Aqueous Humor Dynamics Research Articles

Strain and Age Effects on Aqueous Humor Dynamics in the Mouse.

We evaluated differences in aqueous humor dynamics (AHD) among several mouse strains within younger and older age groups. Albino (A/J, BALB/cJ) and pigmented (C3H/HeJ, C57-BL/6J) mice (young [2½-4½ months] and aged [10-12 months]) were studied. Intraocular pressure (IOP) was measured. In cannulated eyes, episcleral venous pressure (Pe) was assessed (blood reflux). Other AHD parameters (outflow facility [C], aqueous humor formation rate [Fin]) were assessed (constant flow infusion). Uveoscleral outflow rate (Fu) was obtained by calculation (Fu(calc)) using the modified Goldmann equation, and in additional eyes (for comparison), by FITC-dextran perfusion (Fu(FITC-dex)). Intraocular pressure was higher in pigmented strains, but did not exhibit age-dependence, except in the C57-BL/6J strain. Fu(calc) decreased with age in BALB/cJ (↓83.3%), C3H/HeJ (↓78.0%), and C57-BL/6J (↓85.0%) strains. In the A/J strain, Fu(calc) decreased with age (↓70.0%), but not significantly. Fin decreased with age in the C3H/HeJ (↓53.6%) strain. In C57-BL/6J and A/J strains, Fin decreased with age, but not significantly. C in the BALB/cJ strain increased with age (↑62.5%). In C3H/HeJ and C57-BL/6J strains, C increased with age, but not significantly. Episcleral venous pressure ranged from 6.0 to 6.6 mm Hg (albino strains) to 8.5 to 8.9 mm Hg (pigmented strains). Pe was not age dependent, but was higher in pigmented animals. In mouse, Fu and Fin diminish with age. C tends to increase as animals progress to middle life. There are strain differences in Fu, IOP, C, Fin, and Pe. The current findings provide an important foundation for comparisons among different strains in different study reports.

A simple method for evaluation of aqueous humor dynamics “A weight on-off test” in patients with glaucom

Purpose:To evaluate aqueous humor (AH) dynamics in patients with glaucoma through a newly developed method termed the “Weight on-off test”Methods: Patients: primary open angle glaucoma (POAG)(n=124), primary angle closure glaucoma (n=16), Pseudoexfoliation syndrome(n=17), or senile cataract (n=93) without other eye diseases. For evaluation of AH dynamics, a 50 g weight was placed onto the eye of a subject in a supine position for 5 min and then removed. Intraocular pressure (IOP) was measured before and immediately after removal, and thereafter every minute until IOP returned to baseline. Based upon IOP changes (decreases during the weight on and recovery after removal), we defined AH outflow resistance: IOP drop rate (IOPdrop) (%) = (P0-Pe) – (P5-Pe) / (P0-Pe) x 100 (P0: IOP at baseline, Pe: assumed episcleral venous pressure, P5: IOP at 5 min) and AH outflow resistance index (Raq out)= 100 - IOP drop, and AH production: IOP recovery time (IOPrec) (min) reached to baseline IOP, and AH production index (Paq) was an IOP increase rate during the IOPrec by least squares method.Results:AH outflow resistance was significantly higher in glaucoma subjects than the control. AH production in glaucoma subjects was slightly increased compared to that in control. In POAG, prostaglandin-analogues (PG) caused a significant delay of AH production (IOPrec).Conclusions: The current data suggests that a “Weight on-off test” may be simple and useful for estimating AH dynamics in patients with glaucoma and provides a better understanding of glaucoma etiology as well as its pharmacology.

