Differential effects of angiotensin II type I receptor blockers on reducing intraocular pressure and TGFß signaling in the mouse retina.

PURPOSE: Angiotensin II type 1 receptor blockers (ARBs) have been investigated for their neuroprotective and intraocular pressure (IOP) lowering effects in treating glaucoma, but the reports have been inconsistent possibly because different compounds and models have been used. Here we selected three ARBs for head-to-head comparisons of their effects on IOP and transforming growth factor ß (TGFß) signaling, which is believed to play an important role in glaucoma pathogenesis. METHODS: Three ARBs (losartan, irbesartan or telmisartan) or vehicle controls were administered via chow to C57BL/6J mice for up to 7 days. Drug concentrations in the eye, brain, and plasma were evaluated by liquid chromatography mass spectrometry. Cohorts of mice were randomly assigned to different treatments. IOP and blood pressure were measured before and after ARB treatment. Effects of ARBs on TGFß signaling in the retina were evaluated by phosphorylated Smad2 (pSmad2) immunohistochemistry. RESULTS: Physiologically relevant concentrations of losartan, irbesartan and telmisartan were detected in eye, brain and plasma after drug administration (n = 11 mice/treatment). Blood pressure was significantly reduced by all ARBs compared to vehicle-fed controls (all p-values < 0.001, n = 8-15 mice/treatment). Compared to vehicle control, IOP was significantly reduced by irbesartan (p = 0.030) and telmisartan (p = 0.019), but not by losartan (n = 14-17 mice/treatment). Constitutive pSmad2 fluorescence observed in retinal ganglion cells was significantly reduced by telmisartan (p = 0.034), but not by losartan or irbesartan (n = 3-4 mice/treatment). CONCLUSIONS: Administration via chow is an effective delivery method for ARBs, as evidenced by lowered blood pressure. ARBs vary in their abilities to lower IOP or reduce TGFß signaling. Considering the significant roles of IOP and TGFß in glaucoma pathogenesis, specific ARBs with dual effects, such as telmisartan, may be more effective than other ARBs for treating glaucoma.