50 fig or 100 fig of
`PGF2cv produced a miotic response (P < 0.05) of 1
`mm at 1.5 hr, which returned to baseline values at 5
`hr (Fig. 4).
`Cats. Topical administration of 500 jug, 750 ^g, or
`1000 ng of PGF2« caused significant (P < 0.01) miotic
`responses similar in magnitude (Fig. 5). A dose of 500
`fig of PGF2a produced an apparently maximum miotic
`response (9 mm decrease in pupillary diameter) at 1
`hr, the pupillary diameter 7 mm less than the control
`
`Downloaded From: http://iovs.arvojournals.org/ on 04/07/2018
`
`Micro Labs Exhibit 1044-3
`
`

`

`INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / Seprember 1984
`
`Vol. 25
`
`N
`-.^_.-.___._JC;==9=O=/£=:O
`250iig N=4
`„
`I I I I I I I I I I I I I I
`
`I
`
`-
`
`po o o~ o-°\ s
`
`5 0 0 > ig
`I I I I I I I 1 I I I I I I
`
`N = 4
`
`|
`
`I I I I I I I II I I I I I
`
`_
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`••
`
`
`
`«
`
`^»
`
`•
`
`••
`
`
`
`•
`
`642
`
`E 0
`
`DC 4
`LJ
`
`LJ
`
`20
`
`6
`§ 4
`d 2
`I 0
`
`Q_
`
`420
`
`I I I I I I I I I I I I I
`0 I 2 3 4 5 6
`HOURS
`Fig. 6. Effects of topically applied PGF2c, on the pupillary diameter
`of PG-treated (
`) and control (- O - O - O -) eyes of all
`observed monkeys. The greatest SE was ±0.6 mm.
`
`24
`
`hr after the topical application of 50 ng, or 100 fig of
`PGF2a (Fig. 7). Topical application of PGF2« in
`amounts of 50 ng at 1-3 hr (P < 0.05) and 100 /xg at
`0.5-6 hr (P < 0.005) produced a significant aqueous
`flare in treated eyes as compared with control eyes.
`Aqueous flare was observed in the anterior chamber
`of the treated eye of some cats at 2-6 hr after 500 ng,
`750 ng, or 1000 /xg of PGF2a administration (Fig. 8).
`This was significant (P < 0.05) as compared with con-
`trol eyes at 3 hr after 500-1000 ng of PGF2a application.
`Aqueous flare was not observed in any of the eyes
`of monkeys at any time after the topical application
`of250-1000MgofPGF 2 o.
`
`In 21 cats, 2 hr after a topical dose of 750 fig of
`PGF2a, the intraocular pressure was (P < 0.001) re-
`duced significantly in treated eyes as compared with
`baseline values and control eyes, and the mean outflow
`facility was increased significantly (P < 0.001) 48
`± 12% as compared with control eyes. In the control
`eyes, the outflow facility was not significantly altered,
`as compared with baseline values.
`In monkey eyes 4 hr after administration of 500 ng
`of PGF2a, the intraocular pressure was significantly
`reduced as compared with baseline values (P < 0.005)
`
`1090
`
`rr
`LJ
`:> £
`< E
`
`0
`
`-J x "I
`E- -2
`Q_
`
`o-o-°
`
`N = 6
`N = 9
`
`24
`
`• 50 M9
`o
`lOOjug
`I I I I I I I I I I I I I I
`0 I 2 3 4 5 6
`HOURS
`Fig. 4. Effects of topically applied PGF 2a on the pupillary diameter
`of rabbit eyes as compared with the pupillary diameter of control
`eyes. The greatest SE was ±0.4 mm.
`
`eyes for 5 hr, followed by redilation to near baseline
`values at 24 hr.
`Monkeys. Topical application of PGF 2a doses pro-
`duced a small decrease in pupillary diameter in the
`treated eyes and an increase in the control eyes. The
`effects of topically applied PGF2a on the pupillary size
`of monkeys occurred between 15 min and 4 hr after
`PGF2a administration (Fig. 6). The miotic response of
`the treated eyes and the dilation of the pupil of the
`control eyes were significant (P < 0.02) as compared
`with the baseline values 0.5 hr after the application of
`1000 /ig of PGF2a. Topical application of PGF2ff in
`amounts of 250-1000 Mg produced a significantly (P
`< 0.05) smaller pupil in treated eyes as compared with
`control eyes at various times.
