Glaucoma is characterized by elevated intraocular pressure (IOP) which may lead to blindness if not adequately controlled by appropriate therapy. The studies outlined in this proposal are to gain a better understanding of the efficacy and safety of the different drug treatments to lower IOP, which may help prevent loss of vision in patients with glaucoma. Although there has been considerable interest in the mechanisms by which adrenergic (eg, epinephrine and timolol) and cholinergic (eg, pilocarpine, carbachol, echothiophate iodide) drugs reduce IOP, as well as to understand the effects of new alpha adrenergic and dopaminergic agents, previously it has not been possible to study drug effects directly on the target cells involved in the regulation of aqueous humor inflow and outflow. As a new and major advance, we have recently developed methods which allow the propagation of human non-pigmented (NPE) and pigmented (CPE) ciliary epithelial cells in culture. These cell culture systems (and our prior work on human trabecular meshwork cells) appear to provide useful resources to define relevant drug responses. The initial quantitative measurements of specific drug receptor characteristics, pharmacological dose-response relationships, and agonist/antagonist properties which we have conducted using these cell cultures lines appear quite encouraging. Direct evaluations on tissues will also be performed when possible to help verify the specific applications of the cell culture systems (e.g. beta adrenergic drug receptors and responses have been examined in HIM tissue, and cholinergic drug actions have been assessed in isolated ciliary epithelium and ciliary muscle tissues). The beta blocker radioreceptor assays we developed during the last grant period will provide pharmacokinetic data to help in evaluating aqueous humor and plasma drug levels. These studies should be useful in assessing the IOP effects and systemic side effects of new ophthalmic beta blockers. Comparison of our findings with those from other laboratories studying signal response coupling in the anterior segment (and in vivo physiological measurements of aqueous humor dynamics) should permit our findings to be integrated into the growing body of knowledge of glaucoma physiology and pharmacology.
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