Effects of brinzolamide on aqueous humor dynamics in monkeys and rabbits.

This study examines the mechanisms by which brinzolamide reduces intraocular pressure (IOP) in healthy rabbits and in monkeys with unilateral ocular hypertension. Intraocular pressures were measured by pneumatonometry and aqueous flow was determined by fluorophotometry before and after three twice-daily drops of 1% brinzolamide to both eyes per monkey and after similar treatment to one eye per rabbit. In monkeys, outflow facility was determined by fluorophotometry and uveoscleral outflow was calculated. In rabbits, outflow facility was determined by two-level constant pressure infusion and uveoscleral outflow was measured by an intracameral tracer technique. Compared with contralateral vehicle-treated rabbit eyes, IOP was reduced in brinzolamide-treated eyes by 2.5 +/- 1.9 mmHg (mean +/- standard deviation; p =.006) at four hours after the second dose. Aqueous flow was reduced by 0.50 +/- 0.65 microl/min (p =.02). This effect was found in rabbits previously treated with brinzolamide but not in naive rabbits. Treated hypertensive eyes of monkeys had a reduction in IOP of 7.3 +/- 8.8 mmHg (p = 0.01) and aqueous flow of 0.69 +/- 1.10 microL/min (p = 0.05) when compared with baseline. Brinzolamide did not affect outflow facility or uveoscleral outflow in either rabbits or monkeys. It is concluded that, in normotensive eyes of rabbits and hypertensive eyes of monkeys, brinzolamide reduces IOP by reducing aqueous flow and not by affecting aqueous humor drainage.     

The effect of topical PGF2 alpha on uveoscleral outflow and outflow facility in the rabbit eye.

Prostaglandin F2 alpha (PGF2 alpha) is a powerful ocular hypotensive agent in rabbit, cat, dog, monkey and human. In cynomolgus monkeys, the intraocular pressure (IOP) lowering is due to increased uveoscleral outflow (Fu). Because the anatomy of the rabbit outflow apparatus differs significantly from that of the primate, we sought to determine whether the mechanism of the PGF2 alpha-induced IOP fall was the same. PGF2 alpha tromethamine salt (PGF2 alpha-TS) (50 micrograms) applied to one eye of 14 conscious rabbits produced a significant IOP fall of 7.4 +/- 0.9 mmHg (P less than 0.001). In untreated control eyes, Fu determined from the quantity of intracamerally perfused [125I]albumin found in the ocular and periocular tissues accounted for 5-8% of total aqueous outflow. In 15 unilaterally PGF2 alpha-treated rabbits, after 4-6 hr dosing Fu was 49 +/- 14% higher in the treated than in the contralateral control eyes. Total outflow facility of outflow from the anterior chamber to the general circulation were measured concurrently in 11 rabbits using a two-level constant pressure perfusion and isotope accumulation technique. Both facilities tended to be higher in the treated eyes than in the controls, with a strong correlation between drug-induced changes in total facility and changes in facility of flow to blood (r = 0.85, P less than 0.001). In eight rabbits treated unilaterally with 50 micrograms PGF2 alpha-TS, the fluorophotometrically determined aqueous formation rate was probably not decreased relative to control eyes. Protein levels in the aqueous humor were approximately eight-fold higher in PG-treated vs. control eyes, suggesting a drug-induced compromise of the blood-aqueous barrier.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of isoglaucon on the hydrodynamics and haemodynamics of the eye (author's transl)]

By animal experiments and clinically we could prove that isoglaucon instillation caused the decrease in IOP due to both increase in outflow and reduction of humor secretion; the IOP decrease and changes in hydrodynamics being manifested more markedly in the fellow-eye. As reoophthalmography demonstrated "Isoglaucon" produced lumen narrowing in the anterior portion of the uveal tract. "Isoglaucon" was prescribed to 20 patients having open-angle-glaucoma, Two hours after instillation the 23 decreased in 26 eyes (of 28) by 9.3 +/- 1.0 mm Hg. When prescribed regularly "Isoglaucon" raised the outflow facility coefficient from 0.10 +/- 0.01 to 0.20 +/-0.02. The secretion decreased from 2.0 +/- 0.2 to 0.9 +/- 0.15. Thus, IOP decrease after "Isoglaucon" is accounted for by both improved outflow and reduction of aqueous humor secretion. The "isoglucon" instillation produced a rather moderate decrease in the total arterial pressure, though no expected parallelism in arterial and intraocular pressure was marked.     

