title: A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage.
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.
authors.affiliation: Division of Neurology, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Takizawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Uesugi
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Nagata
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Takagi
authors.forename: Charles
authors.initials: C
authors.lastname: van Ypersele de Strihou
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D017127:Glycation End Products, Advanced; D006973:Hypertension; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D018384:Oxidative Stress; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D017127:Glycation End Products, Advanced; D007093:Imidazoles; C532154:R 147176; D011945:Receptors, Angiotensin; D045162:Thiazolidinediones