Eicosanoids are ubiquitous biological substances which have many potent actions throughout the body. In the eye, two classes of eicosanoids, prostaglandins and leukotrienes, are thought to be mediators of inflammation and may contribute to the regulation of intraocular pressure. Topically administered prostaglandins reduce intraocular pressure in man, most likely by increasing uveoscleral outflow. The role of these agents in the pharmacologic treatment of glaucoma is being evaluated. Further, the intraocular pressure- lowering effects of other drugs, such as epinephrine, can be accounted for, in part, by their effects on uveoscleral outflow; this effect may be mediated endogenously-produced prostaglandins. In the proposed studies, we will evaluate eicosanoid formation, metabolism and action in tissues of the inflow and outflow pathways of the eye and its modulation by pharmacologic agents used in the treatment of glaucoma, other substances, flow and laser irradiation. Trabecular meshwork and ciliary muscle, and cells derived from these tissues, will be incubated in the presence and absence of radiolabeled arachidonic acid; the products formed will be measured either by radioimmunoassay or by conversion of radiolabeled substrate after separation of products by high performance liquid chromatography. These studies also will evaluate the modulation of eicosanoid biosynthesis by phospholipase A2 and C and the role of cyclic nucleotides and calcium in these cellular processes. Since drugs that increase uveoscleral outflow may do so by direct effects on the ciliary muscle, we will evaluate the morphology of the ciliary muscle, the proposed site of action of prostaglandins, using light and electron microscopic methods. The results of these studies will enhance our understanding of glaucoma (particularly primary open-angle, inflammatory and steroid glaucoma) and its treatment with pharmacologic agents and the laser. These studies also are relevant to our understanding of uveitis and its treatment with anti-inflammatory drugs.
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