Ocular hypertension is the most significant risk factor for glaucoma, and lOP reduction remains the primary goal of glaucoma treatment. The steady state lOP is set by aqueous production and outflow, and it is our knowledge of aqueous dynamics that provides a rational basis for understanding ocular hypertension and the various treatment modalities used to manipulate lOP. The goal of this project is to address a fundamental gap in our knowledge of aqueous dynamics: the role of ciliary blood flow in aqueous production. The project will test the hypothesis that a critical level of ciliary perfusion exists for a given level of secretory stimulation, and that aqueous production is blood flow independent until blood flow is reduced below that critical level. The project's specific aims are to quantify the interrelationships between ciliary blood flow, metabolism, and aqueous production over a wide range of perfusion pressures under control conditions and after administration of drugs expected to alter aqueous production or ciliary blood flow, or both. The experiments will be performed in anesthetized rabbits instrumented with hydraulic occluders on the inferior vena cava and aorta to control mean arterial pressure (MAP), which will be measured via an arterial cannula. The eye will be cannulated to measure lOP. Ciliary blood flow will be measured by laser Doppler flowmetry using a fiber optic probe placed on the sclera over the ciliary body. Ciliary metabolism will be estimated from ciliary PO2 measurements. Episcleral and anterior uveal venous pressures will be measured by the servonull technique. Aqueous production will be measured by fluorophotometry. The standard protocol will entail changing ciliary blood flow by holding the MAP at different levels above and below baseline for 60-90 min to obtain steady state measurements. The protocol will be performed initially in control animals to establish the normal relationships between the measured variables, and then under conditions of drug-induced secretory stimulation and inhibition, and ciliary vasodilation and vasoconstriction. Plotting the aqueous flow as a function of ciliary blood flow will indicate which drugs alter aqueous production directly at the cellular level, those that affect production indirectly due to their vascular effects, and those that affect production directly and indirectly. This information will further our understanding of the physiology of aqueous dynamics and the pharmacology of drugs used in the treatment of glaucoma, and will also be used to continue the development of a comprehensive mathematical model of ocular hydrodynamics.
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