Consensual ocular hypertensive response to prostaglandin. Tzu Sung Chiang and Robert P. Thomas

Transcription

1 Consensual ocular hypertensive response to prostaglandin Tzu Sung Chiang and Robert P. Thomas The effects of intracameral injection of prostaglandin E, (PGEi) PGEi, and PGF :a in one eye on the intraocular pressure (1OP) of both eyes and the systemic blood pressure were studied in rabbits. PGE, and PGE :, 10 fig, consistently produced a contralateral 1OP rise and a lowering of blood pressure, in addition to the well-known ipsilateral ocular effect. The consensual response to PGEi was not prevented by intracranial transection of the optic nerve, the oculomotor nerve, and the trigeminal nerve or by topical treatments with several PG antagonists such as polyphloretin phosphate (PPP), 7-oxa-l3-prostynoic acid (7-OPA) and l-acetyl-2-(8- chloro-10,ll-dihydrodibenz) (b, f) (1, 4) oxazepine-10-carbonyl) hydrazine (SC-19220). It was prevented by pretreatment of the contralateral side with topical epinephrine and cross-infusion of PPP into the lingual artery and enhanced by intravitreous PPP, topical PPP, topical 7-OPA, topical 7-OPA vehicle, and transection of the trigeminal nerve. This potentiation is probably due to a nonspecific irritation of the contralateral eye. Slow intravenous infusion of PGE t (0.79 fig per minute) produced a comparable IOP rise. It is suggested that the consensual ocular hypertensive response to PG is due to the transfer of PG from the injected eye to the contralateral eye via the blood circulation. Key words: consensual reaction, intraocular pressure, prostaglandin, optic nerve, oculomotor nerve, trigeminal nerve, epinephrine, polyphloretin phosphate, 7-oxa-13-prostynoic acid, SC C. 'onsensual ocular hypertension has been known to occur following subconjunctival injection of nitrogen mustard, 1 intracranial stimulation of the trigeminal nerve, 2 and intracameral injection of prostaglandin (PG) 3 or formaldehyde 4 in rabbits. In general, these consensual responses occurred inconsistently in terms of frequency and magnitude. The onset was usually slow. The mechanism of the consensual response has been thought to result from an antidromic reflex via the trigeminal nerve. 1 " 3 From the Department of Ophthalmology, Medical College of Georgia, Augusta, Ga Manuscript submitted Dec. 27, 1971; manuscript accepted Jan. 17, Intracranial stimulation of the trigeminal nerve as well as stimulation of its nerve endings at the iris did produce ipsilateral ocular hypertension, presumably due to the release of PG. 2 > G Another possible mechanism for consensual reaction would relate the transfer of an active principle from the ipsilateral eye to the contralateral eye by way of the systemic blood circulation. Although the circulator)^ pathway was generally ruled out, the evidence against it was mostly indirect. The present report describes a consistent and rapid rise in intraocular pressure (IOP) of the contralateral eye following the intracameral injection of 10 /xg of PG in the ipsilateral eye in rabbits. The role of several cranial nerves and the effects of PG an-

2 170 Chiang and Thomas Investigative Ophthalmology March 1972 tagonists such as epinephrine, polyphloretin phosphate (PPP), 7-oxa-13-prostynoic acid (7-OPA), and l-acetyl-2-(8-chloro-10,lldihydrodibenz) (b, f) (1,4) oxazepine-10- carbonyl) hydrazine (SC-19220) 3-7 " 9 on this consensual response were also investigated. Methods Measurements of 1OP and mean arterial blood pressure (BP). Albino rabbits weighing approximately two kilograms were anesthetized with 1 to 2 Cm. per kilogram of urethane administered intravenously as a 2 per cent solution in distilled water. The femoral artery was cannulated with No. 0 polyethylene tubing (PE 0) which was filled with heparin solution and connected to a Statham P 23 Db pressure transducer. The animal was then placed in a prone position. The anterior chambers of both eyes were cannulated at the 12 o'clock position with a 22 gauge needle connected by a PE 0 tubing to a Statham P 23 Db pressure transducer. A reservoir containing a balanced salt solution 10 and set at 30 mm. Hg height was also connected to the transducer for calibration. The changes in IOP and BP were recorded on a Sanborn Twin-Viso Recorder and a DR-8 Recorder from the Electronics for