Aqueous Humor Outflow: Dynamics and Disease

This review summarizes the goals and outcomes of the eighth annual ARVO/Pfizer Ophthalmic Research Institute conference that was held on May 4th and 5th, 2012, at the Embassy Suites Fort Lauderdale, Fort Lauderdale, Florida. This conference series has been funded by the ARVO Foundation for Eye Research with the help of a generous grant from Pfizer Ophthalmics. Funding from the ARVO/Pfizer Ophthalmics Research Institute has allowed a series of “think tanks” for the leading experts on various subspecialties of ophthalmology research. These meetings have helped to define various challenges and potential solutions to issues relevant to the field of ophthalmology. In 2012, the emphasis of the conference was on the physiological role of the conventional outflow pathway in aqueous humor dynamics in normal and glaucomatous eyes. In particular, clinical observations associated with aqueous humor outflow in health and disease, animal models in the understanding of aqueous outflow, role of mechanosensing in aqueous humor fluid flow, and new paradigms in cell and extracellular matrix crosstalk within the conventional outflow pathway were discussed. The primary goal of the conference was to bring together a diverse group of experts who are pioneers in conventional outflow biology and related nonocular areas of research with the hope of utilizing the group's knowledge and experience to evaluate the current understanding of aqueous outflow regulation and problems thereof. The invited group consisted of 29 investigators directly involved in conventional outflow research. Also present were three invited outside experts in cellular mechanics and cytoskeleton structures (Jeffrey Fredberg, PhD, Harvard School of Public Health, Boston, MA, USA), molecular mechanisms of cell adhesion and mechanosensing (Benjamin Geiger, PhD, Weizmann Institute of Science, Rehovot, Israel), and murine genetics (Richard Libby, PhD, University of Rochester Medical Center, Rochester, NY, USA). In addition, the conference was attended by 27 observers who participated in discussion of key topics at the end of each presentation. Together, the group was tasked with reviewing the current scientific dogma regarding aqueous outflow diseases and identifying the most pressing research questions and needs in the current funding environment. Above all, the group was asked to think “outside the box” to develop future research directions. The conference generated a list of highly relevant but currently unanswered questions with the hope that solutions to these issues would improve understanding of the role of the conventional outflow pathway in normal and glaucoma eyes. The meeting was organized into four sessions: (a) clinical insights into conventional outflow dysfunction, (b) the use of mice as model systems for conventional outflow, (c) mechanosensing within the conventional outflow pathway, and (d) the role of the extracellular matrix and signaling in conventional outflow dynamics. Speakers presented their thoughts on the preselected topics and provided key research goals that have been addressed or need to be addressed in the near future. The sessions were followed by discussion aimed at summarizing and interpreting the current knowledge as well as identifying unique research questions that were as yet unanswered. Anatomy and Physiology of the Conventional Aqueous Humor Outflow Pathway The conventional outflow pathway is mainly a pressure-driven system. Under homeostatic conditions, this pathway regulates the drainage of aqueous humor from the anterior chamber of the eye, thereby maintaining a constant intraocular pressure (IOP).1 Relevant tissues of the anterior segment that are anatomically involved in IOP control include the ciliary muscles, trabecular meshwork (TM), Schlemm's canal (SC), collector channels, and aqueous veins. The ciliary muscle is composed of smooth muscle fibers that have a true elastic net of tendons that anchor into the choroid posteriorly and the scleral spur, TM, and inner wall of SC anteriorly.2,3 It is widely accepted that contraction of the ciliary muscle causes expansion of the TM and opening of SC, which subsequently increases the conductivity of aqueous humor (AH) through the TM. All these, along with reports of nerve innervation in the TM, indicate that the TM is a self-regulating tissue with both afferent and efferent nervous components responsible for controlling its functions.2,4

Pharmacologic Trabeculectomy—Modulation of Aqueous Humor Outflow Through the Trabecular Meshwork

“Pharmacologic trabeculectomy” is a term used to describe the modulation of aqueous outflow by the biochemical manipulation of the trabecular meshwork. Most of the medications currently in use either reduce aqueous production or increase its outflow through the ciliary body. However, there is a new group of agents being investigated, which can increase the facility of aqueous humor outflow through the trabecular meshwork. Thus, these agents will be able to provide a more physiologic means to control aqueous humor dynamics. This review sheds light on this concept of “medical trabeculectomy.”

Long-term effects of neonatal hypoxia-ischemia on structural and physiological integrity of the eye and visual pathway by multimodal MRI.

