To investigate the effect of prostaglandins (PGs) on the permeability of human sclera in vitro.
Twenty-three pairs of human eye bank eyes were studied. Circular pieces of sclera were cultured in ...low-serum DMEM/F-12 media. Scleral hydration was assessed by measuring wet and dry weight of scleral cultures incubated with medium for 3 days and with Hanks' buffered saline solution (HBSS) for 4 hours. To assess scleral permeability, organ-cultured scleral tissues were exposed to 100 to 500 nM PGF(2alpha), 17-phenyltrinor PGF(2alpha), or PhXA85 (the active form of latanoprost) for 1, 2, and 3 days. Scleral permeability was measured using a two-chamber Ussing apparatus and rhodamine-dextran polymers dissolved in HBSS (MW = 10,000, 40,000, and 70,000). The movement of each rhodamine-dextran across the cultured sclera was measured using a spectrofluorometer. To understand the biological basis of the permeability change, the media were collected from the treated cultures, and the concentration of MMP-1, 2, and 3 was measured using an enzyme-linked immunosorbent assay.
There was no difference in scleral hydration among fresh sclera and sclera incubated with medium for 3 days, with HBSS for 4 hours, or with medium for 3 days followed by HBSS for 4 hours. Compared to tracer movement across untreated scleral cultures (1.5 x 10(-6) cm/sec for 10 kDa dextran, 0.7 x 10(-6) cm/sec for 40 kDa dextran, and 0.4 x 10(-6) cm/sec for 70 kDa dextran), exposure to PGF(2alpha), 17-phenyltrinor PGF(2alpha), or PhXA85 each increased scleral permeability in a dose- and time-dependent manner. Increases in permeability were greater with the10 kDa dextran than with the 40 or 70 kDa dextran. The magnitude of these effects was greatest with exposure to PhXA85 and similar with exposure to PGF(2alpha) or 17-phenyltrinor-PGF(2alpha). MMP expression also was significantly increased after PG exposure. These increases were generally time and dose dependent and greater with MMP-2 and -3 than with MMP-1.
There is increased permeability of human sclera exposed to various PGs in organ culture. This increased permeability is accompanied by increased expression of MMPS:
To determine whether topical treatment of mouse eyes with latanoprost alters intraocular pressure (IOP).
In a masked study design, NIH Swiss mice received a 2-microL topical instillation of 0.00015%, ...0.0006%, 0.0025%, or 0.01% latanoprost or vehicle (phosphate-buffered saline PBS). After 1, 2, or 3 hours, the animals were anesthetized, and a fluid-filled glass microneedle connected to a pressure transducer was inserted through the cornea into the anterior chamber to measure IOP. The reduction of IOP after latanoprost measurement was calculated by the comparison between treated and nontreated eyes in the same mouse. The effect of latanoprost after a single 0.01% dose was also measured at 6, 12, and 24 hours. As in the previous study, the identity of all eye drop solutions was masked.
In mouse eyes receiving topical PBS, the mean IOP was 14.8 +/- 2.2 mm Hg (n = 173 males). There was no significant difference in IOP between male and female eyes and between right and left eyes. At 1 hour after topical treatment with 0.00015% or 0.0025% latanoprost, IOP increased by as much as 11% +/- 7%. At 2 and at 3 hours after application, IOP decreased in a dose-dependent manner. These decreases were significant in eyes receiving 0.0025% or 0.01% latanoprost (P < 0.05, Student-Newman-Keuls test) and the largest decrease (14% +/- 8%) was noted 2 hours after treatment with 0.01% latanoprost. At 6, 12, or 24 hours after treatment, there was no difference in latanoprost- and PBS-treated eyes.
Latanoprost reduces mouse IOP in a dose-dependent manner. The mouse may be a useful model for studying the effect of drugs on IOP.
To characterize the 24-hour pattern of intraocular pressure (IOP) in untreated patients with newly diagnosed early glaucomatous changes.
