Effect of general anesthetics on IOP in rats with experimental aqueous outflow obstruction

PURPOSE: To determine the effect of several common general anesthetics on intraocular pressure (IOP) after experimental aqueous outflow obstruction in the rat. METHODS: A single episcleral vein injection of hypertonic saline was used to sclerose aqueous humor outflow pathways and produce elevated IOP in Brown Norway rats. Animals were housed in either standard lighting or a constant low-level light environment. Awake IOPs were determined using a TonoPen (Mentor, Norwell, MA) immediately before induction of anesthesia by either isoflurane, ketamine, or a mixture of injectable anesthetics (xylazine, ketamine, and acepromazine). For each anesthetic, IOPs were measured immediately after adequate sedation (time 0) and at 5-minute intervals, up to 20 minutes. RESULTS; Awake IOPs ranged from 18 to 52 mm Hg. All anesthetics resulted in a statistically significant (P: < 0.01) reduction in measured IOP at every duration of anesthesia when compared with the corresponding awake IOP. With increasing duration of anesthesia, measured IOP decreased approximately linearly for both the anesthetic mixture and isoflurane. However, with ketamine, IOP declined to 48% +/- 11% (standard lighting) and 60% +/- 7% (constant light) of awake levels at 5 minutes of anesthesia, where it remained stable. In fellow eyes, the SD of the mean IOP in animals under anesthesia was always greater than the corresponding SD of the awake mean. Anesthesia's effects in normal eyes and eyes with elevated IOP were indistinguishable. CONCLUSIONS: All anesthetics resulted in rapid and substantial decreases in IOP in all eyes and increased the interanimal variability in IOPs. Measurement of IOP in awake animals provides the most accurate documentation of pressure histories for rat glaucoma model studies.     

Evaluation of inducible nitric oxide synthase in glaucomatous optic neuropathy and pressure-induced optic nerve damage

PURPOSE: To determine whether inducible nitric oxide synthase (NOS-2) is involved in glaucomatous optic neuropathy. METHODS: Chronic elevation of rat intraocular pressure (IOP) leading to optic nerve damage was induced by episcleral injection of hypertonic saline, which caused sclerosis and blockade of aqueous humor outflow pathways. Expression of NOS-2 in the retina and optic nerve head (ONH) was evaluated by immunohistochemistry, gene array analysis, and quantitative PCR (Q-PCR). Immunohistochemistry was also used to assess the NOS-2 level in the ONH from primary open-angle glaucoma (POAG) and nonglaucomatous human eyes. Finally, an NOS-2 inhibitor, aminoguanidine, administered orally in the drinking water, was tested for its effect on optic nerve injury in rats with ocular hypertension. RESULTS: Chronically elevated IOP in the rat produced optic nerve damage that correlated with pressure change (r(2) = 0.77), but did not increase NOS-2 immunoreactivity in the optic nerve, ONH, or ganglion cell layer. Retinal and ONH NOS-2 mRNA levels did not correlate with either IOP level or severity of optic nerve injury. Similarly, there was no difference in NOS-2 immunoreactivity in the optic nerve or ONH between POAG and nonglaucomatous eyes. Furthermore, aminoguanidine treatment did not affect the development of pressure-induced optic neuropathy in the rat. CONCLUSIONS: As demonstrated by several independent methods, glaucomatous optic neuropathy was not associated with a significant change in the expression of NOS-2 in the retina, ONH, or optic nerve.     

Do alpha-adrenergic receptors participate in control of the circadian rhythm of IOP?

