The long term goals of the work proposed in this application are to understand receptor mediated events in the ciliary processes which may be responsible for regulation of the rate of formation of aqueous humor. Toward this end we propose to study interactions among beta2-, alpha2-, VIP, ANF, and somatostatin receptors in regulating cyclic nucleotide production by ciliary processes and examine the roles of VIP, ANF, and somatostatin in regulating aqueous flow and IOP. Most of the in vitro experiments proposed will explore cyclic AMP and cyclic GMP production by intact, excised rabbit ciliary processes; however, where significant results are obtained in this model system we will explore the possibility that similar mechanisms occur in human ciliary processes. The premise of our long term goals is that it is only by a thorough understanding of the mechanisms underlying normal regulation of aqueous flow that we will understand how some drugs currently used or proposed for use in glaucoma therapy reduce IOP and will build a logical framework within which to search for new therapeutic drugs for treatment of glaucoma.
The specific aims of this proposal are to determine 1. Whether alpha2-adrenergic receptors inhibit beta2-adrenergic receptor mediated cyclic AMP production in human ciliary processes; 2. What is the nature of alpha2-adrenergic receptor-mediated inhibition of VIP-stimulated cyclic AMP production in rabbit ciliary processes; 3. What is the nature of somatostatin receptor-mediated inhibition of beta2-adrenergic and VIP receptor-mediated stimulation of cyclic AMP production in rabbit ciliary processes; 4. Whether cyclic GMP is the intracellular mediator of the ANF receptor in ciliary processes and whether ANF inhibits beta2- adrenergic and VIP receptor mediated cyclic AMP production; 5. Whether the inhibitory effects of alpha2-adrenergic and somatostatin receptors on cyclic AMP production are mediated by the guanine nucleotide binding protein Ni; 6. ANF, VIP, or somatostatin regulate aqueous flow and IOP in rabbits; 7. Whether similar mechanisms identified in rabbit ciliary processes (#2-4) occur in human ciliary processes.