h-p. h’y Rrs. (1989) 48, 707-716 Increased Uveoscleral Outflow as a Possible Mechanism of Ocular Hypotension Caused by Prostaglandin F,,-1-Isopropylester in the Cynomolgus Monkey SIV F. E. NILSSON*$. MARIA SAMUELSSON*, AXDERS BILL* AND JOHAN STJERNSCHAYTZ~ * Ilepartment of Physiology and Medical Biophysics, .CXversity of Uppsala, and t Pharmacia Ophthalnrics AB, Fppsala. Sweden (Rewind 1.5 September 198X and accepted in rwised form 6 December 1988) The effects of topical application of a single dose of prostaglandin F,,. administered as the isopropylester. on the intraocular pressure (IOP). aqueous humor flow (AHF). conventional. and uveoscleral outflow were studied in cynomolgus monkeys under pentobarbital anesthesia. 1 fig PGF,, decreased the IOP by 29kO.6 mmHg (3 hr after the application) as compared with the vehicle-treated control eye. The mean BHF during the whole experiment was slightly higher in t.he experimental than in the control eye, 1.34*@11 ,~l min-’ compared with 1.16+@09 ,~l min-‘. The uveoscleral outflow was significantly increased in the PGF,;treated eye, W98 5 @12 pi min-’ compared with 0.61 kO.10 pl min-’ for the control eye. The conventional outflow was lower in the experimental eye throughout the experiment. Topical application of 10 pug pilocarpine at the time when the fall in IOP was expected prevented the drop in the TOP. Simultaneously the increase in the uveoscleral outflow was abolished. After systemic pretreatment with atropine. 1 mg (kg body weight)-’ i.v., there was no significant difference in IOP, AHF. conventional or uveoscleral outflow between the PGF,,-treated. and the control eye. The results of the present investigation suggest that PGF,, decreases the intraocular pressure by increasing the uveoscleral outflow. The mechanism behind the increase in the uveoscleral outflow remains to be established. Relaxation of the riliary muscle as well as enlarged intramuscular spaces and loss of extracellular material mav contribute to the effect. key words: aqueous humor flow : atropine : ciliary muscle : conventional outflow ; cynomolgus monkey; intraocular pressure : pilocarpine : prostaglandin F,, : uveoscleral outflow. 1. Introduction In rabbits, prostaglandins (PGs) can cause either an increase or a decrease in the intraocular pressure (IOP). Starr (1971) observed that, after intracameral adminis- tration, the well-known hypertensive phase sometimes was followed by a hypotensive phase of longer duration. Later studies have shown that the normal pattern of response, to topical application of PGs in rabbits, is indeed an initial increase in IOP followed by a more long-lasting decrease (Camras, Bito and Eakins, 1977 ; Lee, Podos and Severin, 1984). The initial hypertensive phase, which is more marked at higher doses. is associated with miosis, breakdown of the blood aqueous barrier (BAB), and protein leakage into the ayueous humor. As high doses and rabbits were commonly used in the early studies on the ocular effects of PUS, the abtention was focused on the involvement, of PGs in ocular inflammation (see Eakins, 1977). In ot’her species PGs cause ocular hypotension without, or with a less marked. initial hypertensive phase, and have litt,le or no effect on t,he BAB (Camras and Bit#o, 1981; Stern and Bito, 1982). This has prompted the suggestion that PGs may prove useful in the treatment of glaucoma (Bito. 1984a). and a recent study, showed that $ To whom all correspondence should be sent at l~cpartrnrnt of l’)rysiotoyy and Medical I%ophysics. 1%0x 572. S-751 23 Uppsata. Sweden. 0 19x9 .I\c*adrmic Press 1,imitrtt
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`The mechanism behind the ocaular hypotensivr eflect of PC& has remained obsrure. however. The out,flow facility seems to be either unaffec+d ((‘rawford. Kaufman and True (iabelt. 1987: tiaufmnn, 1986) or slightly incwasetl by I’(&. but not enough to nccount for the IO t’-reduc.tion (1,~ et al., 19X4). Sor do l’C:s diminish t’he aqueous humor formation (Lee et al., 1983: C’aIIlraS. Podos. Rosenthal. Lee and Severin. 1987). on t,he contrary P(:s may in SOIW instances ww increase the rate of ayurous humor formation (Crawford et al.. 1987). This has led to the suggestion that PGs may lower the IOP by increasing the uvrosc~lrral outflow (Bit,o, 19%&a). lndirec*t evidence supporting this hypothesis has been present,etl (( ‘rawford and Ka,ufman. 