The alpha 2-adrenergic antagonists, yohimbine and rauwolscine, and the alpha 1-adrenergic antagonist, bunazosin, were used to explore the role of alpha-adrenergic receptors in the regulation of the circadian rhythms of intraocular pressure and aqueous flow in New Zealand white rabbits. Blockade of alpha 2-adrenergic receptors with yohimbine or rauwolscine produced small decreases in intraocular pressure during both light and dark phases. Rauwolscine had no effect on aqueous flow during the light or dark, but it increased the concentration of norepinephrine in the aqueous during both light and dark. These observations are difficult to reconcile with earlier suggestions that increased sympathetic input to the eye increases intraocular pressure and aqueous flow during the dark. The role of alpha 2-adrenergic receptors in the control of the circadian rhythm of intraocular pressure is unclear. Blockade of alpha 1-adrenergic receptors with bunazosin produced a dose-dependent reduction of IOP during the dark phase of the circadian cycle, a smaller reduction during the light phase, and no reduction during either light or dark in rabbits after superior cervical ganglionectomy or preganglionic section of the cervical sympathetic trunk (decentralization). Bunazosin decreased pupil diameter during the dark phase but had no effect on aqueous flow. Because it is unlikely that alpha 1-adrenergic blockade increased outflow facility or uveoscleral outflow, the mechanism for the role of alpha 1-adrenergic receptors in the control of the circadian rhythm of intraocular pressure in rabbits remains to be identified.     

Aqueous humor messengers in the transient decrease of intraocular pressure after ganglionectomy.

Intraocular pressure (IOP) decreases in rabbits 1 day after superior cervical ganglionectomy. It was hypothesized that this IOP decrease was caused by an accumulation of norepinephrine (NE) released from the iris-ciliary body into the aqueous humor during nerve degeneration. Direct measurement of aqueous humor NE concentration, however, was not successful because of the technical difficulty. In the current study, aqueous humor NE after superior cervical ganglionectomy was extracted and quantified using high-performance liquid chromatography-electrochemical detection. Twelve New Zealand albino rabbits were maintained in a daily 12-hr light-12-hr dark environment. Unilateral ganglionectomy was done on these rabbits during the light phase under halothane anesthesia. Twenty-two hours after the procedure, a significant IOP decrease occurred. The IOP was 16.1 +/- 0.6 mmHg (mean +/- the standard error of the mean) in the operated eye and 20.9 +/- 0.6 mmHg in the contralateral eye (P < 0.01). Aqueous humor NE concentration in the operated eye (475 +/- 81 pg/ml) was not different from that in the contralateral eye (469 +/- 58 pg/ml). However, the concentration of aqueous humor cyclic adenosine monophosphate (cAMP) in the operated eye (29.8 +/- 6.8 pmol/ml) was significantly higher (P < 0.05) than that in the contralateral eye (11.7 +/- 0.8 pmol/ml). These data indicate that aqueous humor NE per se does not cause the transient IOP decrease after superior cervical ganglionectomy and cAMP-mediated ocular activities may be involved in this change in IOP.     

原发性开角型青光眼房水外流通路改变的研究进展

原发性开角型青光眼(POAG)是一种以视神经轴索及相关视网膜神经节细胞丢失为特征的视神经病变.眼压升高是POAG最重要的危险因素.大多数POAG患者眼压升高主要是房水外流阻力异常增高所致.小梁网是产生房水排出阻力的主要部位.目前多数研究者认为POAG患者小梁网功能不良与致炎因子表达、细胞老化、氧化应激损伤及细胞质成分减少等因素有关.小梁网细胞本身及细胞外基质的变化均可以引起房水外流阻力的改变,进而导致眼内压的升高.为了进一步开展对POAG发病机制的研究,有必要就目前有关POAG患者房水外流通路改变的研究进展予以综述,旨在为POAG的深入研究提供参考依据.     

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.     

