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The effect of prostaglandin (PG) F2 alpha-isopropyl ester (IE), PGA2, or PGA2-IE on intraocular pressure (IOP) was tested in eight cynomolgus monkey eyes with argon laser-induced glaucoma. Dose-response testing and baseline IOP measurements were done. For multiple dose testing, 5 micrograms in 25 microliters (0.02%) of each PG was topically applied twice daily for 5 days. The IOP was measured at 30- or 60-minute intervals for 6 hours after the morning dose each day. A significant (P less than 0.05) reduction of IOP peaked at 5-9 mm Hg below baseline values on the 5th day of treatment for each PG. The ocular hypotensive effect of these PGs progressively became more pronounced during the course of twice-daily dosing, with a significant reduction maintained at least 17 hours after some doses. No more than trace aqueous flare and no cells were observed in any eye during the course of treatment. These findings demonstrate that PGs other than F2 alpha are potent ocular hypotensive agents in primates.

After unilateral total iridectomy, maximum accommodation inducible by corneal iontophoresis of carbachol in rhesus monkeys was approximately 40% less in the iridectomized than in the contralateral untouched eyes, irrespective of age. Ultrasonographically measured anterior chamber shallowing and lens thickening were also less in the iridectomized eyes. Neither submaximal accommodation induced by intramuscular pilocarpine infusion nor maximum accommodation inducible by midbrain stimulation differed in iridectomized and intact eyes. The authors hypothesize that at maximum cholinomimetic drug-induced contraction, the iris sphincter muscle pulls the ciliary body farther forward and inward than does maximum ciliary muscle contraction alone, allowing additional rounding of the lens and, consequently, additional accommodative power.

To identify the mediator(s) of the apparently species-specific X-ray-induced inflammation of the rabbit eye, inhibitors of the synthesis and/or release of known or putative mediators of ocular inflammation were administered prior to irradiation. The X-ray-induced ocular inflammation, particularly the rise in intraocular pressure, was found to be inhibited by intravenous pretreatment of rabbits with flurbiprofen, indomethacin, or imidazole (1, 10, and 100 mg/kg i.v., respectively), or by combined intravitreal and topical administration of flurbiprofen. Systemic, intravitreal, and/or topical pretreatment with prednisolone or disodium cromoglycate or the retrobulbar injection of ethyl alcohol or capsaicin failed to block the inflammatory response, whereas vitamin E apparently exerted some protective effect. These findings show that the X-ray-induced inflammation of the rabbit eye is mediated, at least in part, by prostaglandins (PGs) and/or related autacoids. In addition, these results suggest that the unique sensitivity of the rabbit eye to X-ray-induced inflammation is due either to the presence in this species of a unique or uniquely effective triggering mechanism for the release of PG precursors or to the greater sensitivity of this species to the ocular inflammatory effects of PGs. Thus the rabbit eye may provide a unique model for studying some aspects of arachidonic acid release or ocular PG effects, but extreme caution must be exercised in generalizing such findings to other species.

It is generally accepted that exogenous or endogenous prostaglandins (PGs) can give rise to acute increases in intraocular pressure (IOP) and to the development of flare and other signs of uveitis. It was recently shown, however, that low doses of PGE2 and/or PGF2 alpha topically applied to rabbit or owl monkey eyes significantly reduce IOP. The present experiments show that topical application of 10 to 500 micrograms of PGE2 also causes a highly significant IOP reduction in cat eyes lasting up to 48 hr with little or no development of flare or miosis, whereas similar application of PGF2 alpha causes, in addition to an IOP reduction, the development of profound pupillary constriction. Topical application of either PGF2 alpha or PGE2 to the eyes of rhesus monkeys also causes significant dose-dependent reduction in IOP. The hypotensive response in the rhesus monkey is not associated with detectable flare or consistent pupillary constriction, although at higher PG doses, hypotension tends to be preceded in both species by a brief (15 to 30 min) hypertensive phase. It is concluded that the eyes of different species show different patterns of IOP, miotic, and flare responses to topically applied PGs, the only consistent effect being a reduction in IOP. In some species, most notably in primates, a reduction in IOP is the predominant effect of PGs. Thus, PGs or their analogues may provide a new approach to the clinical control of IOP and the treatment of glaucoma.