Neonatal hypoxia-ischemia is a major cause of brain damage in infants and may frequently present visual impairments. Although advancements in perinatal care have increased survival, the pathogenesis of hypoxic-ischemic injury and the long-term consequences to the visual system remain unclear. We hypothesized that neonatal hypoxia-ischemia can lead to chronic, MRI-detectable structural and physiological alterations in both the eye and the brain's visual pathways. Eight Sprague-Dawley rats underwent ligation of the left common carotid artery followed by hypoxia for 2 hours at postnatal day 7. One year later, T2-weighted MRI, gadolinium-enhanced MRI, chromium-enhanced MRI, manganese-enhanced MRI, and diffusion tensor MRI (DTI) of the visual system were evaluated and compared between opposite hemispheres using a 7-Tesla scanner. Within the eyeball, systemic gadolinium administration revealed aqueous-vitreous or blood-ocular barrier leakage only in the ipsilesional left eye despite comparable aqueous humor dynamics in the anterior chamber of both eyes. Binocular intravitreal chromium injection showed compromised retinal integrity in the ipsilesional eye. Despite total loss of the ipsilesional visual cortex, both retinocollicular and retinogeniculate pathways projected from the contralesional eye toward ipsilesional visual cortex possessed stronger anterograde manganese transport and less disrupted structural integrity in DTI compared with the opposite hemispheres. High-field, multimodal MRI demonstrated in vivo the long-term structural and physiological deficits in the eye and brain's visual pathways after unilateral neonatal hypoxic-ischemic injury. The remaining retinocollicular and retinogeniculate pathways appeared to be more vulnerable to anterograde degeneration from eye injury than retrograde, transsynaptic degeneration from visual cortex injury.

Short- and Long-Term Effects on the Ciliary Body and the Aqueous Outflow Pathways of High-Intensity Focused Ultrasound Cyclocoagulation

Several physical methods can be used to coagulate the ciliary body and decrease intra-ocular pressure in patients with glaucoma. The study described here investigated the short- and long-term effects of high-intensity focused ultrasound (HIFU) cyclocoagulation on the aqueous humor production structures and outflow pathways. Thirty-four rabbit eyes were sonicated with a ring-shaped probe containing six miniaturized HIFU transducers. Light, scanning electron and transmission electron microscopy and corrosion casts were performed. In the affected regions, the epithelium of the ciliary processes was degenerated or necrotic and sloughed off. Examinations performed several months afterward revealed involution of the ciliary processes. Vascular corrosion cast revealed focal interruption of the ciliary body microvasculature. In most animals, a sustained fluid space was seen between the sclera, the ciliary body and the choroid, likely indicating an increase in the aqueous outflow by the uveoscleral pathway. These results suggest that HIFU cyclocoagulation has a dual effect on aqueous humor dynamics.

The structure of the trabecular meshwork, its connections to the ciliary muscle, and the effect of pilocarpine on outflow facility in mice.

To determine the connections between the ciliary muscle (CM), trabecular meshwork (TM), and Schlemm's canal (SC) and their innervations that allows CM contraction (by pilocarpine) to influence conventional outflow in mice. Sequential sections and whole mounts of murine corneoscleral angles were stained for elastin, α-smooth muscle actin (αSMA), vesicular acetylcholine transporter (VAChT), neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide (VIP), and tyrosine hydroxylase (TH). Elastic (EL) fibers between the CM, TM, and SC were examined in ultrathin, sequential sections from different planes. The effect of pilocarpine (100 μM) on conventional outflow facility was measured by perfusion of enucleated mouse eyes. The mouse TM contains a three-dimensional (3D) net of EL fibers connecting the inner wall of SC to the cornea anteriorly, the ciliary body (CB) internally and the choroid and CM posteriorly. The CM bifurcates near the posterior TM, extending outer tendons to the juxtacanalicular tissue and inner wall of SC and internal connections to the lamellated TM and CB. Ciliary muscle and lamellated TM cells stain with αSMA and are innervated by VAChT-containing nerve fibers, without TH, VIP, or nNOS. Pilocarpine doubled outflow facility. Mouse eyes resemble primate eyes not only by their well developed SC and TM, but also by their 3D EL net tethering together the TM and SC inner wall and by the tendinous insertion of the CM into this net. The increase in outflow facility following cholinergic stimulation in mice, as in primates, supports using mice for studies of aqueous humor dynamics and glaucoma.

