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Tomoyoshi Fujita, Kazuyuki Hirooka, Takehiro Nakamura, Toshifumi Itano, Akira Nishiyama, Yukiko Nagai, Fumio Shiraga; Neuroprotective Effects of Angiotensin II Type 1 Receptor (AT1-R) Blocker via Modulating AT1-R Signaling and Decreased Extracellular Glutamate Levels. Invest. Ophthalmol. Vis. Sci. 2012;53(7):4099-4110. doi: 10.1167/iovs.11-9167.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the mechanism of the neuroprotective effects of the angiotensin II type 1 receptor (AT1-R) blocker against retinal ischemia–reperfusion injury in the rat.
Retinal ischemia was induced by increasing intraocular pressure. Glutamate release from the rat retina and intravitreal PO2 (partial pressure of oxygen) profiles were monitored during and after ischemia using a microdialysis biosensor and oxygen-sensitive microelectrodes. ELISA was used to measure changes in the expression of AT1-R. Retinal mRNA expressions of p47phox and p67phox were measured by real-time polymerase chain reaction. Reactive oxygen species (ROS) were measured using dihydroethidium.
Administration of candesartan, which is an AT1-R blocker (ARB), suppressed ischemia-induced increases in the extracellular glutamate. Candesartan also attenuated the increase in intravitreal PO2 during reperfusion. AT1-R expression peaked at 12 hours after reperfusion. Although there was an increase in the retinal mRNA expression of p47phox and p64phox at 12 hours after the reperfusion, administration of candesartan suppressed these expressions. The production of ROS that was detected at 12 hours after reperfusion was also suppressed by the administration of candesartan or apocynin.
NADPH oxidase–mediated ROS production increased at 12 hours after reperfusion. Candesartan may protect neurons by decreasing extracellular glutamate immediately after reperfusion and by attenuating oxidative stress via a modulation of the AT1-R signaling that occurs during ischemic insult.
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