Time dependent effects of sympathetic denervation on aqueous humor dynamics and choroidal blood flow in rabbits

PURPOSE: This study investigates the time-dependent effects of superior cervical ganglionectomy (SCGx) on aqueous humor dynamics and ocular blood flow in rabbits. METHODS: Measurements were made at various times between 24 hours and 12 months after SCGx. Intraocular pressure (IOP) was measured by pneumatonometry, aqueous flow by fluorophotometry and outflow facility by tonography. Uveoscleral outflow was determined by an intracameral tracer infusion technique and blood flow to the choroid was evaluated with fluorescent microspheres. Values in denervated eyes were compared with the contralateral, normally-innervated eyes using a paired Student's two-tailed t-test. RESULTS: At 24 hours after SCGx, IOP in denervated eyes was less than in normally-innervated eyes (14.6 +/- 0.8 vs 20.1 +/- 1.5 mmHg, 27%, p < 0.002). At one month, IOPs were not different between eyes. Compared with normally-innervated eyes at 10-12 months, IOP in denervated eyes was greater (20.4 +/- 0.7 vs 17.2 +/- 0.9 mmHg, 19%, p < 0.001), outflow facility was less (0.15 +/- 0.02 vs 0.21 +/- 0.01 microl/min/mmHg, 29%, p < 0.01) and blood flow to the choroid was less (12.1 +/- 5.0 vs 16.2 +/- 6.0 ml/min/gm tissue, 25%, p < 0.05). Aqueous humor flow was not significantly altered by SCGx at any time. CONCLUSIONS: The reduction in IOP at 24 hours after SCGx was not due to any change in aqueous flow or uveoscleral outflow (current study) but rather to an increase in outflow facility (previous studies). At 10-12 months, IOP was elevated because outflow facility was significantly reduced. The reduction in choroidal blood flow at 10-12 months may have occurred because of the increased IOP.     

Outflow facility in the monkey eye: effects of calcitonin gene-related peptide, cholecystokinin, galanin, substance P and capsaicin.

A study in cats has shown that intracameral injection of calcitonin gene-related peptide (CGRP) increases the outflow facility by four- to fivefold concomitant with a decrease in intra-ocular pressure (IOP). Since there are great differences in the anatomy of the aqueous outflow routes between cats and primates, we have examined the effects of CGRP in the cynomolgus monkey. The possible influence of the sensory neuropeptides cholecystokinin (CCK), galanin and substance P on the outflow facility and IOP were also investigated. Determinations were performed using a two-level constant-pressure procedure. At 40-60 min after intracameral injection of 3 micrograms CGRP the outflow facility was increased from 0.68 +/- 0.11 to 1.03 +/- 0.15 microliters min-1 mmHg-1 in the CGRP-treated eyes, and from 0.71 +/- 0.12 to 0.79 +/- 0.10 microliter min-1 mmHg-1 in the control eyes. The mean difference in increase was 0.27 +/- 0.06 microliter min-1 mmHg-1 (P less than 0.01, n = 7). During the experiments there was a small rise in the IOP. CGRP at a dose of 3 micrograms caused a small rise in aqueous humor protein concentration. An attempt to release endogenous CGRP with capsaicin did not result in an increased outflow facility. Three micrograms each of CCK, galanin and substance P had no significant effect on either the outflow facility or the IOP. A miosis was observed in the experiments with CCK in agreement with previous findings. CCK seems thus to cause contraction of the pupillary sphincter but does not influence the ciliary muscle sufficiently to cause a facility effect in the monkey eye.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of latanoprost on outflow facility in the mouse