Medicine, Inc., respectivelntracameral injection of PG. Immediately after cannulation of both eyes, the needle was connected to the transducer and the connection to the reservoir was turned off. The pressure in the transducer fell from 30 mm. Hg to the basal IOP level within 10 to 1 minutes. As soon as the IOP was constant, the anterior chamber of one eye was further cannulated with a 2 gauge needle which had been connected with a PE 20 tubing to a 0 fi\ Hamilton microsyringe and filled with PG solution. Approximately three minutes after the second cannulation a constant volume (10 /*1) of PG solution was injected into the anterior chamber. IOP of both eyes and BP were continuously monitored for 30 minutes after injection. Intravenous infusion of PGE t. PGEi (100 Mg per milliliter) was infused via the ear vein or the femoral vein for ten minutes at a rate of 3.9, 7.9, or 19.7 fi\ per minute with the use of a Harvard infusion pump (Model 940). IOP and BP were monitored continuously during the infusion and for ten minutes after infusion. lntracranial transection of the optic nerve, the oculomotor nerve, and the trigeminal nerve. Transection of the optic nerve was performed under sodium pentobarbital anesthesia (30 mg. per kilogram, intravenously) and aseptic conditions. One side of the skull was opened from the frontoparietal suture to approximately 1 cm. anterior to the suture on the frontal bone. The dura was separated from the frontal bone and the posterior portion of the orbitosphenoid bone and cut open at the optic foramen. The optic nerve was subsequently transected. The animal was tested for loss of light reflex one hour and two weeks after the operation. Intracranial transection of the oculomotor and the trigeminal nerves was performed acutely under urethane anesthesia. The femoral artery and both eyes were cannulated after the nerve transection. Complete transection of the nerve was verified at the end of experiment. To transect the oculomotor nerve one side of the skull was opened approximately 1 cm. in diameter around the frontoparietal suture. The dura was opened and a portion of the cerebral hemisphere was removed. The oculomotor nerve was approached along the posterior portion of the orbitosphenoid bone to presphenoid. The nerve was cut at the side of the hypophyseal fossa before it enters the superior orbital fissure. The trigeminal nerve was transected as follows. After one side of the skull was opened slightly posterior to the frontoparietal suture, the dura was cut open. A pair of tweezers was inserted along the edge of the occipital lobs and then advanced ventromedially along the posterior side of the tendinous septum which separates the frontal cranial cavity from the posterior cavity. Before the tweezers were advanced to the fossa where the trigeminal nerve enters the sphenoidal sulcus and forms the semilunar ganglion, a small hill-like structure could be felt. The nerve was transected preganglionically by a quick scratch movement at the orifice of the sphenoidal sulcus. Drug treatments. One per cent Z-epinephrine (0.1 ml.) was applied topically to the cornea and distributed over the conjunctival sac 60 minutes before the PG injection. Two per cent PPP solution was either applied topically (0.1 ml.) 60 minutes before the PG injection, injected into the vitreous (10 fi\) 24 hours before the PG injection, or cross-infused into the right lingual artery (0.04 ml. per minute) for 20 minutes followed by PG injection two minutes later. 7-OPA, 0.1 per cent, was either applied topically (0.0 ml.) for minutes or infused intravenously at a dose of 1 mg. per milliliter per kilogram and 0.68 ml. per minute before the PG injection. SC was applied topically (0.1 ml. every 2 minutes for three times) as a one per cent suspension followed by PG injection 60 minutes later. SC was also cross-infused into the right lingual artery for 20 minutes (1.2 mg. per milliliter; 0.04 ml. per minute) followed by PG injection 2 minutes later. Preparation of drugs. PG and 7-OPA were dissolved in 9 per cent ethanol (0.1 ml. for each milligram of PG or 7-OPA) and diluted with 0.2 mg. per milliliter of sodium carbonate solution to a final concentration of 1 mg. per milliliter. The