Measurements of IOP, blood pressure, and heart rate were taken ...every 2 hours during a 24-hour period from a group of 24 untreated patients (ages 40-78 years) with newly diagnosed abnormal optic discs and/or abnormal visual fields. In the 16-hour diurnal awake period, IOP was measured sitting and supine, and blood pressure and heart rate were measured supine. In the 8-hour nocturnal sleep period, all measurements were taken in the supine position. Mean diurnal and nocturnal IOP, blood pressure, and heart rate in the glaucoma group were compared with data obtained from an age-matched control group of 24 individuals with healthy eyes.
Mean diurnal IOP, either sitting or supine, was significantly higher in the glaucoma group than in the control group. For both subject groups, nocturnal supine IOP was higher than diurnal sitting IOP. However, this diurnal-to-nocturnal increase in IOP was significantly smaller in the glaucoma group. When compared with the diurnal supine IOP, the nocturnal supine IOP was lower in the glaucoma group but higher in the control group. Around normal awakening time, the supine IOP increased in the glaucoma group and did not change in the control group. There was a diurnal-to-nocturnal decrease in mean blood pressure only in the glaucoma group.
Compared with healthy eyes, the diurnal IOP is higher, the diurnal-to-nocturnal change of habitual IOP is less, and the posture-independent IOP pattern around normal awakening time is different in eyes with early glaucomatous changes.
To evaluate the association between quantitative nerve fiber layer measurements and visual field loss in patients with primary open-angle glaucoma.
Quantitative retinal nerve fiber layer measurements ...were obtained in 53 patients with primary open-angle glaucoma by using confocal scanning laser ophthalmoscopy (cross-section area) and confocal scanning laser polarimetry (retardation ratio). For each eye, three images were obtained with each instrument. An image that was the mean of those three was created and used in all analyses. We investigated the association between global, regional, and hemifield differences in retinal nerve fiber layer measurements and visual field loss with linear regression techniques.
The retardation ratio decreased with increasing mean visual field loss, measured both globally and regionally; R2 (the amount of variation explained by the model) ranged from 8% to 21%. Retinal nerve fiber layer cross-section area was not significantly associated with global measures of visual field loss. The inferior visual field mean deviation increased with decreasing superior retinal nerve fiber layer cross-section area (R2 = 8.2%, P = .04); superior visual field mean deviation was not associated with inferior retinal nerve fiber layer cross-section area (R2 = 2.6%, P = .25). Hemifield differences in visual field mean deviation increased with increasing hemifield differences in retinal nerve fiber layer cross-section area (R2 = 20.0%, P < .001), but not with retardation ratio (R2 = 0.9%, P = .48).
Quantitative measures of the retinal nerve fiber layer using both confocal scanning laser ophthalmoscopy and confocal scanning laser polarimetry were correlated with visual field loss in glaucoma patients.
To compare optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness measurements with established methods for assessment of glaucomatous damage using RNFL photography and visual ...field testing.
Cross-sectional study.
Fifty-eight eyes of 58 healthy volunteer ocular hypertensive patients, glaucoma suspect patients, and glaucoma patients were included.
Optical coherence tomography 3.4-mm diameter circular scans were obtained within 3 months of RNFL photography and standard achromatic visual field testing. Three independent observers graded RNFL photographs using two standardized protocols. For each method, superior and inferior arcuate bundles were scored separately, and interobserver and intraobserver variation was measured. Standard achromatic visual field mean deviation in the superior and inferior hemifields was compared with RNFL damage as assessed by photography and OCT RNFL thickness measurements.
Visual field mean deviation and severity of glaucomatous RNFL damage as assessed by photography.
Optical coherence tomography RNFL thickness decreased with increasing RNFL damage as assessed by photography using both methods of photographic assessment. Standard achromatic perimetry mean deviation was significantly associated with OCT RNFL thickness (
R
2 = 35%–43%) and RNFL photography severity score (
R
2 = 18%–29%).
These results suggest that the OCT shows promise for providing quantitative measures of RNFL thickness for diagnosing and monitoring glaucoma.