PURPOSE: To assess the early effect of latanoprost on outflow facility and aqueous humor dynamics in the mouse. METHODS: Aqueous humor dynamics in NIH Swiss White mice were assessed with an injection and aspiration system, using fine glass microneedles. A single 200-ng (4 microL) dose of latanoprost was applied to one eye 2 hours before measurement. The fellow eye served as a control. Intraocular pressure (IOP) was measured by using an established microneedle procedure. Outflow facility (C) was determined by constant-pressure perfusion measurements obtained at two different IOPs. Aqueous humor flow (Fa) was determined by a dilution method using rhodamine-dextran. Conventional and uveoscleral outflow (Fc and Fu) were calculated by the Goldmann equation. RESULTS: Average IOP, Fa, and C of control eyes were 15.7 +/- 1.0 mm Hg, 0.144 +/- 0.04 microL/min (mean +/- SD, n = 8), and 0.0053 +/- 0.0014 microL/min per mm Hg (n = 21), respectively. Average IOP, Fa, and C of treated eyes were 14.0 +/- 0.8 mm Hg, 0.138 +/- 0.04 microL/min (n = 8 for each), and 0.0074 +/- 0.0016 microL/min per mm Hg (n = 21), respectively. The differences between treated and control eyes were significant for IOP and total outflow facility only. CONCLUSIONS: These data indicate that the early hypotensive effect of latanoprost in the mouse eye is associated with a significant increase in total outflow facility. Alterations in the aqueous dynamics induced by latanoprost can be measured reproducibly in the mouse and may provide a useful model for further determining the mechanism by which latanoprost reduces IOP and alters outflow facility.     

Circadian variation of aqueous dynamics in young healthy adults

PURPOSE: Recent research indicates that intraocular pressure (IOP) does not decrease significantly during the nocturnal period, although aqueous humor flow decreases by 50% or more at night. This study was undertaken to investigate whether changes in outflow facility, episcleral venous pressure, or uveoscleral flow at night could account for the nocturnal IOP. METHODS: Sixty-eight eyes of 34 healthy subjects (age, 18-44 years; mean, 29) were studied. Aqueous humor flow rate, IOP, and outflow facility were measured with pneumatonometry, anterior chamber fluorophotometry, and Schiotz tonography respectively, in each eye during the mid-diurnal (2-4 PM) and mid-nocturnal (2-4 AM) periods. Nocturnal IOP, flow rate, and outflow facility were compared to the same variables during the diurnal period. Mathematical models based on the modified Goldmann equation were used to assess the conditions under which these results could be reconciled. RESULTS: Supine IOP decreased slightly from 18.9 +/- 2.7 mm Hg in the mid-diurnal period to 17.8 +/- 2.5 mm Hg in the mid-nocturnal period (mean +/- SD, P = 0.001). Aqueous flow rate decreased from 2.26 +/- 0.73 to 1.12 +/- 0.75 microL/min (mean +/- SD, P < 0.001). There was a nonsignificant trend toward a nocturnal decrease of outflow facility (diurnal, 0.27 +/- 0.11 microL/min/mm Hg; nocturnal, 0.25 +/- 0.08 microL/min/mm Hg; mean +/- SD, P = 0.13). CONCLUSIONS: Outflow facility measured by tonography does not decrease enough during the nocturnal period to compensate for the decreased aqueous humor flow rate. Modeling results indicate that the experimental results could be reconciled only if nocturnal changes in episcleral venous pressure and/or uveoscleral flow occurred.     