3 Volume 11 Number 3 Consensual response to prostaglandin 171 solution was stored in small test tubes (0. ml. per tube) and kept in a freezer. Z-Epinephrine bitartrate solution was prepared freshly as a one per cent free base in the balanced salt solution. PPP (89.1 per cent pure) was dissolved in 0.1N NaOH to a final concentration of 20 mg. per milliliter. The solution was stored in a freezer. SC was dissolved in 9 per cent ethanol and then diluted with the balanced salt solution to a final concentration of 1.2 mg. per milliliter. The volume of the 9 per cent ethanol used was 10 per cent of the final volume. SC was also prepared as a one per cent suspension in the balanced salt solution with the use of a glass tissue homogenizer. Results IOP and BP responses to PGE,, PGE 2, and PGF 2a. The responses of IOP and BP to intracameral injection of PGE,, PGE 2, and PGF 2 «are shown in Fig. 1. At a dose of 10 fig, PGE, and PGE 2 produced a sustained ocular hypertension in the ipsilateral eye, which reached the plateau response within 10 to 20 minutes after injection. At this dose both PGE t and PGE, also elevated IOP of the contralateral eye and lowered BP. The maximal contralateral IOP and BP responses occurred within to 10 minutes after the injection. In comparison with the response to 10 fig of PGE,, 1/xg of PGE, also produced a similar rise in ipsilateral IOP in terms of magnitude and time course but a small rise in contralateral IOP and no decrease in BP. The ipsilateral IOP rise following PGF 2ft (10 fxg) was smaller than that following PGE, or PGE,,. There was no significant change in contralateral IOP or BP following PGF,«injection. The basal IOP and BP for groups tested with 1 Mg of PGE,, 10 Mg of PGE 2, and 10 Mg of PGF 2 «are shown in Table I, and those for the 10 /ig of PGE, group are shown in Table II. Transection of cranial nerves. Table II summarizes the effects of intracranial transection of the optic nerve, the oculomotor nerve, and the trigeminal nerve on IOP and BP responses to PGE,. Ipsilateral or contralateral transection of the optic nerve two weeks before did not affect the basal IOP and BP or influence the response to PGE,. The basal BP and IOP appeared a» - o o +10 o E 0- c c o jr O Ipsilateral :ontralateral LOP xt^x -^ it Time ( m i n) Fig. 1. The responses of IOP and BP to intracameral injection of PG in rabbits. PGEi (1 Mg, ; 10 /ig, ), PCE 2 (10 Mg, ), or PGFsa (10 fig, ) was injected in a volume of 10 ii[ at 0 minutes. The changes in IOP of both eyes and BP were continuously monitored for 30 minutes after the injection. The basal IOP and BP and the number of experiments for each group are shown in Tables I and II. Mean changes with one standard error at some points are shown in the figure. lower following transection of the oculomotor nerve, probably as a result of bleeding during partial decerebration. The absolute changes in IOP of both eyes following PGE, injection were also decreased. Nevertheless, the change in contralateral IOP expressed as the per cent of ipsilateral IOP change after PGE, injection in this group did not differ significantly from that in the control group. Acute transection of the trigeminal nerve always produced a rise in IOP on the operated side, which subsided during the next 30 minutes when the femoral artery and both eyes were cannulated. Bleeding due to the operation was minimal. Intracameral injection of PGE t

4 172 Chiang and Thomas biocxligntivc Ophthalmology March 1972 Table I. Basal IOP and BP Treatments Intracameral injection PGE, 1 Aig/10 p\ PGE S 10 jttg/10 pi PGF S «10 /tg/10 Ml No. of experiments Basal IOP (mm. Hg) PG-injected eye Contralateral eye Basal BP (mm. Eg) ± 20.8 ± 18.8 ± ± 20. ± 16.7 ± ± ± ± 2.9 Intravenous infusion (PGE! 100 pg/m].) 3.9 /il/min. 7.9 juj/min /u]/min. "Mean ± standard error ± ± ± ± ± ±.0 in the operated eye produced IOP and BP responses comparable to those in control animals. However, when the contralateral trigeminal nerve was transected, injection of PGEt into the ipsilateral eye always produced a contralateral rise which was greater than that in the control group, while the ipsilateral IOP rise was the same. Intravenous infusion of PGEj. Intravenous infusion of PGEt (100 /xg per milliliter) invariably produced an increase in IOP and a decrease in BP (Fig. 2). At a rate of 3.9 and 7.9 /.J per minute, the decrease in BP was around mm. Hg, while the increase in IOP continued during the period of