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Nitric oxide (NO) donors are promising therapeutic candidates for treating intraocular hypertension (IOP) and glaucoma. This study aims to investigate the effect of prolonged use of NO donor sodium nitroprusside (SNP) on IOP. Since SNP has a short biological half-life, a nanoparticle drug delivery system (mesoporous silica nanoparticles) has been used to deliver SNP to the target tissues (trabecular meshwork and Schlemm's canal). We find that the sustained use of NO donor initially reduced IOP followed, surprisingly, by IOP elevation, which could not recover by drug withdraw but could be reversed by the antioxidant MnTMPyP application. The IOP elevation and normalization coincide with increased and reduced protein nitration in the mouse conventional outflow tissue. These findings suggest that the prolonged use of NO donor SNP may be problematic as it can cause outflow tissue damage by protein nitration. MnTMPyP is protective of the nitrative damage which could be considered to be co-applied with NO donors.
∙Prolonged use of NO donor initially reduced IOP followed by IOP elevation.∙Excessive NO exposure can cause toxic side effects through stimulation of endogenous.NO, and O2.- formation.∙Antioxidant MnTMPyP application reversed IOP elevation by protecting the conventional outflow tissue from nitrosative damage.∙Antioxidant could be considered for synergistic use with NO donor to improve drug efficacy.