Open-angle glaucoma is associated with an elevated intraocular pressure (IOP) resulting from the disturbance of normal aqueous humor dynamics. Clinical observations indicate that aqueous humor dynamics is regulated to some extent by the central nervous system (CNS through neural and hormonal pathways. However, laboratory data about such actions were either lacking or inconsistent. This project incorporates advanced technology to systematically investigate endogenous neural and hormonal mechanisms in the regulation of aqueous humor dynamics, using the rabbit as a model. Several physiological actions that have profound effects on IOP in conscious rabbits have been identified. Their signal transductions in vivo will be studied in three experimental conditions: circadian change of IOP (Aim 1), electric stimulation o the cervical sympathetic nerves (Aim 2), and endogenous elevation of circulating catecholamines by intravenous injection of thyrotropin releasing hormone (Aim 3). The ocular neurotransmitters and intracellular second messengers (cyclic AMP, diacylglycerol, and inositol 1,4, 5 trisphosphate) mediating the responses will be identified and quantified. Laser irradiation will be use to halt the degradation of intracellular second messengers. Fluorophotometry will be used to measure aqueous flow. The role of the paraventricular nucleus (Aim 4) and the suprachiasmatic nucleus (Aim 5) in the regulation of aqueous humor dynamics in conscious rabbits will be studied by ablation and electric stimulation of these nuclei. CNS neural circuit and efferent pathways will be determined. The interactions between the pituitary hormonal axes and the endogenous mechanisms affecting aqueous humor dynamics (Aim 6) will be clarified after the hormonal axes are activated by administration of pituitary hormone releasing factors: luteinizing hormone releasing hormone, corticotropin releasing factor, and growth hormone releasing hormone. This project will reveal fundamental neural and hormonal mechanisms in the endogenous regulation of aqueous humor dynamics in rabbits. This new knowledge should benefit relevant research in other species and help to refine the rationale for developing more effective antiglaucoma treatment.
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