Over the past 10 years, studies have demonstrated the potential of adenosine receptors as drug targets and little doubt remains that adenosine plays a significant role as a neuromodulator and an antacoid in cell to cell communication. Research has also identified several subtypes of adenosine receptors (A1a, A1b, A2a, A2b). Preliminary data presented in this proposal demonstrate that adenosine A agonists are effective in lowering intraocular pressure. This ocular hypotensive response in dose-related and can be reversed by adenosine antagonist. In addition, we provide initial evidence that adenosine A agonists are effective modulators of cAMP and neurotransmitter release in ocular tissues. We hypothesize that adenosine agonists reduce intraocular pressure and aqueous flow by the activation of specific receptors located on the ciliary epithelium and sympathetic nerve fibers.
The specific aims of this research project are: 1) to determine the receptor subtype(s) involved in the intraocular pressure and aqueous flow response to adenosine agonists, 2) to determine the importance of sympathetic nerves in the ocular response to adenosine agonists, 3) to investigate signal transduction mechanisms associated with adenosine receptor activation, and 4) to determine the receptor subtypes involved in the modulation of norepinephrine release from sympathetic neurons in the anterior segment. We will evaluate adenosine agonists for their ability to modulate intraocular pressure and aqueous flow in rabbits and cats. Studies on cellular signal transduction and norepinephrine release will use isolated iris/ciliary body preparation also from rabbits and cats. In addition, we will use cell culture of human nonpigmented ciliary epithelial cell to investigate signal transduction mechanisms associated with adenosine agonists. Data from these studies will result in a better understanding of the contribution of adenosine receptors in the modulation of ocular hydrodynamics and will also provide evidence to determine if a rational basis exists for including adenosine receptor agonists in the medical management of glaucoma.
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