In vivo assessment of aqueous humor dynamics upon chronic ocular hypertension and hypotensive drug treatment using gadolinium-enhanced MRI.

Although glaucoma treatments alter aqueous humor (AH) dynamics to lower intraocular pressure, the regulatory mechanisms of AH circulation and their contributions to the pathogenesis of ocular hypertension and glaucoma remain unclear. We hypothesized that gadolinium-enhanced magnetic resonance imaging (Gd-MRI) can visualize and assess AH dynamics upon sustained intraocular pressure elevation and pharmacologic interventions. Gadolinium contrast agent was systemically administered to adult rats to mimic soluble AH components entering the anterior chamber (AC) via blood-aqueous barrier. Dynamic Gd-MRI was applied to examine the signal enhancement in AC and vitreous body upon microbead-induced ocular hypertension and unilateral topical applications of latanoprost, timolol maleate, and brimonidine tartrate to healthy eyes. Gadolinium signal time courses in microbead-induced hypertensive eyes possessed faster initial gadolinium uptake and higher peak signals in AC than control eyes, reflective of reduced gadolinium clearance upon microbead occlusion. Opposite trends were observed in latanoprost- and timolol-treated eyes, indicative of their respective drug actions on increased uveoscleral outflow and reduced AH production. The slowest initial gadolinium uptake but strongest peak signals were found in AC of both brimonidine-treated and untreated fellow eyes. These findings drew attention to the systemic effects of topical hypotensive drug treatment. Gadolinium leaked into the vitreous of microbead-induced hypertensive eyes and brimonidine-treated and untreated fellow eyes, suggestive of a compromise of aqueous-vitreous or blood-ocular barrier integrity. Gadolinium-enhanced MRI allows spatiotemporal and quantitative evaluation of altered AH dynamics and ocular tissue permeability for better understanding the physiological mechanisms of ocular hypertension and the efficacy of antiglaucoma drug treatments.

Mechanism - Based Translational Pharmacokinetic - Pharmacodynamic Model to Predict Intraocular Pressure Lowering Effect of Drugs in Patients with Glaucoma or Ocular Hypertension

To develop a mechanism based translational pharmacokinetic-pharmacodynamic (PKPD) model in preclinical species and to predict the intraocular pressure (IOP) following drug treatment in patients with glaucoma or ocular hypertension (OHT). Baseline diurnal IOP of normotensive albino rabbits, beagle dogs and patients with glaucoma or OHT was collected from literature. In addition, diurnal IOP of patients treated with brimonidine or Xalatan® were also obtained from literature. Healthy normotensive New Zealand rabbits were topically treated with a single drop of 0.15% brimonidine tartrate and normotensive beagle dogs were treated with a single drop of Xalatan®. At pre-determined time intervals, IOP was measured and aqueous humor samples were obtained from a satellite group of animals. Population based PKPD modeling was performed to describe the IOP data and the chosen model was extended to predict the IOP in patients. Baseline IOP clearly depicts a distinctive circadian rhythm in rabbits versus human. An aqueous humor dynamics based physiological model was developed to describe the baseline diurnal IOP across species. Model was extended to incorporate the effect of drug administration on baseline IOP in rabbits and dogs. The translational model with substituted human aqueous humor dynamic parameters predicted IOP in patients following drug treatment. A physiology based mechanistic PKPD model was developed to describe the baseline and post-treatment IOP in animals. The preclinical PKPD model was successfully translated to predict IOP in patients with glaucoma or OHT and can be applied in assisting dose and treatment selection and predicting outcome of glaucoma clinical trials.