1987) : pilocarpine. which is known to stop the uveosclrral outflow almost completely. preventfed the hypotensivr effect of P(:F,,. The present invest,igation. in which the effects of a single dose of prostaglandin F,,- 1-isopropylester (PGF,,-IE) on the IOP. aqUe(JUS humor flow (AHF). conventional and uveoscleral outflow were studied in rynomolgus monkeys. shows that PGs can indeed increase the uveoscleral outflow. The results show also that’ t’his effect’ is modified by both pilocarpine and atropine. Preliminary reports on parts of this investigation have been presented elsewhere (Nilnson. Stjernschant’z and Bill. 1987 ; Silsson. Sperber and Bill. 1989). 2. Materials and Methods 27 cynomolgus monkeys (16 female and Ii male), w-eighing 1.9-3.9 kg. were used for the experiments. Anesthesia was induced by i.m. injection of methohexital sodium (Brietal, Eli-Lilly Co., Indianapolis. IX). 30MO mg (kg body weight)-‘, and maintained by i.v. infusion of pentobarbital sodium (Mebumal. ACIO. Sweden), @3 -+6 mg min-‘, through a tail vein. A polyethylene tube. connecated to a pressure transducer, was inserted into the tail artery for registration of the arterial blond pressure and collection of blood samples. Heating pads were used to maintain the animals’ normal body temperature. Afterwards, the monkeys were allowed to recover. but none was used more than oncar for t,his kind of experiment. Detervnin~ation of ayueou.s humor jlow. conwntioncrl trod u~wsrlrrccl outflow The aqueous humor flow was determined by the labeled albumin dilution method described by Sperber and Bill (1984). Three steel cannulas (external diameter of the tip 034.5 mm) were inserted into the anterior chamber with the help of a special device. Indomethacin, 3 mg (kg body weight)-‘; was given intravenously before the cannulation of the anterior chamber and about Z-2.5 hr later. One of the cannulas was connected to a pressure transducer for registration of the intraocular pressure. The other two cannulas were used to perfuse the anterior chamber with mock aqueous humor (Sperber and Bill, 1984). containing radio actively labeled albumin. Albumin labeled with [lz51] was used in one eye and [‘311]-labeled albukin in the other. enabling the AHF to be determined in both eyes simultaneously. An external pump was used to mix the contents of the anterior chamber with the perfusion fluid, and circulate it’ through a gamma-det’ect,or. Thus, the radioactivity in the anterior chamber was continuously analysrd and the data were entered into a computer for calculation of the AHF. The data on the radioactivity and the AHF were transferred t,o a printer and a weighed mean of the three latest values on the AHF was plotted as a function of time on a graphic terminal. At least during the first hours of the experiments, all the radioactivity appearing in plasma can be assumed to have left t,he eye via the canal of Schlemm (see Bill, 1984). Determination of the plasma radioactivity can therefore be used to calculate the outflow via the conventional route. The uveoscleral outflow can then be calculated as the difference between the measured AHF and the conventional outflow (Sperber and Bill. 1984). In the
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`l’KOSTA(:LANDIN F,, AND ~‘VEOS(‘LEKAL Ol’TFLO\V TO!4 present experiments. arterial blood samples were collected at 20 min intervals. The flow of amerior chamber fluid to blood (J’J was calculated according to the following formula : E’ = tiBW’(C’,--C’,) R r, t where 42 is the plasma eyuivalent albumin space in ml (kg body weight))r, as previously determined (see Sperber and Bill. 1984). BW the body weight in kg, C, and CT, the radioactivity in cpm (ml plasma)-’ at the beginning and end of the period respectively. C’, the mean radioactivity in cpm pll’ in the anterior chamber during the period and t t,he length of the period in min. Prostagtandin F,,-l-isopropylester (PGF,,-TE), dissolved in saline with 95% polysorbate. was used in all experiments. Esterification of the carboxyl group in PGF,, has been shown to increase the penetrat,ion into the anterior chamber (Bit.0 and Baroody, 1987). and