`
`Aqueous Flare and Cellular Response in the
`Anterior Chamber
`
`Cellular response in the anterior chamber was not
`observed under slit-lamp examination in any of these
`animals at any time after the topical application
`ofPGF 2 a.
`Some aqueous flare was observed in the anterior
`chamber of the treated eye of most rabbits at 0.5-5
`
`0
`-2
`-4
`-6
`-8
`-10
`
`GC
`LJ
`oJ ^
`1 E
`
`Hl
`
`v_ O
`oE °
`< Q.
`_J X
`=1 -2i
`Q.
`Q.
`
`A 500ixq N = II
`o 750>jg N = 5
`• IOOOjug N = 5
`I I I I
`'I I I I I I I I I
`0 12 3 4 5 6
`HOURS
`
`24
`
`Fig. 5. Effects of topically applied PGF2a on the pupillary diameter
`of cat eyes as compared with the pupillary diameter of control eyes.
`The greatest SE was ±1.2 mm.
`
`—
`
`&•
`
`Outflow Facility
`
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`
`Micro Labs Exhibit 1044-4
`
`

`

`No. 9
`
`PGF2a AND AQUEOUS HUMOR DYNAMICS / Lee er ol.
`
`1091
`
`• 5 0pg N =6
`O lOCUg N =9
`
`LL)
`
`rr
`
`0
`
`A 500>ig N = II
`o 75O^ig N = 5
`•IOOO>igN = 5
`
`I
`
`II
`
`HOURS
`Fig. 7. Development of anterior chamber flare in all observed
`rabbit eyes after the topical application of 50 ng or 100 ng of PGF2o.
`The greatest SE was ±0.3 scale units.
`
`and to control eyes (P < 0.001), and the outflow facility
`was increased significantly as compared with baseline
`values (P < 0.05) and control eyes (P < 0.025) (Table
`1). In the control eyes, PGF 2a did not produce a con-
`tralateral alteration of outflow facility.
`
`Aqueous Flow
`
`Values of aqueous humor flow were not (P > 0.4)
`changed significantly by unilateral administration of
`750 Mg PGF2a in cats and 500 fig PGF 2a in monkeys.
`Baseline aqueous humor flow (mean jul/min ± SE) in
`treated and control eyes, respectively, was 22.5 ± 2.1
`and 22.7 ± 3.6 in nine cats. Two hours after unilateral
`administration of 750 ng PGF 2a aqueous humor flow
`in 14 cats was similar in the treated eyes, 18.7 ± 1.6,
`and control eyes, 20.9 ± 1.7. Aqueous humor flow in
`the treated eyes of 10 monkeys was 1.9 ±0.1 prior to
`and 1.8 ± 0.1, 4 hr after treatment and was 1.9 ±0.1
`prior to and 1.8 ± 0.1 after diluent in control eyes.
`
`Aqueous Humor Protein
`
`The protein level in the aqueous humor of the treated
`eyes of 11 cats, 2.02 ± 0.33 mg/ml, 2 hr after 750 fig
`of PGF2«, was significantly (P < 0.001) higher than
`that of the control eyes, 0.45 ± 0.07 mg/ml.
`
`2 3 4 5 6
`HOURS
`Fig. 8. Development of anterior chamber flare in all observed cat
`eyes after the topical application of 500 ^g, 750 fig, or 1000 ng of
`PGF2o. The greatest SE was ±0.2 scale units.
