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.