the orular hypotensive potency of PGF,, (Bito. 198413). Tn the first series of experiments (7~ = IO), 1 pg free acid eyuivalents of PGF,,-IE in 10 ,uI was topically applied to one eye in the middle of the first 20 min period, while the contralateral eye received the same amount of vehicle. In the Lwcond series of experiments (n = 8). the same dose was applied to both eyes in the middle of the first 20 min period. At 80 min. when IOP was expected to begin to decrease. pilocarpine, 10 ,ug in 5 ~1 saline. was topically applied to one eye. while the 5 ,uI saline was applied to the other. In the third series of experiments (n = 9). atropine. 1 mg (kg body weight))‘. was given intravenously after t,he cannulation of the anterior chamber, but before the start of the experiment. PGF,,-IE and vehicle were then applied as in the first series of experiments. Statistical analysis was performed by the two-tailed Student’s t-test for paired data. All values are given as the mean+S.E.M. unless otherwise stated. P-values less than 905 were considered as significant.. 3. Results The mean arterial blood pressure was not significantly changed in any of the three experiment,al series [see Figs l(a), 2(a) and 3(a)]. The results from the experiments with unilateral application of PGF,,-IE only are summarized in Fig. 1. In the experimental eye, there was a small, but not statistically significant, initial increase in IOP followed by a slower decrease [(see Fig. l(b)]. The maximal difference in IOP between the control and the experimental eye was 29&O-6 mmHg (P < 0901) and appeared about 3 hr after the application of PGF,,-IE. The aqueous humor flow increased on the PGF,,-IE-treated side during the first. l-l.5 hr and then slowly declined through the rest of the experiment [see Fig. l(c)]. The mean AHF during the whole experiment (4 hr) was slightly higher for the experimental than for the control eye ; l-37 + 011 compared with 1.16 f 609 ,~l min-‘. difference @lS+O.OS ,ul min-’ (P < 005). The flow of aqueous humor to the blood, corresponding t,o the conventional outflow, was lower on the experimenbal side throughout [see Fig. l(d)]. The mean values for the control and the experimental side were 0.55 + 007 and O-36 + 0.04 ,~l min- ‘, difference 0.19&@04 ,~l min-’ (P < 601). The uveoscleral outflow began to increase in the experimental eye already during the first hour and was maximal 1.52 hr after the application of PGF,,-IE. During the second half of the experiments, the uveoscleral outflow tended to increase also in the control eye [see Fig. l(e)]. The mean uveoscleral outflow was @98+0.12 ,~l mini for the experimental, and 0.61f010 ,uI min-’ for the control eye, difference 637 kO.04 ~1 min-’ (P < 0.001).
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`192 - 083 - 094 - e L I 40 80 120 160 200 240 Time (min) FIG. 1. The effects of unilateral topical application of prostaglandin F,,-1-isopropylester (PGF,,-IE) on (a) the mean arterial blood pressure (MAUP), (b) intraocular pressure (IOP), (c) aqueous humor flow (AHF), (d) flow of aqueous humor to the blood (FU) and (e) uveoscleral outflow (USF). Each point represents the mean value during a 20 min period. The application of PGF,,-IE, 1 pg free acid equivalents in 10~1, to the experimental eye (0) and 1011 vehicle to the control eye (0) was made in the middle of the first 20 min period. Mean values and S.E.M. arc given (n = 10).
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`PRGSTAGLANDIS F,, AND U\‘EOS(‘LEKAL Ol’TFLO~~ ill I . 0 I. I . 1. 1 I. 40 80 120 160 200 240 Time (min) FIG. 2. The effects of unilateral topical application of pilocarpine aft,er the bilateral topical application of prostaglandin F,,-l-isopropylester (PGF,,-IE) on (a) the mean arterial blood pressure (MABP), (b) intraocular pressure (IOP). (c) aqueous humor flow (AHF), (d) flow of aqueous humor to the blood (FB) and (e) uveoscleral outflow (USF). Each point represents the mean value during a 20 min period. PGF,,- IE 1 pg free acid equivalents in 10 ~1, was applied bilaterally in the middle of the first 20 min period At 80 min, indicated by the arrow, pilocarpine, 10,~g in 54, was topically applied to one eye. PGF,,-IE (a). PGF,,-IE+pilocarpine (0). Mean values and S.E.M. are given (n = 8).
