Glaucoma is characterized by elevated intraocular pressure (IOP) which may lead to blindness if not adequately controlled by appropriate therapy. Although there has been widespread interest in the mechanisms by which adrenergic (e.g. epinephrine and timolol) and cholinergic agents (e.g. pilocrapine, carbachol, echothiophate iodide) reduce IOP, 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. Our investigations into the cellular mechanisms of glaucoma therapy have employed new methods for isolating and evaluating cells from the trabecular meshwork, ciliary body epithelium, and ciliary muscle. The quantitative measurement of specific receptor characteristics, pharmacological dose-response relationships and agonist/antagonist properties we are conducting should help provide useful information to better understand the ability of adrenergic and cholinergic agents to lower IOP (as well as to understand the mechanisms of reduced effectiveness at the target tissue. Our collaborative studies of cholinesterase drug therapy have recently demonstrated a strong correlation between receptor number changes and the development of subsensitivity to pilocarpine testing. The new radioreceptor assay for beta antagonists we have developed provides a particularly useful measure of beta adrenegic blocking activity to aid in the evaluation of the efficacy (and side-effects) of these drugs after ocular administration. We are also exploring means to obtain differentiated cultures of human ciliary epithelium and ciliary muscle cells (in addition to the human trabecular cells we have already defined) to allow more detailed investigations of the effects of glaucoma medications on these human target tissues under controlled experimental conditions in vitro. The basic investigations outlined in this proposal could provide clinically relevant information, if experiments are designed with regard to observations of physiological responses to drugs in experimental animals and compared to observations of the effects of drug therapy in patients.
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