Effects of K-115, a Rho-Kinase Inhibitor, on Aqueous Humor Dynamics in Rabbits

Purpose: To evaluate the topical instillation of K-115, a selective Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, on intraocular pressure (IOP), ocular distribution, and aqueous humor dynamics in experimental animals.Methods: Kinase inhibition by K-115 was measured by biochemical assay. IOP was monitored using a pneumatonometer in albino rabbits and monkeys after topical instillation of K-115. The ocular distribution of [14C]K-115 was determined by whole-head autoradiography. The aqueous flow rate was determined by fluorophotometry. The total outflow facility and uveoscleral outflow were measured by two-level constant pressure perfusion and perfusion technique using fluorescein isothiocyanate-dextran, respectively.Results: Biochemical assay showed that K-115 had selective and potent inhibitory effects on ROCKs. In rabbits, topical instillation of K-115 significantly reduced IOP in a dose-dependent manner. Maximum IOP reduction was observed 1 h after topical instillation, which was 8.55 ± 1.09 mmHg (mean ± SE) from the baseline IOP at 0.5%. In monkeys, maximum IOP reduction was observed 2 h after topical instillation, which was 4.36 ± 0.32 mmHg from the baseline IOP at 0.4%, and was significantly stronger than that of 0.005% latanoprost. Whole-head autoradiography showed that the radioactivity level was maximum at 15 min after instillation of [14C]K-115 in the ipsilateral eye. Single instillation of 0.4% K-115 showed no effect on aqueous flow rate or uveoscleral outflow, but significantly increased conventional outflow facility by 2.2-fold compared to vehicle-treated eyes in rabbits.Conclusions: These results indicated that K-115 ophthalmic solution, a selective and potent ROCK inhibitor, is a novel and potent antiglaucoma agent.

Daytime and nighttime effects of brimonidine on IOP and aqueous humor dynamics in participants with ocular hypertension.

The effects of brimonidine on daytime and nighttime intraocular pressure (IOP) and aqueous humor dynamics were evaluated in volunteers with ocular hypertension (OHT). Thirty participants with OHT (58.6±1.7 years old, mean±SEM) were enrolled into this randomized, double-masked, cross-over study. For 6 weeks, participants self-administered 0.2% brimonidine or placebo 3 times daily. During daytime and nighttime visits, measurements included aqueous flow (Fa) by fluorophotometry, outflow facility (C) by tonography, episcleral venous pressure (Pev) by venomanometry, and seated and supine IOP by pneumatonometry. Uveoscleral outflow (U) was calculated mathematically. When treated with placebo, nighttime supine Pev (11.2±0.25 mm Hg) was higher (P<0.05) compared with daytime seated Pev (10.2±0.25 mm Hg), and Fa and U were significantly reduced at night. Brimonidine significantly lowered seated IOP at 9:00 AM and 11:00 AM, 9:00 PM and 11:00 PM and supine IOP at 9:00 AM and 11:00 AM. Brimonidine increased U at 9 AM and 11 AM (P<0.01) and had no effect on daytime and nighttime Fa, C, or Pev. In subjects with OHT, brimonidine treatment for 6 weeks significantly reduces seated IOP during the day by increasing uveoscleral outflow. The lack of IOP effect at night can be explained by failure to overcome a normal nighttime reduction of uveoscleral outflow.

The Dynamics of Aqueous Humor Outflow—A Major Review

Aqueous humor outflow occurs through the conventional and unconventional pathway. With aging, the latter becomes less active so that the conventional pathway remains the primary mechanism of aqueous humor outflow. An abnormality of this pathway contributes significantly to disordered aqueous humor dynamics and consequent rise in intraocular pressure seen in primary open angle glaucoma and ocular hypertension. Recently, the ocular lymphatics have been implicated in aqueous humor outflow. Additionally, the trabecular meshwork is now understood to be a complex organization of structures, which are controlled by various biomechanical and biochemical mechanisms. Among others, these include the actinomyosin cytoskeletal system, extracellular matrix, intracellular signaling responses mediated by protein kinase C, Rho/Rho kinase, and other biologic factors. This review shall describe the various pathophysiologic mechanisms involved in aqueous humor dynamics.