`
`in reducing intraocular pressure. Moreover, the du-
`ration of intraocular pressure reduction that follows
`topical PGF2« application is much longer in cat or
`monkey eyes than that in the eyes of rabbits. Cat eyes
`are clearly more sensitive to the hypotensive effects of
`PGF2a than the eyes of rabbits and monkeys. Our re-
`sults are similar to previously reported findings on the
`effects of topically applied PGs on the eyes of rabbits, 6
`cats,7 and monkeys.7'8 These species differences in the
`duration of the hypotensive effect of PGs may arise
`from differences between the ocular pharmacokinetics
`of PGs in these species.7
`PGF2ft reduces intraocular pressure in various species
`of monkeys. Previous experiments show that topical
`application of a single dose of 1000 fig PGF2a onto
`the cornea of five, trained, owl monkeys produces a
`prolonged and highly significant ocular hypotony. The
`intraocular pressure of the treated eye was 4.7 ± 0.9
`mmHg below that of the control eye 18 to 24 hr after
`PGF2a application and remained significantly reduced
`for over 72 hr.8 Topical application of either PGF 2ft
`or PGE2 to the eyes of rhesus monkeys also causes
`significant dose-dependent reduction in intraocular
`pressure.7 The present experiments indicate that topical
`application of 500 fig of PGF2« administered to the
`eyes of cynomolgus monkeys causes significant re-
`duction in intraocular pressure at 3-24 hr after ap-
`plication. The maximum decrease of 4 mmHg below
`
`Discussion
`
`Table 1. The effect of 500
`facility of 20 monkeys
`
`PGF2tt on the outflow
`
`The results presented, here show that topical appli-
`intraocular
`cation of PGF2« can reduce effectively
`pressure in rabbits, cats, and cynomolgus monkeys.
`There are, however, significant species differences.
`Rabbit and cynomolgus monkey eyes have a similar
`tendency to an initial hypertension before the onset
`of PG-induced hypotension. Cynomolgus monkey eyes
`are less sensitive than rabbit eyes to the hypertensive
`effects of topically administered PGF2a. No initial hy-
`pertension occurs in the eyes of cats after the topical
`application of PGF2a in doses that are highly effective
`
`Intraocular pressure
`
`Outflow facility
`
`Mean ± SE
`(mmHg)
`
`Mean ± SE
`(fil/min/mmHg)
`
`Treatment
`
`0 min
`
`4 hr
`
`0 min
`
`4 hr
`
`PGF2a
`Control
`
`18.3 ± 0.4 14.9 ± 0.8*
`17.8 ±0.5 17.7 ±0.8
`
`0.48
`0.50
`
`± 0.03 0.60 ± 0.04f
`± 0.03 0.49 ± 0.04
`
`* Significantly different as compared with 0 min (P < 0.005) and with
`control eyes (P < 0.001), paired t-test.
`t Significantly different as compared with 0 min (P < 0.05) and control
`eyes (P < 0.025), paired t-test.
`
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`

`1092
`
`INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / Seprember 1984
`
`Vol. 25
`
`the intraocular pressure of the control eye is produced
`at 4 hr after 500 ng of PGF 2 a. However, the brief
`ocular hypertensive phase induced by PGF 2a in various
`monkey species must be noted also.
`In our studies, the sensitivity of cat eyes to PGF 2a
`induced miosis is noteworthy. This finding is consistent
`with previous observations.7 No miosis is reported in
`rhesus monkey eyes after the topical application of
`100 /ug, 500 Mg, or 1000 fig of PGF2a.7 However, our
`experiments show that in cynomolgus monkey, there
`is a small decrease in pupillary diameter in the treated
`eyes. This may reflect species difference. The increase
`in pupillary size in the control eyes remains unex-
`plained.
`Although rabbit and monkey eyes are somewhat
`similar with respect to the PG-induced intraocular
`pressure change, these two species are strikingly dif-
`ferent with respect to their sensitivity to the generally
`assumed, primary, pathophysiologic effect of PGs, ie,
`the breakdown of the blood-aqueous barrier. Our
`findings are consistent with previous observations in
`rabbit and cynomolgus monkey eyes. 7 Flare was not
`observed previously under careful slit-lamp exami-
`nation in any cats after the topical application of up
`to 1000 ng of PGF2a.7 However, in our experiments,
`some flare was observed in the anterior chamber of
`most cats 3 hr after the topical application of 500 ng,
`750 Mg, or 1000 ng of PGF2a. Daily or twice daily,
`PGE2 application to cat eyes was shown to maintain
`a reduced intraocular pressure for several months
`without causing substantial flare or cellular response
`and a comparison of the treated and control eyes re-
`vealed no other side effects.1516
`To our knowledge, our study is the first tonographic
`and fluorophotometric analysis of the effect of PGF 2a.
