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Tomoyoshi Fujita, Kazuyuki Hirooka, 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(14):5324.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the mechanism of the neuroprotective effects of the AT1-R blocker on neuronal death in retinal ischemia-reperfusion injury .
Retinal ischemia was induced by increasing intraocular pressure to 130 mmHg for 45 min. At 30 min prior to the ischemia, 1 mg/kg candesartan, which is an AT1-R blocker (ARB), or saline was administered. Glutamate release from the rat retina and intravitreal PO2 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. Expression of retinal mRNA levels of NADPH oxidase membrane components, p47phox and p67phox were measured by real-time polymerase chain reaction. Reactive oxygen species (ROS) were measured using dihydroethidium. Data were analyzed using an independent Student’s t-test or Dunnett’s multiple comparison test.
Administration of candesartan suppressed ischemia-induced increases in the extracellular glutamate. Candesartan also attenuated the increase in intravitreal PO2 during reperfusion. AT1-R expression peaked at 12 h after reperfusion (1.264 ± 0.103 ng/ml; P < 0.001). Although there was an increase in the retinal mRNA expression of p47phox and p64phox at 12 h after the reperfusion (193.0 ± 35.3% of control; P = 0.038, 329.6 ± 94.6; P = 0.016), administration of candesartan suppressed these expressions (75.6 ± 18.0; P = 0.863, 84.0 ± 19.2; P = 0.998). The production of ROS was detected at 12 h after reperfusion (60.20 ± 1.99% of control; P < 0.001). After candesartan administration, a significant suppression of this upregulation was observed (18.14 ± 0.93; P < 0.001)
NADPH oxidase-mediated ROS production increased at 12 h 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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