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

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.

Telmisartan Reduces Axon Degeneration in Mice With Experimental Glaucoma

“…Using a mouse model of glaucoma with sustained IOP elevation, this study provides evidence that telmisartan may be beneficial in treating glaucoma, as had been suggested by our previous study with normal mice. 17 We used the same drug delivery method as in our previous study in which we found reduced BP, indicating physiologically relevant systemic concentrations, as well as reduced IOP. Although BP was not measured in this study, we did find reduced IOP in telmisartan-treated mice, indicating efficacy of the drug delivery method.…”

“…14 ARBs crossed the blood/brain and blood/retinal barriers, suggesting that direct mechanisms of action in the eye are possible using this drug delivery method. 17 Telmisartan was an order of magnitude higher of concentration in plasma, brain, and eyes, compared to the other ARBs, likely due to its lipophilic nature. 4 We found that treatment with telmisartan or irbesartan lowered IOP, whereas losartan did not.…”

“…To investigate the therapeutic potential of telmisartan as a treatment for glaucoma, we used the same method of drug delivery as in our previous study 17 and induced IOP elevation in C57BL/6J mice by injection of microbeads into the anterior chamber of one eye, while the other eye was left uninjected to serve as contralateral control. 18 For mice treated with vehicle, microbead injection resulted in degeneration and loss of RGC axons in the optic nerve, whereas there was no significant loss in mice treated with telmisartan.…”

Local ocular renin–angiotensin–aldosterone system: any connection with intraocular pressure? A comprehensive review

“…In addition, in mice with elevated IOP, treatment with losartan has been described to exert neuroprotective effects on retinal ganglion cells [217]. In a recent study, the IOP lowering and neuroprotective effects of three different systemically administered ARBs, losartan, irbesartan and telmisartan were studied [220]. BP was significantly lowered by all three ARBs when compared to the vehicle control, whereas IOP was significantly reduced by irbesartan and telmisartan but not by losartan probably due to non-equipotent dosages.…”

“…All of these studies support the concept of aldosterone's role in RAAS at least to some extent, in the regulation of neurodegeneration. Moreover, the dual ability of ARBs to lower IOP and act as neuroprotective agents is promising when searching for new effective ways to treat glaucoma [219,220,223].…”