The effects of intravitreally injected prostaglandins (PG's) E1 and F2alpha were studied on conscious, bromcresol green (BrCG)-pretreated and control rabbits. The electroretinogram (ERG) of both the PG-injected and the contralateral control eyes was recorded with contact lens electrodes; and electrocorticogram and the visually evoked response (VER) were recorded from both hemispheres with previously implanted supradural electrodes. In normal rabbits, intravitreal injection of 0.70 mg of PGE1 resulted in a small reduction in the amplitude of the ERG b-wave and of the slow negative wave (SNW) of the contralateral VER. In BrCG-pretreated rabbits, intravitreal injection of 0.70 mg of PGE1 caused a statistically significant decrease in the amplitude of the ERG b-wave and the SNW. Intravitreal injection of 0.7 mg of PGE1 also caused a significantly prolonged inhibition of the ERG in BrCG-pretreated, but not in normal rabbits, following exposure of the eye to a bright light flash. A smaller dose of PGE1 (0.35 mg/eye) caused more moderate effects on some of these parameters. These effects could not be explained by the PG-induced miosis. PGF2alpha (0.7 mg/eye) caused no significant changes in any of the parameters studied. These results indicate that exogenous PG's can have adverse effects on retinal function and that these effects are enhanced by BrCG, a PG-transport inhibitor. Presumably, this inhibitor blocks the PG-removal mechanisms across the blood-retinal barriers and hence allows the accumulation of PG's in the extracellular fluids of the retina.

It has recently been shown that derived prostaglandins (PGs) of the A and B types are much more potent ocular hypotensive agents than primary PGs of the E, F, or D type. The purpose of this study was to determine whether two representatives of these structurally different PGs, namely PGA2 and PGF2 alpha-1-isopropyl ester (PGF2 alpha IE), reduce intraocular pressure (IOP) of the feline eye by similar or dissimilar mechanisms. Aqueous humor flow rate was determined by a fluorophotometric technique, Schiotz electronic tonography was used to measure outflow facility and venomanometry was done to measure episcleral venous pressure. Although at the doses used, both PGF2 alpha IE (2.5 micrograms/eye) and PGA2 (5.0 micrograms/eye) caused significant IOP reduction within 2.5 hr after their topical application, neither caused a significant decrease in aqueous humor flow rate, a significant increase in outflow facility or a change in episcleral venous pressure. It was concluded, therefore, that both of these PGs reduce IOP by an apparently similar mechanism, presumably by increasing uveoscleral outflow.

Protein preparations from commercial suppliers are contaminated with bacterial endotoxins. The continued use of these preparations indicates that many researchers are unaware of this, and they may attribute all observed effects to the proteins themselves. Intravitreous injection of bovine serum albumin has an initial inflammatory effect on the rabbit eye which occurs before an immune reaction to the antigen itself can develop. This direct inflammatory effect can be fully accounted for by endotoxin-like contaminants which are present in protein preparations obtained from commercial suppliers. A pharmaceutical (U.S. Pharmacopeia) serum albumin preparation contains no detectable endotoxin, and has no initial inflammatory effect on the eye. Since endotoxins, even in minute amounts, have a variety of effects, the use of such contaminated protein preparations in biological research can lead to erroneous conclusions and should, therefore, be avoided.

The effects of x-rays and three chemical agents, known to cause intraocular inflammation in mammalian eyes, were studied on the chicken eye because this species was reported to be insensitive to the cataractogenic effects of x-rays. Intravitreal injection of Shigella endotoxin and topical and/or intravitreal administration of PGE2, PGF2alpha, or arachidonic acid caused a breakdown of the blood-aqueous barrier, as indicated by flare and increased protein concentration in the aqueous humor. Following endotoxin injection, there was also a large accumulation of cells in the anterior chamber. The ocular inflammatory effects of endotoxin and arachidonic acid were inhibited by indomethacin. Thus the chicken eye reacts to these inflammatory agents in a manner similar to that previously described for the rabbit. In contrast, the inflammatory response which was reported to occur in the rabbit eye 3 to 4 hr after exposure to 500 or 1000 rads of x-rays was not observed in the chicken eye even after expsoure to 10,000 rads. Minimal flare and a small cellular infiltration were observed in some eyes only after extensive swelling of the surrounding tissues had developed. It is concluded that the insensitivity of the chicken eye to x-rays is due to some unique difference in the chain of events which mediates, or prevents, the effects of ionizing radiation rather than to a general insensivity to inflammatory agents.