infusion. When PGE L was infused at a rate of 19.7 /J. per minute, the decrease in BP was so severe that the rise in IOP was lessened. Both IOP and BP returned to basal levels upon termination of infusion. The basal levels of IOP and BP for these experiments are also shown in Table I. Drug treatments. As shown in Table III, the contralateral IOP response to PGE X injection was prevented by treatments with topical epinephrine and by cross-infusion of PPP into the lingual artery. Contralateral ocular treatment with intravitreous PPP, topical PPP, topical 7-OPA, and topical 7-OPA vehicle significantly enhanced the consensual response to PGE.,. Intravenous infusion of 7-OPA at the dose employed was ineffective. There was a significant decrease in basal IOP of eyes treated with topical epinephrine or inb-avitreous PPP. When one per cent SC was applied topically three times on the contralateral eye, it seemed to enhance the consensual response to PGEi in one experiment (ipsilateral rise, mm. Hg; contralateral rise, mm. Hg). In another experiment, SC was cross-infused into the contralateral lingual artery (1.2 mg. per milliliter, 0.04 ml. per minute for 20 minutes) and found ineffective in modifying the contralateral response to PGE L. Discussion Intracameral injection of 10 /xg of PGE,, PGE,, and PGF 2 «consistently elevated IOP of the injected eye. Since injection of 1 /xg of PGEi also elevated IOP of the injected eye to the same degree, the ipsilateral IOP response obtained following 10 [xg of PGE, and PGE 2 was probably at the maximal level. PGF L «seemed to have weaker ocular hypertensive action. This is consistent with the data published by others. 3 Consensual ocular hypertension has been reported following injection of an eye with various chemicals 1 ' 3> 4 and following intracranial stimulation of the trigeminal nerve.- Its occurrence was infrequent, its magnitude variable, and its onset slow. The consensual response to 10 /xg of PGE, or PGEas described in the present study was observed consistently in terms of frequency, amplitude, and onset. It seemed to depend on the dose and potency of PG injected. Thus, 1 /.ig of PGE, produced consensual response which was smaller than that pro-

5 Volume 1.1 Number 3 Consensual response to prostaglandin 173 Table II. Effects of intracameral injection of PCE, (10 /ig per 10./.d) on the IOP and BP following the intracranial transection of the optic nerve, the oculomotor nerve, and the trigerainal nerve in rabbits Control Treatments Contralateral optic nerve cut (2 wk.) Ipsilateral optic nerve cut (2 wk.) Contralateral oculomotor nerve cut (acute) Contralateral trigeminal nerve cut 4 (acute) Ipsilasteral trigeminal nerve cut 4 (acute) Maximum increase in contralnternl eye/maximum (Mean ± standard error. 4 No. of experiments 14 IOP (mm. Hg) PGE,- injected eye Contralateral eye Maximum Maximum Basal increase Basal increase % 18.6 ± ± ± ± ± ± ± f +39. ± ± ± ± ± ± ± ±1.2 increase in PGEi-injoctecl eye x ±1.9 ± ±3.1 ± ±0.9 ± ± 1.7 ± ±1.6 ±4.9 BP (mm. Hg.) Maximum Basal decrease 89.1 ± ± ± ± ± ± ± ± ± ± ± 1.9 Table III. Effects of various treatments on the response of intraocular pressure and mean femoral arterial blood pressure to intracameral injection of PGE, (10 /xg per 10 /A) in rabbits Control Treatments Topical epinephrine (1 mg. in 0.1 ml., 60 min.) Intralingual artery infusion PPP (0.8 mg./0.04 ml./min., 20 min.)j Intravitreous injection PPP (200 (ig in.10 fi\, 24hr.) Topical PPP (2 mg. in 0.1 ml., 60 min.) J Intravenous infusion 7-OPA (1 mg./ ml./kg., 0.68 ml./min.) Topical 7-OPA (0 ng in 0 /*], min.) Topical 7-OPA vehicle (0 fil, min.) J "Maximum increase in contralateral eve/maxi mu in fmean + standard error. t Treatments on the contralateral side only No. of experiments IOP (mm, Hg) PGE,- injected eye Contralateral eye Basal 18.6t ± ± ± ± ± ± ±0. increase in Maximum increase ± ± ± ± ±2.6 PGE-injected Basal ± ± ± ± 1.3 eye x.100. Maximum increase ± ± ± ± ± ±1.8 % 28.6 ± ± ± ± ± ± ± ±3.7 BP (mm. Hg) Maximum Basal decrease 89.1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±1.9

