Abstract
PurposeAngiotensin 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 β (TGFβ) signaling, which is believed to play an important role in glaucoma pathogenesis.MethodsThree 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 TGFβ signaling in the retina were evaluated by phosphorylated Smad2 (pSmad2) immunohistochemistry.ResultsPhysiologically 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).ConclusionsAdministration 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 TGFβ signaling. Considering the significant roles of IOP and TGFβ in glaucoma pathogenesis, specific ARBs with dual effects, such as telmisartan, may be more effective than other ARBs for treating glaucoma.
Highlights
Glaucoma is a neurodegenerative disorder and the leading cause of irreversible blindness worldwide [1]
Angiotensin II type I receptor blockers (ARBs) vary in their abilities to lower intraocular pressure (IOP) or reduce transforming growth factor β (TGFβ) signaling
Males at 3 months of age were used for all experiments, except for a preliminary experiment investigating IOP effects of losartan delivered via drinking water, which used 1-year old female C57BL/6J mice
Summary
Glaucoma is a neurodegenerative disorder and the leading cause of irreversible blindness worldwide [1]. Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Reducing IOP by surgical or pharmacological intervention remains the only treatment for glaucoma to date. Angiotensin II type I receptor blockers (ARBs) are a group of non-peptide competitive antagonists of the angiotensin II type I receptor (AT1R) [2]. Following the first ARB, losartan, 7 additional ARBs (azilsartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan and valsartan) were developed. These compounds have some structural similarity, including a biphenyl moiety (except for telmisartan and eprosartan), with an attached acidic tetrazole group for losartan, olmesartan, valsartan, irbesartan and candesartan
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