地塞米松对兔眼房水中一氧化氮及钙离子含量的影响

目的　观测兔眼球结膜下注射地塞米松后其眼压 (P)、房水流畅系数 (C)及房水中一氧化氮 (NO)浓度和Ca2 含量的变化 ,探讨NO、Ca2 在皮质类固醇性青光眼 (GIG)发病中的可能作用。方法　隔日定时给新西兰幼龄白兔双眼球结膜下注射地塞米松 0 5mg ,共 15次 ,3 0d ,隔日定时测定双眼眼压及C值 ,实验结束时抽取房水测定房水中NO及Ca2 浓度。结果　地塞米松使兔眼眼压升高 (P <0 0 5 )、C值及房水中NO浓度下降 (P <0 0 5 ) ;但对兔眼房水中Ca2 的含量无明显影响。结论　眼局部长期应用地塞米松可诱导高眼压 ,引起房水中NO含量显著降低 ,提示NO参与了GIG的发病     

Effects of vasoactive intestinal polypeptide (VIP) on intraocular pressure, facility of outflow and formation of aqueous humor in the monkey

Stimulation of the facial nerve causes a non-cholinergic vasodilation in the uvea and a rise in the intraocular pressure in rabbits, cats and monkeys. Vasoactive intestinal polypeptide (VIP) has been suggested as the neurotransmitter mediating these effects. In the present investigation, the effects of VIP on aqueous humor dynamics were studied in cynomolgus monkeys. After intracameral injection of 1 microgram VIP, the outflow facility was higher in the experimental eye than in the control; 0.42 +/- 0.46 compared with 0.33 +/- 0.03 microliter cm H20-1 min-1, difference 0.09 +/- 0.04 microliter cm H2O-1 min-1. Intravenous infusion of VIP, 160 ng min-1, increased aqueous humor flow from 1.12 +/- 0.07 to 1.65 +/- 0.09 microliter min-1. Almost the same effect, a 50% increase in aqueous humor flow, was found after intracameral administration of 90 micrograms VIP. This dose of VIP caused a significant increase in intraocular pressure (IOP) in the experimental eye. The maximal difference in IOP between the experimental eye and the control eye was 7.5 +/- 0.4 cm H2O. A lower dose of VIP, 30 micrograms intracamerally, increased aqueous humor flow by about 20%, but had no consistent effect on IOP. The effect of VIP on aqueous humor flow was not affected by pretreatment with indomethacin. The results suggest that most of the rise in IOP caused by intracameral VIP administration is due to a rise in the pressure in the veins into which the aqueous humor is drained. Enhanced formation of aqueous humor plays a smaller role. The effects of VIP on aqueous humor formation and outflow facility suggest that the facial nerve may be involved in nervous control of aqueous humor dynamics, as VIP is most probably released in the eye by stimulation of the facial nerve.     

The prostanoid EP2 receptor agonist butaprost increases uveoscleral outflow in the cynomolgus monkey

PURPOSE: To investigate the ocular hypotensive effect of the prostanoid EP2 receptor agonist butaprost and to establish its mechanism of action. METHODS: All experiments were performed in cynomolgus monkeys after topical application of butaprost (0.1%). The effects of butaprost on aqueous humor flow were determined by fluorophotometry. Total outflow facility was measured by the two-level, constant-pressure perfusion method, and uveoscleral outflow was determined by perfusion of FITC-labeled dextran through the anterior chamber. Effects on ocular morphology were studied after tissue fixation with transcardial perfusion by paraformaldehyde and immersion fixation of the globe, in animals subjected to long-term treatment with butaprost. Conscious ocular normotensive monkeys and monkeys with unilateral ocular hypertension were used for intraocular pressure (IOP) studies. RESULTS: Butaprost had no significant effect on aqueous humor flow or total outflow facility in ocular normotensive monkeys. Uveoscleral outflow was significantly higher in the butaprost treated eyes than in vehicle treated eyes, 1.03 +/- 0.20 vs. 0.53 +/- 0.18 microL.min(-1). After a 1-year treatment with butaprost, the morphology of the ciliary muscle was changed, showing increased spaces between ciliary muscle bundles and the apparent formation of new outflow channels. In many instances, changes were observed in the trabecular meshwork as well. Butaprost, in a single 0.1% dose, decreased IOP significantly in ocular normotensive monkeys and reduced IOP in laser-induced glaucomatous monkey eyes to the same level as that in the ocular normotensive contralateral eyes. CONCLUSIONS: The prostanoid EP2 receptor agonist butaprost appears to lower IOP by increasing uveoscleral outflow, according to both physiological and morphologic findings. Although the prostanoid EP2 receptor is structurally and functionally distinct from the FP receptor, the effects of EP2 and FP receptor stimulation on aqueous humor outflow are similar.     