The Effect of Selective Laser Trabeculoplasty on Aqueous Humor Dynamics in Patients With Ocular Hypertension and Primary Open-angle Glaucoma

To investigate the effect of primary selective laser trabeculoplasty (SLT) on outflow facility and aqueous flow rate in patients with primary open-angle glaucoma or ocular hypertension. Eighteen eyes (9 with ocular hypertension and 9 with primary open-angle glaucoma) were included in this prospective noncontrolled study. Patients with intraocular pressures (IOPs)>21 to 35 mm Hg were treated with 360-degree SLT after a baseline measurement of IOP, tonographic outflow facility, and morning aqueous humor production. Electronic Schiøtz tonography was used to measure the outflow facility. The aqueous flow rate was measured by fluorophotometry, and a pneumotonometer was used to measure the IOP. All measurements were repeated at least 3 months after the laser therapy. Paired Student t tests were used to compare aqueous dynamics parameters before and after treatment. The mean age of the study population was 56.7 ± 12.4 years. The IOP decreased significantly (21%) from 24.0 ± 3.0 to 18.9 ± 2.7 mm Hg (P<0.001), whereas tonographic outflow facility increased significantly (55.5%) from 0.09 ± 0.05 to 0.14 ± 0.08 µL/min/mm Hg (P=0.003) 3 months after laser treatment. No statistically significant changes in the production of aqueous humor were found (P=0.46). Our results show that SLT lowers the IOP by increasing the outflow through the trabecular meshwork, but it has no significant effect on the aqueous flow rate.

Circadian Variation of Aqueous Humor Dynamics in Older Healthy Adults

Circadian Variation of Aqueous Humor Dynamics in Older Healthy Adults

Circadian Variation of Aqueous Humor Dynamics in Older Healthy Adults

Intraocular pressure in the sitting position changes minimally during sleep, although aqueous humor flow decreases by 50% or more at night. The explanation for this apparent discrepancy has been unclear. This study investigated the roles of outflow facility, episcleral venous pressure (EVP), and uveoscleral outflow in maintaining IOP at night.Forty-two eyes of 21 healthy subjects (age 47-76 years, mean 59 years) were studied. Aqueous humor flow rate, IOP in the sitting position, outflow facility, and EVP were measured in each eye during the middiurnal period (2:00-4:00 PM). Uveoscleral flow was calculated from the other variables by using the modified Goldmann equation. These variables were remeasured during the midnocturnal period (2:00-4:00 AM) and compared with those measured during the diurnal period by using generalized estimating equation models.Intraocular pressure did not change from the middiurnal period (13.9 ± 3.0 mm Hg) to the midnocturnal period (13.0 ± 1.8 mm Hg, mean ± SD, P = 0.07), although aqueous humor flow rate decreased from 2.48 ± 0.96 μL/min to 1.27 ± 0.63 μL/min (P < 0.001). Outflow facility decreased from 0.23 ± 0.06 μL/min/mm Hg to 0.20 ± 0.06 μL/min/mm Hg (P = 0.004), and EVP was unchanged from the middiurnal period (7.4 ± 1.8 mm Hg) to the midnocturnal period (7.4 ± 2.2 mm Hg, P = 0.95). Uveoscleral outflow decreased 93%, from 0.94 ± 1.26 μL/min during the middiurnal period to 0.07 ± 0.78 μL/min (P = 0.008) during the midnocturnal period.The nocturnal decrease in aqueous humor flow rate in older, healthy subjects is compensated by a small decrease in outflow facility and a large decrease in uveoscleral outflow to maintain a stable IOP.

