Significance of angiotensin II receptor blockers with high affinity to angiotensin II type 1 receptors for vascular protection in rats.
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.
Takai
Shinji
S
Department of Pharmacology, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki City, Osaka, Japan. pha010@art.osaka-med.ac.jp
Jin
Denan
D
Ikeda
Hironobu
H
Sakonjo
Hiroshi
H
Miyazaki
Mizuo
M
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*
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