Aqueous Humor Dynamics Associated with the Phorbol Ester-Induced Decrease in Intraocular Pressure in the Rabbit

Purpose To determine the effects of injection of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) into the anterior chamber of the eye on intraocular pressure (IOP) and aqueous humor dynamics. Methods IOP was measured for 24 h after intracameral injection of PMA (3 to 50 pmol) in unanesthetized rabbits. Aqueous humor dynamics (aqueous flow, total outflow facility, and uveoscleral outflow) were determined approximately 6 h after injection of 50 pmol of PMA in animals pretreated with indomethacin. Results Intracameral injection of 50 pmol of PMA induced a biphasic effect on IOP, consisting of a transient increase apparent at 0.5 and 1 h and a sustained decrease apparent after 2 h. This effect of PMA was dose dependent. Whereas pretreatment with indomethacin attenuated the PMA-induced increase in IOP, the sustained decrease in IOP remained apparent in the pretreated rabbits. Intracameral injection of 4α-PMA, an inactive PMA analog, had no effect on IOP. PMA also significantly increased uveoscleral outflow, but it had no effect on aqueous flow or total outflow facility. Conclusion Intracameral injection of PMA reduced IOP in the rabbits by increasing the rate of uveoscleral outflow. This IOP-lowering effect of PMA may be mediated by activation of PKC.     

The ocular hypotensive effects of demeclocycline, tetracycline and other tetracycline derivatives

Demeclocycline, tetracycline and other tetracycline derivatives lowered intraocular pressure (IOP) in rabbits following intravitreal injection, but the onset of this effect was not evident until 1 or more days after drug administration. Of the drugs tested, demeclocycline was the most active ocular hypotensive agent. Demeclocycline caused a dose-dependent decrease in IOP. The maximum IOP decrease of approximately 12 mm Hg occurred 5 days after intravitreal administration of 0.5 mg, with the effect persisting for over a week. Demeclocycline did not alter tonographically measured aqueous humor outflow facility or episcleral venous pressure. Based on calculated aqueous humor flow rates following 0.2 mg demeclocycline, a 62% decrease in aqueous humor formation occurred 7 days after intravitreal injection. The flow-to-diffusion ratio for ascorbate was reduced 54% 6 days after the intravitreal administration of demeclocycline, a change also consistent with suppression of aqueous humor formation. Anterior chamber aqueous humor protein concentration was increased 6 days after demeclocycline administration. No histologic changes were present in the treated eyes by light microscopy. Intravitreal demeclocycline similarly lowered IOP in cats, with the duration of effect lasting up to 20 days.     

Effects of systemic desmopressin on aqueous humor dynamics in rabbits

Intravenous desmopressin, a synthetic antidiuretic hormone, resulted in a dose-dependent increase in intraocular pressure (IOP) in rabbits. IOP was increased 3.6 +/- 0.8 mm Hg 6 hr following injection of desmopressin 200 mUnits/kg with the increase lasting over 10 hr. IOP returned to baseline 24 hr after the injection. Systemic blood pressure, plasma osmolarity and arterial blood gases were not altered by desmopressin. The increased IOP was not associated with alterations in measured outflow facility or episcleral venous pressure. Five hours after desmopressin injection, calculated aqueous humor flow was increased approximately 57%. Aqueous humor ascorbate measurements for calculation of flow to diffusion ratios and anterior chamber fluorophotometry also were consistent with an increased rate of aqueous humor formation as the mechanism for the IOP elevation. Desmopressin administration did not increase aqueous humor protein or aqueous humor cyclic AMP concentration. Systemic pretreatment with indomethacin only partially blocked the IOP increase. Systemic pretreatment with demeclocycline completely blocked the desmopressin-induced increase in IOP.     

