Neuroprotective effects of angiotensin II type 1 receptor (AT1-R) blocker via modulating AT1-R signaling and decreased extracellular glutamate levels

Tomoyoshi Fujita, Kazuyuki Hirooka, Takehiro Nakamura, Toshifumi Itano, Akira Nishiyama, Yukiko Nagai, Fumio Shiraga

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.

Original languageEnglish
Pages (from-to)4099-4110
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume53
Issue number7
DOIs
Publication statusPublished - Jun 2012
Externally publishedYes

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Angiotensin II Type 1 Receptor Blockers
Angiotensin Type 1 Receptor
Neuroprotective Agents
Reperfusion
Glutamic Acid
Reactive Oxygen Species
Ischemia
Oxygen
Messenger RNA
Partial Pressure
NADPH Oxidase
Microdialysis
Biosensing Techniques
Microelectrodes
Reperfusion Injury
Intraocular Pressure
Retina
Real-Time Polymerase Chain Reaction
Oxidative Stress
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Neuroprotective effects of angiotensin II type 1 receptor (AT1-R) blocker via modulating AT1-R signaling and decreased extracellular glutamate levels. / Fujita, Tomoyoshi; Hirooka, Kazuyuki; Nakamura, Takehiro; Itano, Toshifumi; Nishiyama, Akira; Nagai, Yukiko; Shiraga, Fumio.

In: Investigative Ophthalmology and Visual Science, Vol. 53, No. 7, 06.2012, p. 4099-4110.

Research output: Contribution to journalArticle

Fujita, Tomoyoshi ; Hirooka, Kazuyuki ; Nakamura, Takehiro ; Itano, Toshifumi ; Nishiyama, Akira ; Nagai, Yukiko ; Shiraga, Fumio. / Neuroprotective effects of angiotensin II type 1 receptor (AT1-R) blocker via modulating AT1-R signaling and decreased extracellular glutamate levels. In: Investigative Ophthalmology and Visual Science. 2012 ; Vol. 53, No. 7. pp. 4099-4110.
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abstract = "PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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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AU - Fujita, Tomoyoshi

AU - Hirooka, Kazuyuki

AU - Nakamura, Takehiro

AU - Itano, Toshifumi

AU - Nishiyama, Akira

AU - Nagai, Yukiko

AU - Shiraga, Fumio

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N2 - PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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.

AB - PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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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