Significance of Angiotensin II Receptor Blocker Lipophilicities and Their Protective Effect against Vascular Remodeling

Takai, Shinji; Kirimura, Kazuyoshi; Jin, Denan; Muramatsu, Michiko; Yoshikawa, Katsuhiro; Mino, Yoshiki; Miyazaki, Mizuo

doi:10.1291/hypres.28.593

Cited by 63 publications

(60 citation statements)

References 38 publications

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“…This study concurs with previous research showing that vascular ACE activity was significantly increased in SHR-SP compared with WKY rats, indicating the upregulation of angiotensin II formation. 7,8 However, the expression of AT 1 receptors did not differ between WKY rats and SHR-SP. Therefore, the increase in the angiotensin II-positive area might depend on the upregulation of angiotensin II formation, but not on the upregulation of AT 1 receptor expression.…”

Section: Discussionmentioning

confidence: 87%

“…[9][10][11] Expression of p22 phox in vascular tissues was significantly higher in the placebo-treated SHR-SP than in the WKY rats in this study, as has also been reported earlier. 7,8 In the histological evaluation, not only the angiotensin II-positive area but also the p22 phox -positive area was significantly augmented in the placebo-treated SHR-SP compared with the WKY rats. Furthermore, an oxidative stress marker 4-HNE was also higher in the SHR-SP than in the WKY rats.…”

Section: Discussionmentioning

confidence: 99%

“…Acetylcholine-induced vascular relaxation, which is used as an index of endothelial function, was significantly lower in SHR-SP than in WKY rats, as reported earlier. 7,8,15 Endothelial function is directly affected by nitric oxide bioavailability, and its dysfunction is associated with oxidative stress induced by angiotensin II. 16,17 In an earlier report, although losartan and trichlormethiazide at equivalent hypotensive doses were administered for 2 weeks in SHR-SP, the mRNA levels of NADPH oxidase subunits and oxidative stress were significantly reduced by losartan, but not by trichlormethiazide.…”

Section: Discussionmentioning

confidence: 99%

“…PCR products were separated by electrophoresis on 2% agarose gels that were subsequently stained with ethidium bromide and visualized using ultraviolet transillumination. 8 …”

Section: Reverse Transcription-polymerase Chain Reaction (Rt-pcr)mentioning

confidence: 99%

“…7,8 Angiotensin II is well known to induce NADPH oxidase, which in turn has a crucial role in the pathogenesis of vascular dysfunction. [9][10][11] Using SHR-SP, olmesartan, a high-affinity ARB and valsartan, a low-affinity ARB, were compared in terms of protection against vascular dysfunction, at doses that showed the same hypotensive effects.…”

Section: Introductionmentioning

confidence: 99%

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Significance of angiotensin II receptor blockers with high affinity to angiotensin II type 1 receptors for vascular protection in rats

Jin

Ikeda²,

Saito³

et al. 2009

Hypertens Res

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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 À1 ) and valsartan (3 mg kg À1 ) daily for 2 weeks. In another experiment, 12-week-old SHR-SP were fed 8% salt, and olmesartan (1 mg kg À1 ), valsartan (3 mg kg À1 ) 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 valsartantreated 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.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…PCR products were separated by electrophoresis on 2% agarose gels that were subsequently stained with ethidium bromide and visualized using ultraviolet transillumination. 8 …”

Section: Reverse Transcription-polymerase Chain Reaction (Rt-pcr)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Significance of angiotensin II receptor blockers with high affinity to angiotensin II type 1 receptors for vascular protection in rats

Jin

Ikeda²,

Saito³

et al. 2009

Hypertens Res

Self Cite

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Efficacy and safety of supramaximal titrated inhibition of renin‐angiotensin‐aldosterone system in idiopathic dilated cardiomyopathy

Sun

Gao

et al. 2015

ESC Heart Failure

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AimsThe optimal dosing strategies for blocking the renin‐angiotensin‐aldosterone system in idiopathic dilated cardiomyopathy (IDCM) are poorly known. We sought to determine the long‐term efficacy and safety of supramaximal titration of benazepril and valsartan in patients with IDCM.Methods and results480 patients with IDCM in New York Heart Association functional class II–IV and with left ventricular ejection fraction ≤35% were randomly assigned to extended‐release metoprolol (mean 152 mg/day, range 23.75–190), low‐dose benazepril (20 mg/day), low‐dose valsartan (160 mg/day), high‐dose benazepril (mean 69 mg/day, range 40–80), and high‐dose valsartan (mean 526 mg/day, range 320–640). After a median follow‐up of 4.2 years, high‐dose benazepril and valsartan, compared with their respective low dosages, resulted in 41% and 52% risk reduction in the primary endpoint of all‐cause death or admission for heart failure (P = 0.042 and 0.002), promoted functional improvement, and reversed remodelling as assessed by New York Heart Association classes, quality‐of‐life scores, and echocardiographic recording of left ventricular ejection fraction, left ventricular end‐diastolic volume, mitral regurgitation, and wall motion score index. Compared with metoprolol, high‐dose valsartan reduced risk for the primary endpoint by 46% (P = 0.006), whereas high‐dose benazepril and both low‐dose groups showed no significant difference. Major adverse events involved hypotension and renal impairment but were largely tolerated.ConclusionsSupramaximal doses of benazepril and valsartan were well tolerated and produced extra benefit than their low dosages in clinical outcome and cardiac reverse remodelling in patients with IDCM and modest‐severe heart failure. ClinicalTrials.gov identifier: NCT01917149.

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Unpuzzling the Comorbid Type 2 Diabetes and Hypertension-Related Cognitive Dysfunction and Stroke

Sebastião

Candeias

Santos

et al. 2017

Springer Series in Translational Stroke Research

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Significance of Angiotensin II Receptor Blocker Lipophilicities and Their Protective Effect against Vascular Remodeling

Cited by 63 publications

References 38 publications

Significance of angiotensin II receptor blockers with high affinity to angiotensin II type 1 receptors for vascular protection in rats

Significance of angiotensin II receptor blockers with high affinity to angiotensin II type 1 receptors for vascular protection in rats

Efficacy and safety of supramaximal titrated inhibition of renin‐angiotensin‐aldosterone system in idiopathic dilated cardiomyopathy

Unpuzzling the Comorbid Type 2 Diabetes and Hypertension-Related Cognitive Dysfunction and Stroke

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