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`S. F. E. SILSSON ET Al, 12 8 4 b 196 C 192 098 038 - e 12 - 038 - 094 - 40 80 120 160 200 240 Time (min) FIG. 3. The effects of unilateral topical application of prostaglandin F,,-1-isopropylester (PGF,,-IE) after systemic pretreatment with atropine on (a) the mean arterial blood pressure (MASP), (b) intraocular pressure (IOP). (c) aqueous humor flow (AHF), (d) flow of aqueous humor to the blood (FE) and (e) uveoscleral outflow (USF). Each point represents the mean value during a 20 min period. Atropine, 1 mg (kg body weight)-’ was given intravenously before the start of the experiment. The application of PGF,,-IE, 1 pg free acid equivalents in 10 ~1, to the experimental eye (a), and 10 pl vehicle to the control eye (0) was made in the middle of the first 20 min period. Mean values and S.E.M. are given (n = 9).
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`PRORTAGLANDIS F,, AND t’VEOS(‘LER,LZI, OVTFLO\V ii3 Experiments with pilocarpine treatm.ent Unilateral topical application of pilocarpine 70 min after the bilateral application of PGF,,-IE prevented a fall in IOP on the pilocarpine-treated side. The maximal difference in IOP between the two sides was 45 + 1.3 mmHg (P < O-01) and appeared about 4 hr after the application of PGF,,-IE. Pilocarpine also abolished the increase in the uveoscleral outflow caused by PGF,,-IE [see Fig. 2(e)] and simultaneously the convent,ional outflow was enhanced in the pilorarpine-treated eye [see Fig. Z(d)]. There was also a rather immediate decrease in AHF after the applicat’ion of pilocarpine [see Fig. 2(r)]. Part of this effect is likely to be due to the pilocarpine- induced miosis, which initially will reduce the inflow of aqueous humor from the posterior to the anterior chamber. Pilocarpine in itself tends to reduce the aqueous humor format*ion in cynomolgus monkeys (Bill and Wdlinder. 1966). Eq)eriments with atropin,e pretreatment In the experiments with unilateral application of PGF,,-IE after systemic atropine pretreatment, the IOP tended to decrease in the treated eye, but was not significantly different from the IOP in the control eye on any occasion [see Fig. 3(b)]. However, atropine in itself decreases the IOP in the cynomolgus monkey (Bill, 1967). This effect was also apparent in the present study as the starting IOPs in the atropine experiments were about 1 mmHg lower than in the other two series. The initial AHF was relatively high on both sides, in good agreement with the previously reported stimulatory effect of atropine on the AHF (Bill, 1967, 1969). During the experiments, the AHF tended to be higher on the PGF,,-treated side [see Fig. 3(c)] but was not statistically different from the control side. After atropine pretreatment, t’he initial uveoscleral outflow was high on both sides, but increased further during the experiments [see Fig. 3(e)]. Although the uveoscleral outflow on the PGF,,-IE-treated side tended to be higher during most of the experiments, t,he difference was never statistically significant. There was no difference in the conventional outflow between the two eyes [see Fig. 3(d)]. 4. Discussion The capacity of PGF,, to increase the uveoscleral outflow, as shown in the present study and confirmed by another recent report (True Gabelt, Kaufman and Goeckner, 1988), indicates that PGs may lower the IOP by a different mechanism from that of most other ocular hypotensive agents. It cannot be excluded, however, that some agents, such as epinephrine, exert their ocular hypotensive effect partly via release of PGs (Bhattacherjee and Hammond, 1977; Camras et al., 1985; Stabile, Camras, Siegel. Podos and Severin, 1987). The maximal IOP-reduction caused by PGF,, may seem small, but considering the low spontaneous IOP in cynomolgus monkeys under pentobarbital anesthesia it is relatively large. Three hr after the application of PGF,,-IE, the IOP in the treated eye was about 7 mmHg, which is close to what is considered to be the normal episcleral venous pressure (Bill, 1971). The outflow facility was not determined in the present experiments, but assuming a normal value of about 64 ,~l min-’ mmHg-’ less than one mmHg outflow pressure would be enough to result in the observed outflow. With the same assumption, the episcleral venous pressure on the control side can be calculated to be l-2 mmHg below the IOP, i.e. 8-9 mmHg. These calculations suggest
