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Jing Wu, Guorong Li, Carolia Luna, David L. Epstein, Pedro Gonzalez; Extra-cellular Adenosine Pathway In Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4637.
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Activation of adenosine (ADO) receptors has been shown to exert important effects on aqueous humor outflow facility. Currently, specific A1 receptor agonists are being tested as potential therapeutic agents for glaucoma treatment. We investigated the presence of mechanisms for endogenous production of extracellular ADO in the outflow pathway and the potential role of adenosine in the regulation of contraction in trabecular meshwork cells.
Porcine trabecular meshwork (PTM) cells incubated with ATP (15 uM), cAMP (15 uM), or control vehicle were treated with specific inhibitors for ecto-5’-phosphodiesterase (IBMX, 10 mM) or ecto-5’-nucleotidase (AMPCP, 10 mM). Extra-cellular levels of ADO production were evaluated by HPLC. Effects of specific ADO receptor agonists (CPA, CGS-21680, IB-MECA, 20uM) on cell contraction were measured using a three-dimensional collagen gel (1.5 mg/mL COLA1A) contraction assay.
PTM cells produced extra-cellular ADO at a rate that was independent from the extra-cellular concentrations of cAMP or ATP (ecto-5’-phosphodiesterase substrates), and was not affected by inhibition of ecto-5’-phosphodiesterase activity by IBMX. However, inhibition of ecto-5’-nucleotidase activity with AMPCP resulted in a decrease of more than 60% in ADO formation. Serum-induced cell contraction was increased in the presence of adenosine or the specific A1 receptor agonist CPA (37%, SD= 7, p=0.02) and decreased by agonists for the A2, CGS-21680, (58%, SD=12, p=0.05).and A3, IB-MECA, (94%, SD=32, p=0.01) receptors.
TM cells express an extra-cellular ADO pathway that is dependent on Ecto-5’-nucleotidase conversion of AMP into ADO. We hypothesize that endogenous production of extra-cellular adenosine contributes to the regulation of aqueous humor outflow resistance not only through induction of matrix metalloproteinases, but also by affecting the acto-myosin cytoskeleton of TM cells. A better understanding of the role played by this pathway in the outflow pathway should be useful for the development of glaucoma therapies based on adenosine receptor agonist
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