OCULAR NATRIURETIC PEPTIDE ACTIVITY: MODULATION BY DRUGS

Morehouse School Of Medicine, Atlanta GA

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Abstract

Neuroendocrine peptides, such as atrial natriuretic peptide, have been suggested to play a role in modulating ocular hydrodynamics. Dysregulation of this neuroendocrine system may contribute to the etiology of glaucoma. Therefore, this project will test the hypothesis that natriuretic peptide activity (NPA) in the anterior segment mediates, at least in part, changes in aqueous humor dynamics induced by distension and ocular hypotensive drugs. Drugs are presumed to change NPA by increasing release and/or decreasing clearance of one or more of the peptides. This hypothesis will be tested by: l) demonstrating that drug- and distension-related changes in intraocular pressure correlate with elevation of NPA in the aqueous humor, 2) correlating drug-induced changes in aqueous humor dynamics (inflow/outflow) with elevated NPA in the aqueous humor, ciliary body and/or outflow tract(s), and 3) defining the mechanism(s) of action of distension- and drug-induced increases in NPA at the tissue and cellular levels. Accomplishment of these specific aims will involve: i) performance of radioimmunoassays and high performance liquid chromatography for NP levels in aqueous humor samples and ocular tissue extracts, especially the iris-ciliary body, ii) correlation of NPA with changes in intraocular pressure and aqueous inflow/outflow as quantified by tonometry, fluorophotometry and two-stage constant perfi1sion, respectively, and iii) analyses of signal transduction pathways (e.g., protein kinases) that mediate distenston- and drug-induced NPA in the anterior segment. The outcomes of this research project will: a) define the role(s) of NPs in the physiological regulation of aqueous humor dynamics by autocrine and/or paracrine mechanisms, b) determine the cellular mode(s) by which distension and ocular hypotensive drugs can increase NPA at critical sites in the anterior segment, and c) provide a rationale for neuroendocrine approaches in the therapy of glaucoma.