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`‘ill 8. F. E. NILSSON NT AL. that the rpiscleral venous pressure was decreased by PGF,,, which is surprising as the local blood flow in the anterior uvea and sclera is markedly increased at this time (Sjernschantz. Nilsson and Astin, 1989). Such an increase would be expected to result in higher episcleral venous pressure. However, dilatation of the veins, if marked, might result, in a fall in venous pressure. It seems possible that. the tendency to an initial increase in IOP is mainly caused by increased episcleral venous pressure due to vasodilation in t,he aonjunrtiva and anterior sclera. and t,hat with time dilatation of the veins resulted in a fall in pressure in Schlemm’s canal. The slight increase in the AHF observed in the present experiments is in good agreement with another recent report on the effect of multiple dosing of PGF,, (Crawford et al., 1987). In awake monkeys. PGF,, seems to have no effect. on the AHF (Lee et al., 1984; Camras et al.. 1987), possibly due to the higher spontaneous AHF in the awake animal. Direct determination of the uveoscleral outflow (Bill: 1971) and previous determinations with this method (Sperber and Bill, 1984; Nilsson, Sperber and Bill, 1986) have shown that normally 40-50”~ of the aqueous humor is drained via the uveoseleral routes. At the time when t,he uveoscleral outflow was at its highest, in the present experiments, about 80% of the aqueous humor was drained through the uveoscleral route. The increase in the uveoscleral outflow in the control eye during the second half of the experiment may be due to a contralateral effect of the drug, but’ may also reflect a spontaneous change. If anesthesia deepens during the experiment the ciliary muscle may relax, which will increase the uveoscleral outflow. It is worth noting that the mean uveoscleral outflow in the control eye during the whole experiment is comparable with the values previously reported for untreated eyes (Bill, 1971; Sperber and Bill, 1984; Nilsson et al., 1986). It may seem surprising that’ although the uveoscleral outflow in the t,reated eye starts t.o increase already during the first hour aft’er the application of PGF,,-IE, the maximal IOP-reduction is not observed until 3 hr lat,er. There are several possible explanations for t’his, however. Firstly. the increased AHF at the beginning of the experiment and possibly also higher episcleral venous pressure. due to vasodilation in the conjunctiva and anterior sclera (Stjernschantz et al., 1989), may initially counteract the IOP-reduring effect of the increased uveoscleral outflow. Secondly, the inflow of aqueous humor into the ciliary muscle may not necessarily be parallel to the outflow from the muscle. In other words, there may initially be a period during which the inflow to the ciliary muscle is higher than the outflow. which will result in swelling of the muscle. The uveoscleral outflow is highly dependent on the degree of tone in the ciliary muscle. Pilocarpine-induced contraction of the ciliary muscle blocks the uveoscleral outflow almost completely, while atropine increases it (Bill and Wblinder, 1966; Bill, 1967, 1969). This suggests that if the ocular hypotensive effect of PGs is caused by increased uveoscleral outflow it might be abolished by pilocarpine. As shown by the present experiments, pilocarpine indeed blocked the ocular hypotensive effect of PGF,,, which is in good agreement with another recent report (Crawford and Kaufman. 1987), and simultaneously the effect of PGF,, on the uveoscleral outflow was abolished. In the experiments with systemic atropine pretreatment, the uveoscleral outflow in the PGF,,-treated eye was not different from that in the control eye. This suggests that most of the short term effect of PGF,, on the uveoscleral outflow could be due