6 174 Chiang and Thomas Investigative Ophthalmology March T Time (m i n ) Fig. 2. The response of IOP and BP to intravenous infusion of PGEi in rabbits. PGEi (100 fig per milliliter) was infused via the ear vein or the femoral vein at a rate of 3.9 fi\ per minute ( ), 7.9 fi\ per minute ( ), or 19.7 fi\ per minute ( ) beginning at 0 minute. The changes in IOP of both eyes and BP were continuously monitored during the infusion and for 10 minutes after infusion. The basal IOP and BP and the number of experiments for each group are shown in Table I. Mean changes with one standard error at some points are shown in the figure. 20 duced by 10 Aig of PGE X, and 10 Mg of PGFoa did not produce a rise in IOP in the contralateral eye. The consensual response has been generally thought of as an antidromic reflex via the trigeminal nerve. Davson and Machett 1 did not obtain a rise in IOP following subcutaneous injection of nitrogen mustard but did encounter a consensual rise in IOP following subconjunctival injection. They suggested a neuroreflex mechanism for the consensual IOP rise. In discussion of the mechanism of consensual ocular response (IOP rise, increase in protein in aqueous humor, and increase in temperature of ciliary body), Perkins 2 cited four evidences in favor of the nervous pathway: (1) The type of response is the same in both eyes. (2) The onset of response is about the same in both eyes. (3) The association between depth of anesthesia and the frequency of the contralateral changes suggests a nervous pathway. (4) Stimulation of an intact trigeminal nerve on one side did not produce consensual reaction after cutting the nerve on the contralateral side in seven experiments. However, the first three evidences are not in conflict with other hypotheses (discussed below). Furthermore, no experimental data were available in the text for the last evidence. In his experiments with 11 rabbits which had the fifth nerve cut two to four weeks before, stimulation of the nerve distal to the section produced more cases of consensual reaction than did stimulation of the nerve on the cranial side of the section. This would argue against the nervous pathway for the consensual reaction. The data from trans ection of cranial nerves in the present experiments have demonstrated that neither the optic nerve, the oculomotor nerve, nor the trigeminal nerve is involved in the consensual response following intracameral injection of PGEj. In fact, mechanical irritation of the contralateral trigeminal nerve caused by transection of the nerve seemed to enhance the consensual response to ipsilateral PGE, injection. A wide variety of ocular insults generally results in a similar ocular reaction, namely, a rise in IOP, miosis, and hyperemia in the treated eye. Irritation of the trigeminal nerve endings in the treated eye has been suggested as the common cause. 11 Indeed, irritation of the trigeminal nerve consistently produces these ocular reactions on the same side. 2 The great variation in the consensual response following various ocular irritation does not seem to suggest the involvement of contralateral trigeminal nerve in this response. Two other explanations are possible for the consensual response following PG injection. There might be some connection, vascular or extracellular fluid, between both eyes. In rabbits, each optic nerve foramen communicates with the cranial cavity and also with its fellow across the midline. The communication between the left and right orbits is approximately mm. in diameter.

7 Volume 11 Number 3 Consensual response to prostaglandin 17 PG injected into one eye could pass to the opposite eye through this access between them. The most likely pathway seems to be the systemic blood circulation. The decrease in blood pressure after intracameral injection of PGE, strongly suggests that the PG reaches the systemic blood circulation. Although it is generally acknowledged that PGE X, PGE,, and PGF,«are rapidly inactivated by the pulmonary circulation 12 and that a single intravenous injection of PGE, elevates IOP only transiently, 13 a continuous supply of PG from the injected eye via the blood circulatory system to the contralateral eye might possibly produce the observed contralateral IOP rise in the present study. Therefore, a slow continuous intravenous infusion of PGE L was undertaken. When the rate of infusion was approximately 0.8 fxg per minute, the rise in IOP continued during the infusion, reaching the similar magnitude as that observed in consensual IOP rise. At a higher rate of infusion (approximately 2 jig per minute) the IOP rise was diminished due to a decrease in blood pressure (Fig. 2). The question remained to be answered is whether the injected PG is wholly responsible for the contralateral IOP rise in the present experiments. PGE.. and PGF,«are present in rabbit irises. 