`Previous tonographic studies of the action of prosta-
`glandins have been during the time of intraocular pres-
`sure elevation.4-5 Kass and Podos4 note a statistically
`significant increase in outflow facility after topical PGE,
`in rabbits, suggesting that increased aqueous produc-
`tion rather than increased resistance to outflow is the
`cause of the intraocular pressure elevation. Camras,
`Bito, and Eakins6 report that the gross outflow resis-
`tance, measured by constant-rate infusion of the PG-
`treated eye is 40 to 50% of that of the contralateral
`control eye, in an experiment done in the hypotonic
`phase of eyes of rabbits after topical application of 50
`jig of PGE2. They suggest that the reduction in intra-
`ocular pressure could not be due to an alteration in
`secretory mechanisms or pseudofacility, and, hence,
`must be attributed primarily to a reduction in true
`outflow resistance. One point we sought to clarify was
`the mechanism of the intraocular pressure reduction
`due to PGF 2a. Our tonographic results demonstrate a
`significant mean increase in outflow facility when in-
`
`traocular pressure is reduced after PGF 2a therapy in
`cats and monkeys. However, the changes in outflow
`facility do not account for the total observed reduction
`in intraocular pressure. In our studies of the ocular
`hypotensive phase, one may calculate from the Gold-
`mann flow equation, F = C (Po-Pe), that in monkeys
`there is a 24% reduction of aqueous flow at 4 hr after
`PGF2a, assuming PGF 2a has no effect on episcleral
`venous pressure. However, direct measurements of
`aqueous humor formation by fluorophotometry do not
`show a significant (P > 0.8) change in flow in monkeys
`after PGF2a administration. No apparent change in
`aqueous flow could be accounted for by an actual de-
`crease in flow but with a small increase in permeability
`in the presence of breakdown of the blood-aqueous
`barrier. A possible explanation of the decreased intra-
`ocular pressure due to PGF 2a, in addition to an increase
`of pressure sensitive outflow, is an increase in uveo-
`scleral outflow. Other mechanisms may be possible.
`
`Absolute, tonographic results in cat eyes as calculated
`from the 1955 Friedenwald human tables are probably
`not valid. Our normal values of outflow facility are
`much lower than those determined by Eakins. 17 Com-
`parison of treated and control eyes appeared precise.
`Thus, the increase in outflow facility that we are re-
`porting in cats is in percent change. Our baseline tono-
`graphic results in normal monkey eyes are similar to
`those reported by Kaufman and Barany, 18 who used
`a two-level constant pressure perfusion
`technique.
`Three hours after the topical treatment with pilocarpine
`in our unpublished tonographic studies in monkeys,
`we find an increase of outflow facility, from 0.53 ± 0.09
`jul/min/mmHg to 0.72 ± 0.08 jul/min/mmHg (Mean
`± SD), similar to what they reported. Our baseline
`rates of aqueous flow are similar to previously reported
`values for cats9 and monkeys.19 However, fluoropho-
`tometric techniques to measure aqueous flow may not
`be valid in eyes with breakdown of the blood-aqueous
`barrier. PGF2« produces aqueous flare in cats but not
`monkeys in our study. Our findings of a small signif-
`icant increase in aqueous humor protein concentration
`after topical PGF2a in intact eyes of cats provides ev-
`idence for some breakdown of the blood-aqueous bar-
`rier. The effect of PGF2a on aqueous humor protein
`in monkeys is being studied.
`We also find a significant reduction in intraocular
`pressure of the fellow eye of cats over the baseline level
`when treated in one eye with PGF 2«. PGE, adminis-
`tered to one eye, is reported to elevate the intraocular
`pressure of the fellow eye of rabbits.4'20 The consensual
`response may be due to the transfer of prostaglandin
`from the treated to the untreated eye via the blood-
`stream. However, evidence of the prompt breakdown
`of E prostaglandins by circulating enzymes and in the
`lungs makes this explanation unlikely. 4 Diurnal vari-
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`No. 9
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`PGF2a AND AQUEOUS HUMOR DYNAMICS / Lee er ol.
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`1093
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`ations may account for these results as well as the
`variations in baseline pressures in the various species.
`Other consensual effects cannot be ruled out.
`Key words: prostaglandin F2a, intraocular pressure, outflow
`facility, aqueous humor flow, uveoscleral outflow.
`
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