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`PROSTAGLANDIN F,, AND t-VEOM’LERAL OI~‘l’PLO&’ 715 to relaxation of the ciliary muscle. Recent morphological studies show that following 4-8 days of PGF,,-treatment, the ciliary muscle has a relaxed appearance and the spaces between ciliary muscle fiber bundles are enlarged. There is also a loss of extracellular material, which may decrease the resistance to flow and thus increase the uveoscleral outflow (Liitjen-Drecoll and Tamm, 1988, 1989). Interestingly, a larger IOP-reduction has been observed after 4-5 days of daily PG-treatment than after a single dose (Camras et al., 1987; Crawford et al., 1987). Furthermore, the increase in uveoscleral flow is also larger after multiple dosing than after a single dose (Nilsson and Mgepea, unpubl. res.). Thus, one may suspect that the long term effect of PGs on the uveoscleral outflow is at least’ partly caused by structural and/or metabolic changes, while the short term effect, is mainly due t.o relaxabion of t.he eiliary muscle. ACKKOWLEDGMENTS We wish to thank MS Annsofi Holst for valuable t,echnical assistance. This work was financially supported by Pharmacia Ophthalmics AR, Uppsala, Sweden. by grant 5 ROl EYOO475 from the National Eye Institute, U.S. Public Health Service and by grant 85-14X 00147 from the Swedish Medical Research Council. REFEREKCES Bhattacherjee, P. and Hammond, B. R. (1977). Effect of indomethacin on the ocular hypotensive action of adrenaline in the rabbit. Exp. Eye Res. 24, 307-13. Bill, A. (1967). Effects of atropine and pilocarpine on aqueous humor dynamics in cynomolgus monkeys (Macaca iv-us). Exp. Eye Res. 6. 120.-5. Bill, A. (1969). Effects of atropine on aqueous humor dynamics in t.he vervet monkey (CTercopithecus ethiops). Exp. Eye Res. 8, 284-91. Bill. A. (1971). Aqueous humor dynamics in monkeys (Macaea irus and Cercopithecus ethiops). Exp. Eye Res. 11, 195206. Bill, A. (1984). Physiology of the outflow mechanism. In Applied Pharmacology in the Medical Treatment of Glaucomas. (Ed. Drance. S. M.). Pp. 11 l-33. Grune and Stratton: pu’ew York. Bill. A. and Wilinder, P.-E. (1966). The effect of pilocarpine on the dynamics of aqueous humor in a primate (Macaca irus). Invest. Ophthalmol. Vis. Sci. 5, 17&5. Bito, I,. Z. (1984a). Prostaglandins, other eicosanoids, and their derivatives as potential antiglaucoma agents. In Applied Pharmacology in the Med,ical Treatment of Glaucomas (Ed. Drance, 8. M.). Pp. 477-505. Grune and Stratton : lVew York. Bito, L. Z. (1984b). Comparison of the ocular hypotensive efficacy of eicosanoids and related compounds. Exp. Eye Res. 38, 181-94. Bito, L. Z. and Baroody, R. A. (1987). The ocular pharmacokinetics of eicosanoids and their derivatives. 1. Comparison of ocular eicosanoid penetration and distribution following the topical application of PGF,,. PGF,,-l-methyl ester and PGF,-l-isopropyl ester. Exp. Eye Res. 44, 217-26. Camras, C. B. and Bito, L. Z. (1981). Reduction of intraocular pressure in normal and glaucomatous primate (Aotus triuirgatus) eyes by topically applied prostaglandin F,,. (htrr. Eye Res. 1, 205-9. Camras, (1. B.. Bito, L. Z. and Eakins, K. E. (1977). Reduction of intraocular pressure by prostaglandins applied topically to the eyes of conscious rabbits. Invest. Ophthalmol. Vis. A’ci. 16, 1125-34. Camras. C. B.. Feldman, S. G., Podos, S. M.. Christensen, R. E.. Gardner, S. Ii. and Fazio. I$. T. (1985). Inhibition of the epinephrine-induced reduction of intraocular pressure by systemic indomethacin in humans. Am. J. Ophthalmol. 100. 169-75. Camras, C. B., Podos, S. M., Rosenthal, J. S., Lee, P. and Severin, C. H. (1987). Multiple dosing of prostaglandin F,, or epinephrine on cynomolgus monkey eyes. I. Aqueous humor dynamics. Znwst. OphthaZn~oZ. Vis. Sci. 28, 463-9.
