title: Significance of angiotensin II receptor blocker lipophilicities and their protective effect against vascular remodeling.
abstract: Although the lipophilicities of the various angiotensin II receptor blockers (ARBs) are very different, the relationship between lipophilicity and the protective effect against vascular remodeling is unclear. In this study, we compared the protective effects of a highly lipophilic ARB, telmisartan, and an ARB with low lipophilicity, losartan, on vascular function and oxidative stress in stroke-prone spontaneously hypertensive rats (SHR-SP). SHR-SP received oral placebo, 1 mg/kg telmisartan, or 10 mg/kg losartan for 2 weeks. The blood pressure (BP) in SHR-SP was significantly higher than that in Wistar-Kyoto (WKY) rats before treatment, and the BP was reduced equally in telmisartan- and losartan-treated SHR-SP compared to placebo-treated SHR-SP. Acetylcholine-induced vasorelaxation in isolated carotid arteries was significantly weaker in SHR-SP than in WKY rats, but in both telmisartan- and losartan-treated SHR-SP, acetylcholine-induced vasorelaxation was significantly higher than in placebo-treated SHR-SP. Moreover, acetylcholine-induced vasorelaxation in telmisartan-treated rats was significantly stronger than in losartan-treated SHR-SP. The expression of the endothelial nitric oxide synthase gene was significantly higher in telmisartan- and losartan-treated rats than in placebo-treated SHR-SP, and was significantly higher in telmisartan-treated rats than in losartan-treated rats. In contrast, the expression of the NAD(P)H oxidase subunit p22phox gene in telmisartan-treated SHR-SP was significantly lower than that in losartan-treated SHR-SP. Immunohistochemistry showed that angiotensin II expression in the aorta was significantly lower in telmisartan-treated SHR-SP than in losartan-treated SHR-SP. In conclusion, a highly lipophilic ARB, telmisartan, may be useful for preventing NAD(P)H oxidase activity, and thereby for conferring vascular protection.
authors.affiliation: Department of Pharmacology, Osaka Medical College, Takatsuki, Japan. pha010@art.osaka-med.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kirimura
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.forename: Michiko
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Mino
authors.forename: Mizuo
authors.initials: M
authors.lastname: Miyazaki
mesh_terms: D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics*; D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics*; D001565:Benzoates / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002340:Carotid Artery Diseases / Q000473:pathology / Q000517:prevention & control*; D015870:Gene Expression; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D008055:Lipids; D019808:Losartan / Q000493:pharmacokinetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D009206:Myocardium / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D009929:Organ Size; D010750:Phosphoproteins / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012083:Renin / Q000097:blood; D000077333:Telmisartan; D014664:Vasodilation
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D008055:Lipids; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D000804:Angiotensin II; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; C086986:CYBA protein, human; D012083:Renin; D019808:Losartan; D000077333:Telmisartan