Glaucoma is a leading cause of world blindness, and retinal ganglion cell death is its pathological hallmark. There is accumulating evidence that glaucomatous damage extends from retinal ganglion ...cells to vision centers in the brain. In an experimental primate model of unilateral glaucoma, degenerative changes are observed in magnocellular, parvocellular, and koniocellular pathways in the lateral geniculate nucleus, and these changes are presented in relation to intraocular pressure and the severity of optic nerve damage. Neuropathological findings are also present in lateral geniculate nucleus layers driven by the unaffected fellow eye. Finally, there is information on changes in the visual cortex in relation to varying degrees of retinal ganglion cell loss. The implications of these findings for refining concepts regarding the pathobiology of progression, and the detection and treatment of glaucoma, are discussed.
This study investigates the possibility that prostaglandins (PGs) induce changes in extracellular matrix (ECM) adjacent to ciliary muscle cells.
Human ciliary smooth muscle cells were grown to ...confluence in monolayer cultures and were treated with PGF2alpha, 11-deoxy-PGE1, or PhXA85 (the nonesterified analogue of PhXA41) for 12 to 72 hours. The amount of collagens type I, III, and IV in the cultures was determined, using sandwich enzyme immunoassays. The distributions of these collagens were assessed in the PG-treated cultures by immunocytochemistry.
Twenty-four-hour treatment with 20 nM PGF2alpha, 11-deoxy-PGE1, or PhXA85 reduced the amount of collagen type I in extracts of the cell layer by 65+/-10%, 56+/-7%, and 46+/-7%, respectively, when compared with levels of those substances in vehicle-treated cultures. In similar fashion, collagen type III in cell layer extracts was reduced by 41+/-5%, 33+/-9%, and 3+/-5%, respectively. When the concentration of PGs was increased to 200 nM, the amount of type III collagen in the cell layer extracts was reduced by 93+/-7%, 99+/-1%, and 99+/-1%, respectively. Changes in type IV collagen in cell layer extracts after treatment with 20 nM PGs were not statistically significant. When the concentration of PGF2alpha, 11-deoxy-PGE1, or PhXA85 was increased to 200 nM, the amount of collagen type IV in the cell layer extract increased by 101+/-16%, 14+/-5%, and 89+/-11%, respectively. There were minimal changes in the staining pattern for collagen type I after 24-hour treatment with 20 nM PGs. When the PG concentration was increased to 200 nM, there were reductions in the density of collagen type I fibrils and clumping of collagen type III immunoreactive elements. The delicate lacework of collagen type IV immunoreactivity was replaced by bundles or clumps of heavy immunoreactive strands, separated by areas without immunoreactivity. These changes were present in cultures exposed to 20 nM PGs and were marked when PG concentration was increased to 200 nM.
These results indicate that PGs can induce substantial changes in the ECM around ciliary smooth muscle cells in vitro. These data support the possibility that changes in ciliary muscle ECM may contribute to increased uveoscleral outflow facility after topical PG administration.
To compare the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure (IOP) in patients with ocular hypertension or early glaucomatous changes.
Prospective, open-label, ...experimental study with crossover design.
Eighteen patients with ocular hypertension or early glaucomatous changes (aged 41 to 79 years) each received topical treatments with timolol (0.5% Timoptic-XE), latanoprost (0.005% Xalatan), and no IOP-lowering medication, for at least 4 weeks. Timolol was given once in the morning upon awakening and latanoprost once in the evening at bedtime. At the end of each treatment period, the patient was housed in a sleep laboratory for 24 hours and IOP was measured every 2 hours using a pneumatonometer. Measurements were taken sitting and supine during the 16-hour diurnal/wake period and only supine during the 8-hour nocturnal/sleep period. Mean diurnal and nocturnal IOP levels were compared among the treatments with timolol, latanoprost, and no medication.
In the diurnal period, the mean IOP under the timolol or the latanoprost treatment was significantly less than the mean IOP under no medication in both the sitting and the supine positions. There was no statistical difference between the timolol and latanoprost treatments. In the nocturnal period, supine IOP with timolol treatment was not different from the supine IOP with no medication but was significantly higher than supine IOP with the latanoprost treatment.
Although both once-daily timolol and latanoprost were effective in lowering IOP during the diurnal period, only latanoprost reduced IOP during the nocturnal period.
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