Effect and Mechanism of Phosphodiesterase Inhibitors on Trabecular Outflow
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Purpose: Phosphodiesterase (PDE) inhibitors increase matrix metalloproteinase (MMP) production by inhibitingre-uptake of adenosine and may potentiate nitric oxide (NO) activity. This study was performed to investigatethe effects and mechanisms of PDE inhibitors on trabecular outflow in cultured human trabecular meshworkcells (HTMCs). Methods: Primary HTMC cultures were exposed to 0, 20, and 50 μM dipyridamole (DPD) or theophylline (TPN). Permeability through the HTMC monolayer was assessed using carboxyfluorescein. The production of NOwas assessed using the Griess assay and MMP-2 levels were measured via Western blotting. Results: DPD significantly increased permeability accompanied with increased nitrite concentration and MMP-2levels (all p < 0.05). TPN increased nitrite but did not affect permeability or MMP-2 levels significantly (p > 0.05). When treated with DPD and TPN together, both permeability and nitrite production were increased; however,MMP-2 levels showed no difference compared to DPD exposure alone (p > 0.05). Conclusions: DPD increased trabecular permeability accompanied with increased nitrite production and MMP-2 levels. PDE inhibitors may increase trabecular outflow by increasing MMP-2 levels and by potentiating NOactivity through cyclic GMP in HTMC.
Abstract
Purpose: Phosphodiesterase (PDE) inhibitors increase matrix metalloproteinase (MMP) production by inhibitingre-uptake of adenosine and may potentiate nitric oxide (NO) activity. This study was performed to investigatethe effects and mechanisms of PDE inhibitors on trabecular outflow in cultured human trabecular meshworkcells (HTMCs). Methods: Primary HTMC cultures were exposed to 0, 20, and 50 μM dipyridamole (DPD) or theophylline (TPN). Permeability through the HTMC monolayer was assessed using carboxyfluorescein. The production of NOwas assessed using the Griess assay and MMP-2 levels were measured via Western blotting. Results: DPD significantly increased permeability accompanied with increased nitrite concentration and MMP-2levels (all p < 0.05). TPN increased nitrite but did not affect permeability or MMP-2 levels significantly (p > 0.05). When treated with DPD and TPN together, both permeability and nitrite production were increased; however,MMP-2 levels showed no difference compared to DPD exposure alone (p > 0.05). Conclusions: DPD increased trabecular permeability accompanied with increased nitrite production and MMP-2 levels. PDE inhibitors may increase trabecular outflow by increasing MMP-2 levels and by potentiating NOactivity through cyclic GMP in HTMC.
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