Ocular hypotensive and aqueous outflow-enhancing effects of AL-3037A (sodium ferri ethylenediaminetetraacetate)

AL-3037A (Sodium ferri ethylenediaminetetraacetate), a novel compound shown to stimulate the degradation of glycosaminoglycans, was evaluated for its effects on aqueous humor outflow and intraocular pressure (IOP) in four experimental models. Its effect on outflow facility was assessed in bovine and human ocular perfusion organ cultures. Its IOP effect was tested in normotensive and dexamethasone-induced ocular hypertensive rabbits. In bovine eyes, perfusion with AL-3037A (0.1% w/v, 2.3 m M) significantly increased the outflow facility well above the normal 'wash-out' effect. At 30 min after perfusion, the outflow facility of drug-treated eyes increased by 26.0+/-2.8% (mean +/- S.E.(M.), n = 8), significantly higher than the 12.1 +/- 2.8% increase in vehicle-treated eyes. This difference sustained throughout the study period (2 hr). The compound also enhanced aqueous outflow in perfused human anterior segments. In non-glaucomatous eyes, it produced a small decrease in IOP (15.4 +/- 4.6%, n = 17), but in tissues derived from glaucoma patients, bolus administration of 3 mg (7 micromol) of AL-3037A lowered the IOP by 52-68% (n = 2) lasting for at least 3 hr. This outflow-enhancing effect of AL-3037A in ex vivo studies was confirmed by in vivo results. In normotensive rabbits, oral (50 mg kg(-1)), intravenous (10 mg kg(-1)), or topical (2 mg; 50 microl of 4% w/v solution) administration of AL-3037A produced maximum reduction of IOP, when compared to vehicle-treated animals, by 34.7+/-3.5% (n = 10), 22.0 +/- 4.6% (n = 10), and 21.6 +/-4.5% (n = 10), respectively. In dexamethasone induced ocular hypertensive rabbits, topical application of the compound (0.5 mg; 25 microl of 2% w/v solution) reduced IOP significantly by 19.2+/- 0.4% (n = 7) at 3 hr after dosing. Importantly, the IOP lowering effect of AL-3037A did not diminish even after repeated treatments in consecutive days. Thus, in the four study models across three animal species, AL-3037A was demonstrated to be an efficacious ocular hypotensive compound whose effect is most likely mediated by augmentation of the aqueous outflow. Its proposed action on the metabolism of glycosaminoglycans may provide a new and unique mechanism for the treatment of glaucoma.     