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`716 s. F. E. SII,SSON ET .iL. Crawford, K. and Kaufman, P. L. (1987). Pilocarpine antagonizes prostaglandin F,,-induced ocular hypotension in monkeys. Evidence for enhancaement of uveoscleral outflow by prostaglandin F,,. Arch. Ophfhaln~ol. 105. 1112-6. Crawford, K.. Kaufman. P. L. and True Gabelt, B. (1987). Effects of t’opical P(+F,, on aqueous humor dynamics in cynomolgus monkeys. (‘w-r. Eye Res. 6. 1035--U. Eakins. K. E. (1977). Prostagland’in and non-prostaglandin mediated breakdown of the blood-aqueous barrier. 2C.r~. Eye Res. 25 (Suppl.). 483-98. Kaufman, P. L. (1986). Effects of intracamerally infused prostaglandins on outflow facilit,) in cynomolgus monkey eyes with intact or retrodisplaced ciliary muscle. E.rp. Eye Reti. 43, 819-27. Lee, P.. Podos. S. M. and Severin. (1. (1984). Effect of prostaglandin F,, on aqueous humor dynamics of rabbit, cat. and monkey. Invest. Ophthaimol. Vis. Sci. 25, 1087.-93. Liitjen-Drecoll, E. and Tamm, E. (1988). Morphological study of the anterior segment of cynomolgus monkey eyes following treatment with prostaglandin F,,. E.rp. E’ye RP.s. 47, 761-9. Liitjen-Drecoll, E. and Tamm, E. (1989). The effects of ocular hypotensive doses of PGF,,- isopropylester on anterior segment morphology. In The ocular effects of prostaylandins and other eicosanoids. (Eds Bito. L. Z. and Stjernschantz, J.) Pp. 737-776. Allan R. Liss Inc.: New York. Xilsson. S. F. E., Sperber. G. 0. and Bill, A. (1986). Effects of vasoactive intestinal polypeptide (VIP) on intraocular pressure, facility of outflow and formation of aqueous humor in the monkey. Exp. Eye Res. 43. 849-57. Nlsson, S. F. E., Sperber, G. 0. and Bill, A. (1989). The effect of prostaglandin F,,-l- isopropylester (PGF,,-IE) on uveoscleral outflow. In The ocular effects of prostwglandins and other eicosanoids. (Eds Bito. L. Z. and Stjernschantz, J.) Pp. 729-736. Allan R. Liss Inc. : New York. I%lsson, S. F. E., Stjernschantz, J. and Bill. A. (1987). PGF,, increases uveoscleral outflow. Invest. Ophthalnwl. Viis. Sci. 28, (Suppl.), 284. Sperber. G. 0. and Bill, A. (1984). A method for near-continuous determination of ayueous humor flow: Efferts of anaesthetics. temperature and indomethacin. Esq. Eye Res. 39. 435-53. Stabile. C. A., Camras, C. B., Siegel. M. tJ., Podos, S. M. and Severin, C. H. (1987). Possible role of prostaglandins (PGs) in the intraocular pressure (IOP)-lowering effect of some clinically-used and experimental ocular hypotensive agents. Invest. Ophthalmol. Vis. Sci. 28, (Suppl.), 265. Starr, M. S. (1971). Further studies on the effect of prostaglandin on intraocular pressure in the rabbit. Exp. Eye Res. 11, 170-7. Stern. F. A. and Bito, L. Z. (1982). Comparison of the hypotensive and other ocular effects of prostaglandins E, and F,, on cat and rhesus monkey eyes. Invest. Ophthalmol. Vis. Sci. 22, 588-98. Stjernschantz, J., Nilsson, S. F. E. and Astin, M. (1989). Vasodynamic and angiogenic effects of eicosanoids in the eye. In The ocular effects of prostaglandins and other eicosanoids. (Eds Bito, L. Z. and Stjernschantz, J.) Pp. 155-170. Allan R. Liss Inc.: Pu’ew York. True Gabelt, B., Kaufman, P. L. and Goeckner. P. A. (1988). Direct measurement of increased uveoscleral outflow following PGF,, using two methods. Invest. Ophthalmol. Vi’is. 8ci. 29, (suppl.), 127. Villumsen; J. and Aim, A. (1987). The effect of prostaglandin F,, eye drops in open angle glaucoma. Invest. Ophthalmol. Vis. Sci. 28 (Suppl.), 378.
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