Experimental research on intraocular aqueous flow by PIV method

BackgroundAqueous humor flows regularly from posterior chamber to anterior chamber, and this flow much involves intraocular pressure, the eye tissue nutrition and metabolism.PurposeTo visualize and measure the intraocular flow regular pattern of aqueous humor.MethodIntraocular flow in the vitro eyeball is driven to simulate the physiological aqueous humor flow, and the flow field is measured by Particle Image Velocimetry(PIV). Fluorescent particle solution of a certain concentration was infused into the root of Posterior Chamber(PC) of vitro rabbit eye to simulate the generation of aqueous and was drained out at a certain hydrostatic pressure from the angle of Anterior Chamber(AC) to represent the drainage of aqueous. PIV method was used to record and calculate the flow on the midsagittal plane of the eyeball.ResultsVelocity vector distribution in AC has been obtained, and the distribution shows symmetry feature to some extent. Fluorescent particle solution first fills the PC as it is continuously infused, then surges into AC through the pupil, flows upwards toward the central cornea, reflecting and scattering, and eventually converges along the inner cornea surface towards the outflow points at the periphery of the eyeball. Velocity values around the pupillary margin are within the range of 0.008-0.012 m/s, which are close to theoretical values of 0.0133 m/s, under the driving rate of 100 μl/min.ConclusionsFlow field of aqueous humor can be measured by PIV method, which makes it possible to study the aqueous humor dynamics by experimental method. Our study provides a basis for experimental research on aqueous humor flow; further, it possibly helps to diagnose and treat eye diseases as shear force damage of ocular tissues and destructions on corneal endothelial cells from the point of intraocular flow field.

In Vitro and In Vivo Comparison of Two Suprachoroidal Shunts

To compare fibrosis, aqueous humor dynamics, and intraocular pressure (IOP) of two suprachoroidal shunts as part of a new class of glaucoma drainage devices. Following proliferation analysis in vitro, 20 rabbits were implanted with either a gold shunt (GS, GMSplus+, SOLX) or a polypropylene shunt (PS, Aquashunt, OPKO). Ten eyes received mitomycin C (MMC) and triamcinolone. Peak and trough IOP were monitored with a pneumatonometer and tono-pen for 15 weeks. Aqueous humor dynamics were evaluated fluorophotometrically and tonographically. Fibrosis was quantified. In vitro proliferation was similar. In vivo, both shunts were devoid of foreign body reaction but exhibited fibrosis, and GS showed vascularization. There was no significant difference in aqueous or uveoscleral flow. Preoperative morning IOP was 23.7 ± 2 mm Hg, and evening IOP was 26.5 ± 2 mm Hg (P = 0.000). Morning IOP was decreased through 15 weeks and evening IOP through 8 weeks in all groups. The morning IOP decrease was most profound at 15 weeks in PS (41%) compared to GS (18%). Antifibrotics initially enhanced but eventually diminished shunt performance. At 15 weeks, thickness of scleral fibrosis was greater in GS (246 ± 47 μm) and PS (188 ± 47 μm, P = 0.285) compared with GS+MMC (109 ± 26 μm, P = 0.023 to GS) and PS+MMC (48 ± 30 μm, P = 0.028 to PS). In a rabbit model, suprachoroidal polypropylene and gold shunts allow access to a new drainage pathway with different IOP profiles that can be modified with antifibrotics.

MRP4 and MRP5 in the ciliary epithelium of the eye and their potential role in regulating extracellular cAMP levels

The purpose was to determine if the ciliary epithelium expresses multidrug resistance‐associated proteins (MRPs) that transport cyclic nucleotides, and if their activity can influence extracellular cAMP levels. MRP4 and MRP5 were detected in human ciliary body by microarray. mRNAs (RT‐PCR) for both transporters were also detected in a human ciliary epithelial (CE) cell line. Activity for MRP4/5 in CE cells was assessed using monochlorobimaneglutathione. The intracellular accumulation of monochlorobimaneglutathione increased dose‐dependently in the presence of the MRP inhibitors: indomethacin, probenecid, ibuprofen and furosemide. Treatment of CE cells with isoproterenol (100 μM) and IBMX (500 μM) increased intracellular cAMP levels 4.8‐fold (4.1 to 19.7 pmoles/106 cells) and extracellular cAMP 5.8‐fold (2.7 to 15.6 nM). The β‐adrenergic stimulation of extracellular cAMP levels was reduced 27–46% by ibuprofen, furosemide and probenecid (500 μM each), whereas indomethacin (500 μM) nearly prevented it completely (94%). MRP4/MRP5 activity may play an important role in aqueous humor dynamics through modulation of the extracellular cAMP‐adenosine signaling pathway. Funding: CIHR, NSERC and NIH.