Substantial evidence indicates that a single topical application of prostaglandins (PGs) can reduce intraocular pressure (IOP) in the eyes of several species. However, earlier literature, dealing with ocular hypertensive and inflammatory responses, shows the development of tachyphylaxis to subsequent doses of PGs. If similar tolerance developed to the ocular hypotensive effects of PGs, it would preclude the use of these agents in the treatment of chronic glaucoma. The present study shows, however, that although tachyphylaxis to the ocular hypotensive effects of PGs develops in rabbits, this is not a typical response among mammals. Significant IOP reduction was maintained in cats for up to 9 months by topical application of PGE2 at 12-, 24-, or 48-hr intervals. The IOP reduction was jeopardized seriously only when the PG was applied every other day for several days or when, on a few occasions, 3 days were allowed to elapse between PGE2 applications. Ocular hypotension was also maintained during the course of topical treatment of rhesus monkey eyes with PGF2 alpha. Short periods of pupillary constriction followed the application of each dose of PGF2 alpha to cat eyes, but the miotic response of rhesus monkeys to PGF2 alpha and cats to PGF2 was negligible. Other apparent side effects were noted, but none of these were severe or progressive. These results clearly demonstrate that tachyphylaxis, or tolerance, is not expected to present an obstacle to the development of eicosanoids and/or their derivatives as therapeutic agents for the long-term treatment of ocular hypertension and chronic glaucoma.

Much of our knowledge of the ocular responses to irritants is derived from studies on the effects of mustards applied topically to the rabbit eye. The present study shows, however, that vertebrate eyes display profound species variations in the initial (first 6 hours) response to nitrogen mustard (NM). Rabbits and guinea pigs showed two episodes, ducks and cats one, and owl monkeys no episode of increased intraocular pressure. Development of anterior chamber flare and cellular invasion was seen in all species except ducks and owl monkeys. Pupillary constriction of differing time-course and magnitude was observed in all species except guinea pigs and ducks. At least one indomethacin-sensitive component of the NM-induced inflammatory response was demonstrated in each subprimate species, the nature of which depended upon the predominant ocular effect of prostaglandins in each. The present work suggests that while rabbits and guinea pigs may be of particular value for the study of some aspects of the ocular response to irritation and trauma, these species may be unsuitable for studying ocular inflammation and therapeutics as applicable to man.

Daily or twice daily prostaglandin E2 (PGE2) application to cat eyes was shown to maintain a reduced intraocular pressure (IOP) for several months without causing substantial flare or cellular response. We report now on detailed ophthalmic examinations performed on these cats after 5-9 months of such treatment (ie, after 150 to 250 unilateral PGE2 applications; 100 micrograms/treatment per eye). A comparison of the treated and contralateral control eyes revealed no differences in the axial length of ocular compartments, in the biomicroscopic appearance of the lens, vitreous, retina, or optic nerve head, in the rate of light-induced pupillary constriction or in the wave form of the electroretinogram. The cell density of the corneal endothelium was not decreased, but the endothelial surface did contain a few small "dark spots." A slight iridial heterochromia was generally apparent. In three of the cats PGE2 application had a sialagogic effect that became a conditioned reflex. Cats tended to keep their lids closed after each treatment; lid closure was more prolonged in the PGE2-treated eye than in the contralateral eye that received the same volume (50 microliters) of vehicle solution. It is concluded that daily treatment with PGE2, in doses sufficient to cause a maintained reduction in IOP, does have some side effects. However, none of these side effects are of sufficient importance to exclude the use of eicosanoids as potential anti-glaucoma agents.

As part of an ophthalmic and anthropometric survey of two free-breeding rhesus monkey (Macaca mulatta) populations, intraocular pressure (IOP) of 114 animals was measured under ketamine catalepsia with the use of a floating-tip pneumatonometer. The mean IOP of the 102 animals included in the main analyses was 14.9 +/- 2.1 (S.D.) mm Hg. The age distribution of animals in this sample ranged from 7 months to 21 years and reflected reasonably well the estimated age distribution in the total population (approximately 1600 macaques). Since ketamine does not have a barbiturate-like effect on IOP, this value can be regarded as a good estimate of the normal IOP of rhesus monkeys. No significant differences were found between left and right eyes nor between males and females. However, the mean IOP of infants and juveniles (7 months to 3 years) was significantly higher (15.7 +/- 2.0 mm Hg; n = 33) than that of young adult and adult rhesus monkeys (14.5 +/- 2.0; n = 69). The IOP of young animals (less than or equal to 6 years) showed a decline between 9 A.M. and 2 P.M., whereas the IOPs of older animals showed only small fluctuations between 8 A.M. and 5 P.M. This study shows that the normal IOP of macaques is remarkably similar to that of humans and demonstrates the fesibility of surveying IOP in free-ranging primates.

