A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage

Shunya Takizawa, Takashi Dan, Tsuyoshi Uesugi, Eiichiro Nagata, Shigeharu Takagi, Charles Van Ypersele De Strihou, Toshio Miyata

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Angiotensin II receptor blockers (ARBs) have a potent ability to inhibit oxidative stress and advanced glycation, in addition to their protective effects originated from blood pressure lowering and angiotensin II type 1 receptor (AT 1)-blockade. To obtain a pharmacological tool to dissect the mechanisms of ARBs protective benefits in experimental stroke, we synthesized a novel ARB-derivative, R-147176, which is 6,700 times less potent than olmesartan in AT 1-binding inhibition and therefore has a minimal antihypertensive effect, but retains marked inhibitory effects on oxidative stress and advanced glycation. We evaluated the effect of R-147176 (10-30 mg/kg per day), administered orally or intravenously, on brain infarct volume in transient thread occlusion and photothrombotic models in rats. The antioxidative and antiinflammatory properties were also investigated. R-147176 significantly reduced infarct volume, without influence on blood pressure, in both models. R-147176 significantly reduced the numbers of ED-1-positive cells and of TUNEL-positive cells, and protein carbonyl formation in the damaged brain. This ARB derivative, despite its significantly lower AT1 affinity and virtually no antihypertensive effect, ameliorated ischemic cerebral damage through antioxidative and antiinflammatory properties. These findings suggest potential usefulness of R-147176 as a pharmacological tool to investigate the ARBs protective effect in experimental stroke and open new therapeutic avenues.

Original languageEnglish
Pages (from-to)1665-1672
Number of pages8
JournalJournal of Cerebral Blood Flow and Metabolism
Volume29
Issue number10
DOIs
Publication statusPublished - 2009 Oct

Keywords

  • Angiotensin receptor
  • Blood pressure
  • Cerebral infarction
  • Neuroprotection
  • Oxidative stress

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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