Non-Analgesic Effects of Opioids: Neuroprotection in the Retina

Inadequate blood flow in the retina (ischemia) is a common cause of visual impairment and blindness. Retinal ischemia plays a pivotal role in a number of ocular degenerative diseases such as diabetic retinopathy, glaucoma, and retinal artery occlusion. The sequence of events by which ischemia leads to retinal degeneration are not completely understood, but likely involve both necrotic and apoptotic processes. A variety of diverse chemical mediators (e.g., glutamate, oxygen free-radical, nitric oxide, and proinflammatory cytokines) have been implicated as participants in ischemic retinal injury. In the eye, experimental and/or clinical evidence has suggested roles for endogenous opioids and their receptors in the regulation of iris function, aqueous humor dynamics, corneal wound healing, and retinal development and neuroprotection. In numerous vital organs, opioid receptor activation prior to ischemia or severe hypoxia is neuroprotective. Recently, activation of opioid-receptors, particularly δ-opioid-receptors (DOR), has been demonstrated to suppress several steps in the deleterious cascade of events during ischemic/hypoxic stress. In providing neuroprotection against ischemia, opioid-receptor activation appears to block proinflammatory cytokines, such as TNF-α, and glutamate excitotoxicity. Depending on duration and severity of cellular stress, DOR activation can trigger different mechanisms at multiple levels to preserve neuronal survival, including: stabilized ionic homeostasis, augmented pro-survival signaling (e.g., PKC, ERK, PI3K/Akt) and enhanced anti-oxidative capacity. This review will summarize the potential roles of opioids in protecting the viability of ocular tissues. Special emphasis will be focused on enhancing the understanding of the molecular mechanisms of opioid actions in protecting the retina against ischemic/hypoxic injury.

Diurnal and Nocturnal Variations in Aqueous Humor Dynamics of Patients With Ocular Hypertension Undergoing Medical Therapy

To evaluate the interaction of intraocular pressure(IOP)–lowering medications with physiologic day and night changes in aqueous humor dynamics in participants with ocular hypertension. Thirty participants were enrolled in thisdouble-masked, randomized, crossover study. Each participant underwent aqueous humor dynamics measurements at baseline and at 2 weeks of dosing in random order with latanoprost in the evening and placebo in the morning, timolol maleate twice daily, and dorzolamide hydrochloride twice daily. Measurements included central corneal thickness by ultrasound pachymetry, anterior chamber depth by A-scan, seated and habitual IOP by pneumatonometry, blood pressure by sphygmomanometry,episcleral venous pressure by venomanometry,and aqueous flow by fluorophotometry. Outflow facility was assessed by fluorophotometry and by tonography. Uveoscleral outflow was mathematically calculated using the Goldmann equation. Latanoprost use significantly decreased IOP during the day and night. It increased daytime uveoscleral outflow by a mean (SD) of 0.90 (1.46) μL/min (P=.048), but a nighttime increase of 0.26 (1.10) μL/min (P=.47)did not reach statistical significance. Timolol use decreased IOP during the day by reducing aqueous flow by 25%. Dorzolamide use lowered IOP only at the noon measurement and reduced daytime aqueous flow by 16%. Neither dorzolamide nor timolol use added to the physiologic 47% reduction in nighttime aqueous flow. The daytime IOP-lowering effects of latanoprost are mediated by an increase in uveoscleral outflow,and those of timolol and dorzolamide are mediated by aqueous flow suppression. Nighttime physiologic changes in uveoscleral outflow limit the nighttime pharmacodynamic efficacy of latanoprost. Aqueous flow suppression with timolol and dorzolamide was ineffective in obtaining IOP lowering at night.