Radioactive copper (67Cu++) was injected into the center of the vitreous body of rabbits. The relatively rapid initial loss of 67Cu from the vitreous was associated with its accumulation in intraocular tissues. At 24 hr, 20% of the injected 67Cu was found in the retina, representing the highest 67Cu concentration among all ocular tissues, and this high 67Cu concentration was maintained in this tissue throughout the 10-day observation period. Significant amounts of 67Cu were not detected in the aqueous humor at any time. About one-half of the injected 67Cu was lost from the whole globe in 5 days, but the remaining Cu was retained in the globe during the next 5 days. Eyes that received a large dose of CuSO4 in addition to the tracer showed decreased 67Cu activity in the retina and a slight increase in the aqueous humor. Endotoxin-induced ocular inflammation decreased the rate of 67Cu loss from the vitreous, reduced its accumulation by the retina, and increased 67Cu entry into the aqueous humor. It is concluded that 67Cu is retained in the vitreous and the globe due to its binding by, and/or uptake into, intraocular tissues, especially the retina. Cu does not effectively enter the anterior chamber from the vitreous, apparently due to its effective removal by the ciliary processes, thus ruling out the possibility of identifying the existence of Cu-containing intraocular foreign bodies in the posterior segment of the eye by analysis of Cu in the aqueous humor.

The refractive power and axial dimensions of the eye were measured under resting and fully accommodated conditions in 123 caged rhesus monkeys ranging in age from 0.5 to greater than 30 years. The mean resting refraction measured under ketamine anesthesia was -5 diopters. Accommodative amplitude, calculated as the difference between resting refraction and the most negative refraction measured 0.5 to 1 hr after topical application of a maximally effective dose of a cholinomimetic, showed an age-dependent decline. The mean accommodative amplitude of 1- to 5-year-old rhesus monkeys was a remarkable 34 D, while animals over 25 years of age averaged 5 D of accommodation. Some greater than 25-year-old animals showed no measurable change in refraction regardless of the dose or the type of cholinomimetic (carbachol, pilocarpine, or echothiophate) used. The resting axial thickness of the lens was found to increase with age throughout adulthood, well past the end of the growth period. A strong correlation was found between pharmacologically induced change in the refractive power of the eye and change in lenticular thickness. These similarities to the human condition suggest that the rhesus monkey represents a highly suitable animal model for the study of accommodation and presbyopia.

The concentration gradients of Mg(++) and K(+) in the cerebrospinal fluid system indicate that the (Mg(++)) is higher and the (K(+)) is lower in the extra-cellular fluid of the cerebral cortex than the concentrations of these cations in either plasma-dialysate or cisternal fluid. Such cation distribution demonstrates the existence of an active transport process across the blood-brain barrier.

1. Corneal thickness was measured in vivo in normothermic and hibernating (body temperature = 7-10 degrees C) woodchucks and the [Na(+)], [K(+)], [Mg(2+)] and water content of woodchuck and rabbit corneas were determined on freshly isolated tissues.2. Woodchuck eyes from both normothermic and hibernating animals were incubated in moist chambers at 5 or 11 degrees C and the corneal thickness was measured periodically.3. Woodchuck corneas undergo continuous swelling when kept in vitro in a moist chamber at either 5 or 11 degrees C. The rate of this swelling was the same for eyes from active and hibernating animals; it was almost completely reversible upon rewarming at 35 degrees C.4. In the hibernating woodchuck the corneal thickness did not increase measurably, even after several days of hibernation, although the mean corneal temperature was 9.4 degrees C.5. At 7 degrees C, the lactate production of corneas from both hibernating and normothermic woodchucks was reduced to about one fifth its levels measured at 37 degrees C. Oxygen consumption was also greatly reduced in the cold although the endothelial O(2) consumption of corneas from hibernating woodchucks appears to be relatively insensitive to cold.6. It is concluded that removal of the eye and/or the in vitro conditions per se render the cornea more vulnerable to the effects of cold, possibly as a result of the elimination of the influences of orbital tissues and/or secretions or as a result of changes in some intrinsic properties of the cornea due to the elimination of neurohumoural factors or the release of autocoids.7. The finding that normal corneal thickness can be maintained under conditions where the environment is maintained essentially constant for days strongly argues against the validity of the recently proposed nonsteady-state theory of corneal thickness control.