Aqueous humor dynamics in ocular hypertensive patients

PURPOSE: To evaluate the mechanism of the intraocular pressure (IOP) elevation in ocular hypertension (OHT), aqueous humor dynamics were compared in patients with OHT versus age-matched ocular normotensive (NT) volunteers. METHODS: In this retrospective study, one group included patients diagnosed with OHT (IOPs > 21 mm Hg, n = 55) for at least six months. All eye medications were discontinued for at least three weeks before the study visit. A second group included age-matched NT subjects (n = 55) with no eye diseases. The study visit included measurements of IOP by pneumatonometry, aqueous flow and outflow facility by fluorophotometry, anterior chamber depth and corneal thickness by pachymetry and episcleral venous pressure by venomanometry. Uveoscleral outflow and anterior chamber volume were calculated mathematically. RESULTS: Significant differences in the OHT versus the NT groups were as follows: increased IOP (21.4 +/- 0.6 versus 14.9 +/- 0.3 mm Hg, respectively; P < 0.0001), reduced uveoscleral outflow (0.66 +/- 0.11 versus 1.09 +/- 0.11 microL/min; P = 0.005) and reduced fluorophotometric outflow facility (0.17 +/- 0.01 versus 0.27 +/- 0.02 microL/min/mm Hg; P < 0.0001). With respect to age, anterior chamber volume decreased in both groups at a rate of 2.4 +/- 0.3 microL/year (r(2) = 0.5, P <.001) and aqueous flow decreased at a rate of 0.013 +/- 0.005 microL/min/year (r(2) = 0.07, P = 0.005). CONCLUSIONS: The increased IOP in ocular hypertensive patients is caused by a reduction in trabecular outflow facility and uveoscleral outflow. Aqueous flow remains normal. When both ocular normotensive and hypertensive groups are combined, aqueous flow and anterior chamber volume decrease slightly with age.     

Effect of flunarizine, a calcium channel blocker, on intraocular pressure and aqueous humor dynamics in monkeys

PURPOSE: To evaluate the effects of flunarizine, a nonselective calcium channel blocker, on intraocular pressure (IOP) in monkeys with laser-induced unilateral glaucoma and on aqueous humor dynamics in normal monkeys. METHODS: The IOP was measured before and hourly for 6 hours after single-dose administration of 0.5%, 1%, or 2% flunarizine to the glaucomatous eye of 8 monkeys with unilateral laser-induced glaucoma. In a separate multiple-dose study, 0.5% flunarizine was applied twice daily for 5 consecutive days to the glaucomatous eye of the same 8 monkeys. IOP was measured at untreated baseline, after treatment with vehicle only, and on treatment days 1, 3, and 5. Tonographic outflow facility and fluorophotometric flow rates of aqueous humor were measured in 7 normal monkeys before and after the fifth dose of twice-daily treatment with 0.5% flunarizine. RESULTS: Unilateral application of 50 microL of 0.5%, 1%, or 2% flunarizine reduced IOP bilaterally. In the treated glaucomatous eyes, flunarizine reduced the IOP for 2, 3, or 5 hours, with a maximum reduction of 2.5+/-0.5 (mean+/-SEM) mm Hg (9%), 3.0+/-0.4 mm Hg (10%), and 5.0+/-0.8 mm Hg (18%) following the 0.5%, 1%, and 2% concentrations, respectively (P<0.01). The maximum reductions in IOP in the contralateral untreated eyes were 1.3+/-0.5 mm Hg, 1.5+/-0.3 mm Hg, and 2.9+/-0.7 mm Hg following the 0.5%, 1%, and 2% concentrations, respectively (P<0.05). Both the magnitude and duration of the ocular hypotensive effect of 0.5% flunarizine were enhanced with twice-daily administration for 5 days. Outflow facility in normal monkey eyes was increased (P<0.05) by 39% in the treated eyes compared with vehicle-treated contralateral eyes and by 41% compared with baseline values, and aqueous humor flow rates were unchanged (P>0.30). CONCLUSIONS: Flunarizine reduces IOP in a dose-dependent manner when administered to glaucomatous monkey eyes, but also has an ocular hypotensive effect on the contralateral untreated eyes. An increase in tonographic outflow facility seems to account for the IOP reduction in normal monkey eyes.     

Reliable measurement of mouse intraocular pressure by a servo-null micropipette system.