A new procedure for the measurement of the outflow facility in conscious rabbits

A new procedure for measuring the outflow facility in conscious rabbits is described. The Langham pneumatic tonometer is applied horizontally against the eye; the intraocular pressure (IOP) is recorded before, during and immediately following 2 min of a pre-determined increased ocular pressure that is maintained at a fixed value by digital pressure applied through the eyelids. An increased volume of aqueous humor outflow resulting from the IOP increase is evaluated from the initial and final IOP values and the pressure volume relation for eyes of living rabbits. Close agreement in values of the outflow facilities in pairs of eyes of individual rabbits and excellent reproducibility of the procedure were found in repeated measurements made over a 24-hr period. The mean values of the IOP and the total outflow facility in 60 eyes of 30 rabbits were 20.5 +/- 0.2 mmHg and 0.17 +/- 0.01 microliter min-1 mmHg-1 respectively. Thirty minutes after an intravenous injection of acetazolamide, the IOP had decreased in both eyes of individual rabbits. This was associated with a decrease in the outflow facility and with a decrease of more than 50% in the rate of aqueous humor formation. One hour after the unilateral application of epinephrine the IOP had decreased in the treated eyes while the outflow facility remained unchanged.     

Aqueous humor cyclic AMP and circadian elevation of intraocular pressure in rabbits.

Rabbits entrained in a daily light-dark environment show a circadian elevation of intraocular pressure (IOP) around the onset of dark. It was reported that concentration of cyclic AMP (cAMP) in aqueous humor increases significantly during this time period. Whether or not the increase of ocular cAMP-mediated activities is related to the circadian elevation of IOP is unclear. Light-dark entrained rabbits maintain the circadian IOP elevation in a constant dark environment. Corresponding to this IOP elevation in the constant dark, no change of aqueous humor cAMP concentration was found. Thus, the circadian IOP elevation in the constant dark is probably unrelated to the cAMP-mediated activities. This finding also suggests that a significant portion of the circadian IOP elevation in the light-dark environment is unrelated to the cAMP-mediated activities.     

Rho激酶抑制剂在青光眼治疗中的应用进展

青光眼是以特征性视神经萎缩和视野缺损为共同特征的不可逆性致盲性眼病,高眼压是其最主要的发病机制,而导致高眼压的主要原因是房水传统流出途径中小梁网的病理学改变导致的房水流出阻力增加。Rho激酶抑制剂(ROCKi)是直接作用于小梁网(TM)的降眼压药物,主要通过影响细胞骨架改变TM细胞形态、细胞运动、胞质分裂和平滑肌收缩等,从而增加房水流出、降低眼压,在美国和日本已被批准用于临床; 具有改善视网膜血管灌注、促进视神经再生等作用,可能存在视神经保护作用; 此外,具有减少滤过泡瘢痕化等作用。因此,ROCKi作为新型抗青光眼药物备受关注,本文将针对Rho/Rho激酶信号通路、ROCKi的作用机制及其临床应用展开综述。     

Effects of ibopamine eye drops on intraocular pressure and aqueous humor flow in healthy volunteers and patients with open-angle glaucoma

PURPOSE: On the basis of intraocular pressure measurements and fluorophotometry we assessed the effects of 2% ibopamine eye drops on aqueous humor production in normal and glaucomatous eyes. METHODS: Thirty subjects (15 healthy volunteers and 15 open-angle glaucoma patients with ocular hypertension) were included in a placebo-controlled study with random assignment of treatment from masked containers. All subjects underwent ophthalmologic examinations and intraocular pressure (IOP) measurements. Fluorophotometry was done in both eyes at baseline (without treatment) and during treatment. Each subject was treated with 1 drop of 2% ibopamine in one eye and 1 drop of placebo in the fellow eye 30 minutes before fluorophotometric scans and every hour after the first instillation (for a total of 4 times). Safety was evaluated by recording adverse events and ocular symptoms and signs. Aqueous humor flow data were analyzed using the paired t-test, comparing ibopamine and placebo-treated eyes. RESULTS: No changes in IOP were detected in normal eyes, whereas glaucomatous eyes showed a mean increase of 4 mmHg (95% CI 3.46-4.51) from baseline. The difference in IOP between healthy eyes and those with glaucoma was significant (p < 0.0001). In normal eyes and patients with glaucoma ibopamine led to a significant increase in aqueous humor flow compared with placebo-treated eyes (p < 0.01). The safety profile of ibopamine was very good. CONCLUSIONS: The results seem to confirm that ibopamine increases aqueous humor production in normal and glaucomatous eyes, raising IOP only in eyes with glaucoma.