1 A > xr> Irritation of ipsilateral eye by injected PG could release PG from the iris. Release of other active substance from the injected eye is also possible. However, there is no evidence for the latter conjecture. Topical epinephrine and cross-infusion of PPP into the lingual artery have been shown to antagonize the ipsilateral ocular response to PG or other irritants. 3 ' 4> 1G The consensual response to PGE X was also significantly prevented by these pretreatments. This suggests the involvement of PG in the contralateral IOP rise. Topical treatments with PPP, 7-OPA, and SC-19220, which are known PG antagonists in vitro, s> 9 have resulted in potentiation of the consensual response. Intravitreous injection of PPP which has been shown to be very effective in preventing the IOP rise following intravenous injection of PG 17 also resulted in potentiation. Since topical application of 7-OPA vehicle also enhanced the consensual response, the potentiation was probably due to a nonspecific irritation of the eye. It is interesting to recall that irritation of the contralateral trigeminal nerve due to transection of the nerve also induced potentiation. We would like to thank Dr. John E. Pike of The Upjohn Co. for the generous supply of prostaglandin, Dr. Josef Fried of the University of Chicago for 7-OPA, Dr. John H. Sanner of C. D. Searle & Co. for SC-19220, and Dr. B. Hogberg of Leo Lab. for PPP. REFERENCES 1. Davson, H., and Machett, P. A.: The control of the intraocular pressure in the rabbit, J. Physiol. (Lond.) 113: 387, Perkins, E. S.: Influence of the fifth cranial nerve on the intraocular pressure of the rabbit eye, Br. J. Ophthalmol. 41: 27, Beitch, B. R., and Eakins, K. E.: The effect of prostaglandins on the intraocular pressure of the rabbit, Br. J. Pharmacol. 37: 18, Chiang, T. S., and Leaders, F. E.: Antagonism of formaldehyde-induced ocular hypertension by phenylethylamines, Proc. Soc. Exp. Biol. Med. 13: 249, Ambache, N., Kavanagh, L., and Whiting, J.: Effect of mechanical stimulation on rabbits' eyes: Release of active substance in anterior chamber perfusates, J. Physiol. (Lond.) 176: 378, Ambache, N., and Brummer, H. C: A simple chemical procedure for distinguishing E from F prostaglandins with application to tissue extracts, Br. J. Pharmacol. 33: 162, Waitzman, M. B.: Influences of prostaglandin and adrenergic drugs on ocular pressure and pupil size, in Ramwell, P. W., and Shaw, J. E., editors: Prostaglandin Symposium of the Worcester Foundation for Experimental Biology, New York, 1968, John Wiley & Sons, Inc., p Fried, J., Santhanakrishnan, T. S., Himizu, L., Lin, C. II., Ford, S. H., Rubin, B., and Crigas, E. O.: Prostaglandin antagonists: Synthesis and smooth muscle activity, Nature (Lond.) 223: 208, Sanner, J. H.: Antagonism of prostaglandin E = by l-acetyl-2-(8-chloro-10, 11-dihydrodibenz) (b,f) (1,4) oxazepine-10-carbonyl) hydrazine (SC-19220), Arch. Int. Pharmacodyn. 180: 46, Barany, E. H.: Simultaneous measurement of

8 176 Chiang and Thomas Investigative Ophthalmology March 1972 changing intraocular pressure and outflow facility in the vervet monkey by constant pressure infusion, INVEST. OPHTHALMOL. 3: 13, Thomas, R. P.: Neurohumoral factors in experimental glaucoma, Am. J. Ophthalmol. 6: 729, Piper, P. J., Vane, J. R., and Wyllie, J. H.: Inactivation of prostaglandins by the lungs, Nature (Lond.) 22: 600, Waitzman, M. B., and King, C. D.: Prostaglandin influences on intraocular pressure and pupil size, Am. J. Physiol. 212: 329, Ambache, N., Brummer, H. C, Rose, J. C, and Whiting, J.: Thin-layer chromatography of spasmogenic unsaturated hydroxy-acids from various tissues, J. Physiol. (Lond.) 18: 77P, Waitzman, M. B., Bailey, W. R., and Kirby, C. G.: Chromatographic analysis of biologically active lipids from rabbit irises, Exp. Eye Res. 6: 130, Cole, D. F.: Prevention of experimental ocular hypertension with polyphloretin phosphate, Br. J. Ophthalmol. 4: 482, Starr, M. S.: Further studies on the effect of prostaglandin on intraocular pressure in the rabbit, Exp. Eye Res. 11: 170, 1971.