title: Significance of angiotensin II receptor blockers with high affinity to angiotensin II type 1 receptors for vascular protection in rats.
abstract: Angiotensin II receptor blockers (ARBs) vary in their binding affinities to angiotensin II type 1 (AT(1)) receptors in in vitro experiments. We compared a high-affinity ARB, olmesartan, and a low-affinity ARB, valsartan, in terms of their vascular protective effects in stroke-prone spontaneously hypertensive rats (SHR-SP). Blood pressure was equally reduced by placebo, olmesartan (1 mg kg(-1)) and valsartan (3 mg kg(-1)) daily for 2 weeks. In another experiment, 12-week-old SHR-SP were fed 8% salt, and olmesartan (1 mg kg(-1)), valsartan (3 mg kg(-1)) or placebo were administered daily until a survival rate of 60% was reached. In the experiment using SHR-SP, the reduction of acetylcholine-induced vascular relaxation and the increase of p22(phox) expression in the placebo-treated group were significantly attenuated by olmesartan and valsartan, but this attenuation was significantly greater for olmesartan. In immunohistological analysis, all areas positive for angiotensin II, p22(phox) and 4-hydroxy-2-nonenal were significantly reduced by olmesartan and valsartan, but again this reduction was significantly greater for olmesartan. In salt-loaded SHR-SP, the number of days to reach a 60% survival rate was 25 and 42 in placebo and valsartan-treated rats, respectively, and this represented a significant difference. The survival rate in olmesartan-treated rats was 95% at day 42, when valsartan-treated rats reached 60% survival, and this difference was also significant. In the surviving rats, olmesartan, but not valsartan, augmented acetylcholine-induced vascular relaxation and attenuated vascular p22(phox) expression. Thus, heterogeneity in binding affinity to AT(1) receptors among ARBs may result in different degrees of vascular protection and lifespan extension.
authors: Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki City, Osaka, Japan. pha010@art.osaka-med.ac.jp
authors: Shinji
authors: S
authors: Takai
authors: Denan
authors: D
authors: Jin
authors: Hironobu
authors: H
authors: Ikeda
authors: Hiroshi
authors: H
authors: Sakonjo
authors: Mizuo
authors: M
authors: Miyazaki
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism* / Q000627:therapeutic use*; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000473:pathology; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D020011:Protective Agents; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012083:Renin / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000068756:Valsartan; D014652:Vascular Diseases / Q000517:prevention & control*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D020011:Protective Agents; D044140:Receptor, Angiotensin, Type 1; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; C437965:olmesartan; D019255:NADPH Oxidases; C515768:Cyba protein, rat; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D014633:Valine; D000109:Acetylcholine