The overall objective of this project continues to be an understanding of the prejunctional mechanisms that control sympathetic neurotransmission in the anterior segment of the eye. Agents that modify sympathetic neurotransmitter release have potential usefulness in glaucoma therapy. In rabbit studies, we have identified a variety of prejunctional inhibitory and facilitatory receptors that modulate norepinephrine secretion in the isolated, superfused iris-ciliary body and excised ciliary processes. We will determine, in each case, whether a pharmacological basis exists for selective manipulation of prejunctional or postjunctional uveal receptors of the same type. We will evaluate the hypothesis that prejunctional inhibitory receptors of different types share a common mechanism - decreased cAMP formation - for inhibition of norepinephrine release. The role of GTP-binding (G) proteins in receptor-mediated regulation of neurosecretion and/or adenylate cyclase will be evaluated and correlated. Using newly developed in vitro techniques, we will identify and characterize prejunctional receptors that modulate sympathetic neurosecretion in the human iris and ciliary body. The results of these studies will improve our knowledge of the pharmacologically accessible targets for regulation of sympathetic neurotransmission in the eye, and will establish their potential relevance to human ocular pharmacology, particularly with regard to glaucoma therapy.
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