PURPOSE. To develop a reliable technique for measuring intraocular pressure (IOP) in the mouse. METHODS. An electrophysiologic approach-the servo-null micropipette system (SNMS)-for measuring hydrostatic pressure was adapted for the mouse eye. Fine-tipped (5 microm in diameter) micropipettes were advanced across the cornea with a piezoelectric micromanipulator, and the IOP was continuously monitored for up to 46 minutes. RESULTS. The micropipette tip was visualized in the anterior chamber. With the SNMS, the IOP of black Swiss outbred mice under ketamine anesthesia was 17.8 +/- 0.4 mm Hg, higher than values previously estimated in inbred mouse strains by a larger bore microneedle manometric technique. After withdrawal of the micropipette, a second penetration led to a similar level of IOP. Hypotonic solutions increased and hypertonic solutions decreased IOP. Drugs that decrease inflow (acetazolamide, timolol) or increase outflow facility (pilocarpine, latanoprost) in primates and humans lowered steady state IOP in the mouse. The transient initial increase in IOP produced by pilocarpine reported in other animals was also observed in the mouse. Xylazine-ketamine anesthesia lowered IOP substantially in comparison with systemic anesthesia with either ketamine or tribromoethanol alone. CONCLUSIONS. The SNMS is the first reliable, reproducible method for measuring mouse IOP. The mouse IOP is sensitive not only to drugs known to reduce aqueous humor inflow but also to drugs that increase aqueous humor outflow facility in the eyes of primates and humans. The development of the SNMS is an enabling step in the use of the mouse for glaucoma research, including molecular genetics, molecular pharmacology, and the search for novel antiglaucoma drugs.     

Effects of a cyclic AMP phosphodiesterase inhibitor, 8'-pivaloyloxymethyl ester of griseolic acid, on aqueous humor dynamics in rabbits.

The mechanism by which pivaloyloxymethyl (POM) ester of griseolic acid (GA), a potent cyclic AMP-phosphodiesterase inhibitor, lowers intraocular pressure (IOP) in albino rabbits was studied. The rate of aqueous flow, measured by fluorophotometry, was significantly lower in GA POM ester-treated eyes (2.36 +/- 0.24 microliters/min) than in control eyes (3.02 +/- 0.24 microliters/min). Topically applied GA POM ester did not alter tonographic outflow or uveoscleral outflow. No differences in aqueous humor protein concentrations between GA POM ester-treated and control eyes were observed. It was thought that the GA POM ester lowered the IOP by decreasing the aqueous inflow. Topical application of this compound caused no inflammatory response in the eye or changes in the blood aqueous barrier.     

晚期青光眼的房水动力学变化

目的：观察晚期青光眼高眼压对睫状体功能的损害作用及对角膜透明性的影响。方法：应用扫描荧光光度计及Ｓｃｈｉｏｔｚ电子眼压计分别测定１５只正常眼和１５只晚期原发性青光眼眼压、房水排出率和房水流畅系数,并观察角膜的透明性。结果：晚期青光眼眼房水排出率显著下降,下降程度与眼压水平及病程成正比。房水排出率降低至０．８μｌ／ｍｉｎ。角膜出现水肿混浊,房水排出率下降愈甚,角膜透明性改变愈明显。结论：持续高眼压将     

Iloprost, a stable prostacyclin analog, reduces intraocular pressure

Topical application of Iloprost caused a dose-dependent decrease in intraocular pressure (IOP) in rabbits and ocular hypertensive beagles. In rabbits, the IOP response was biphasic and miosis was observed. In beagles, there was no initial hypertensive phase, and the fall in IOP was more pronounced (up to 37%). In beagles, Iloprost did not influence pupillary diameter. A mild transient hyperemia was noted in both rabbit and beagle eyes. Iloprost led to an increase in the aqueous humor protein concentration in rabbits but not in beagles. The use of artificial tears as vehicle enhanced the effect on intraocular pressure but also aqueous protein in rabbits. The central corneal temperature was increased after application of Iloprost in both rabbits and beagles. In rabbits, tonography revealed an increase in outflow facility during both the hypertensive and the hypotensive phases. Iloprost caused a decrease in mean arterial pressure in beagles; the effect on pulse rate was inconsequential. It is suggested that similar low doses of an analog of Iloprost or carboprostacyclin that does not affect the hemodynamic equilibrium could be of value in the treatment of glaucoma.