Ciliary blood flow and aqueous humor production

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Abstract

Aqueous humor production is a metabolically active process sustained by the delivery of oxygen and nutrients and removal of metabolic waste by the ciliary circulation. This article describes our investigations into the relationship between ciliary blood flow and aqueous humor production. The results presented indicate that there is a dynamic relationship between ciliary blood flow and aqueous humor production, with production being blood flow independent above a critical level of perfusion, and blood flow dependent below it. The results also show that the plateau portion of the relationship shifts up or down depending on the level of secretory stimulation or inhibition, and that oxygen is one critical factor provided by ciliary blood flow. Also presented is a theoretical model of ocular hydrodynamics incorporating these new findings.

Introduction

Moses (1981) published one of the most iconic yet enigmatic graphs in the field of aqueous humor dynamics in the 7th edition of Adler’s Physiology of the Eye (Fig. 1). The graph is iconic because it concisely illustrates the fundamental concept that steady state intraocular pressure occurs when aqueous humor inflow and outflow are equal. The graph is enigmatic because data for the aqueous humor inflow curves were scant at the time, and the “equation unknown”. Even more enigmatic, Moses was silent about the graph showing two inflow curves rather than one and mum about what might cause multiple curves to occur. Regarding the shape of the inflow curves, he said only “the rate of aqueous humor formation decreases slightly as intraocular pressure increases until the region of ciliary artery blood pressure is approached, when it decreases rapidly.” It was known at the time that ciliary blood flow is autoregulated (Bill, 1981) and that aqueous humor production is a metabolically active process, (Sears, 1981) and so it is plausible he hypothesized that production is blood flow dependent and so declines when the autoregulatory range is exceeded. It was also known that aqueous humor production can be stimulated or inhibited pharmacologically, and so multiple inflow curves would also perhaps have seemed reasonable. We will never know his rationale for the inflow curves, but recent studies on the relationship between ciliary blood flow and aqueous humor production support the predictions of Moses’ iconic graph.

Section snippets

Gross anatomy and vasculature

Aqueous humor is produced in the ciliary processes, which form a ring of leaf-like projections into the posterior chamber under the iris root and limbus (Fig. 2) (Gabelt et al., 2006). The arterial supply to the ciliary processes is derived from the major arterial circle of the iris fed primarily by the long posterior ciliary arteries (Fig. 3) (Morrison et al., 1987). The ciliary circulation typically divides into three zones (Funk and Rohen, 1990, Lutjen-Drecoll and Rohen, 1994). The first

Stages of aqueous humor formation

Fig. 5 shows a schematic overview of aqueous humor production (Kiel, 1998). Aqueous humor is formed in three stages: 1) convective delivery of water, ions, proteins and metabolic fuel by the ciliary circulation, 2) ultrafiltration and diffusion from the capillaries into the stroma driven by the oncotic pressure, hydrostatic pressure, and concentration gradients, and 3) ionic transport into the basolateral spaces between the non-pigmented epithelial cells followed by water movement down the

Methodology

The results described below are based on 305 experiments conducted over the last decade. Some of the results are published and some not, so a brief description of the methods is warranted. All experiments were performed in New Zealand albino rabbits (1.8–2.5 kg, either sex) anesthetized with pentobarbital sodium (30 mg/kg, i.v., supplemented as needed), and paralyzed with gallamine triethiodide (1 mg/kg) to eliminate eye movement. The animals were intubated through a tracheotomy and respired

Control

The original study data and data from subsequent studies indicate that in the anesthetized rabbit model the normal aqueous humor flow rate is 3.06 ± 0.6 μl/min (mean ± SE, n = 225) and the LDF ciliary blood flow is 58.01 ± 0.97 P.U. (mean ± SE, n = 213); based on experiments with simultaneous measurements (n = 133) the values are 3.08 ± 0.08 μl/min and 59.65 ± 1.27 P.U., respectively. When ciliary blood flow was varied under control conditions by holding MAP at 40, 55, 70 and 80 mmHg, aqueous

Theoretical model of ocular hydrodynamics

In the 8th Edition of Adler’s Physiology of the Eye, Moses provided his most thorough mathematical analysis of aqueous humor dynamics, relying heavily on his own and Barany’s earlier analyses (Barany, 1963, Moses, 1987). However, Moses also rightly raised a cautionary note “to warn those readers who would extrapolate from the mathematical model presented here: predictions from such a model must be checked by observation and experiment. The actual living organism is so complex that our model

Conclusion and future directions

Moses’ admonition to be wary of mathematical models in the absence of experimental verification is timeless advice; however, his inflow curves with the “equation unknown” appear to have been remarkably accurate. The experimental results presented in this article indicate that there is a dynamic relationship between ciliary blood flow and aqueous humor production, with production being blood flow independent above a critical level of perfusion, and blood flow dependent below it. The results also

Acknowledgements

Supported by: NIH EY09702 (JWK), a Research to Prevent Blindness Lew R Wasserman Merit Award (JWK), Austrian FWF J1866-MED (HAR), the van Heuven endowment (JWK) and an unrestricted grant from Research to Prevent Blindness Inc. Sincere appreciation is expressed to Ms Alma Maldonado for her technical contributions and performance of many of the experiments.

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