Intraocular pressure is determined by several components, such as secretory mechanisms, vascular permeability, vascular perfusion (blood flow) and vascular pressure, and each of these components have cellular sites where adrenergic receptors (Alpha and Beta) regulate the physiological mechanisms. Because of these multiple sites of action the adrenergic pharmacology of the ocular pressure response appears to be paradoxical. Both Beta-agonists and beta-antagonists are effective ocular hypotensives used in glaucoma therapy. Alpha adrenergic drugs show a similar paradox with agonists and antagonists both causing a decrease in ocular pressure in the rabbit. This proposal will focus on molecular adrenergic receptor mechanisms in iris and ciliary tissues of the rabbit. A comprehensive study of the regulatory effects of adrenergic drugs on adenylate cyclase correlated with subclasses of adrenergic receptors determined by direct ligand binding will be undertaken. A careful analysis of adenylate cyclase regulation by receptor ligands will be obtained by quantitative dose response data for agonists and antagonists with Beta1 and Beta2 specificity, and for the Alpha1 and Alpha2 subclasses of adreno receptor ligand. The dose response data will be generated from receptor ligand sensitive activations of membrane bound adenylate cyclase mediated via the guanyl nucleotide regulatory site of the cyclase enzyme. The adenylate cyclase studies will be correlate by drug binding studies using displacement competition against radioactive ligands. A few selected ligands with high specificity for receptor subclasses will also be studied with following the time course for pupil size, pressure changes, aqueous humor dynamics, aqueous humor c-AMP, and ciliary blood flow after topical treatment of the rabbit eye. Secondary effects of receptor activation will also be studied including uncoupling of receptors from adenylate cyclase, down-regulation and/or up-regulation of Beta and Alpha ligand binding sites, and changes in calmodulin and phosphodiesterase activity.
The aim of this project is to establish the molecular pharmacology of adrenergic regulation of ocular pressure so that the knowledge can be applied to the drug treatment of glaucoma.
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