Primary open- angle glaucoma is associated with an elevated intraocular pressure (IOP). Although lowering IOP has been the only therapeutic means, how IOP is regulated endogenously is largely unclear. Clinical observations indicate that IOP is regulated to some extent by the central nervous system (CNS). How CNS signals affect ocular tissues in vivo, especially inside the target cells, has not been established. The circadian rhythm of IOP in rabbits has been used as an experimental model to study the endogenous regulation of IOP. Rabbit's IOP is high in the dark phase due to the activation of ocular sympathetic nerves. Using this nocturnal IOP elevation as the basic model, in vivo intracellular signal transduction in the ciliary processes will be studied (Aim 1). Levels of second messengers will be probed using laser irradiation. The activation of protein kinases and the inhibition of protein phosphatases will be assayed. Changes in the activity of Na+-K+ ATPase will be determined. These intracellular events will be verified using various pharmacological and physiological techniques. Since the synchronization of the circadian IOP rhythm in rabbits is probably mediated through the sensation of short-wavelength light by the blue cones, the afferent neural pathway affecting the nocturnal IOP elevation will be studied (Aim 2). The circadian IOP rhythm in rabbits without functional blue cones will also be characterized. Recently there have been several human studies showing an unexpected IOP elevation in the dark/sleep phase. Under a strictly controlled environment, the circadian IOP pattern in young healthy adults will be critically examined (Aim 3). Its relationship with the light-dark cycle and the sleep patterns will be studied. Its mechanism via the change of outflow resistance will be clarified. The spectral effects on the nocturnal IOP will be examined. The circadian IOP rhythm in older healthy adults will be characterized as well. The common goal of these diversified approaches is to define the endogenous mechanisms involved in the regulation of IOP. This information should be useful for the development of antiglaucoma medicines. The human studies may lead to further studies in glaucoma patients and possibly a refinement of glaucoma therapy.
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