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 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.

Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

“…10 mRNA was measured by real-time polymerase chain reaction on a LightCycler with software (Roche Diagnostics, Tokyo, Japan) using TaqMan fluorogenic probes. For real-time polymerase chain reaction of p22 phox , (TGF)-b, monocyte chemoattractant protein (MCP)-1 and collagen I, all primers and probes were designed by Roche Diagnostics.…”

“…10 Sections were incubated with an anti-p22 phox antibody, then reacted with a labeled streptavidin-biotin peroxidase kit (Dako) and 3,3-diaminobenzidine. Sections were incubated with an anti-MCP-1 antibody, and later reacted with a labeled streptavidin-biotin peroxidase kit (Dako) and 3-amino-9-ethylcarbazol.…”

Candesartan and amlodipine combination therapy provides powerful vascular protection in stroke-prone spontaneously hypertensive rats

“…The sections were incubated with mouse anti-4-hydroxy-2-nonenal (4-HNE) antibody (Nikken Seil, Shizuoka, Japan). 5 A secondary biotinylated anti-IgG antibody (Invitrogen) was used. Sections were visualized using horseradish peroxidase and 3-amino-9-ethylcarbozole as the substrate chromogen (Dako).…”

“…5 The mRNA was measured by Real-time PCR on a LightCycler with Roche Diagnostics software (Tokyo, Japan) using TaqMan fluorogenic probes. All primers and probes for Real-time PCR of endothelial nitric oxide synthase (eNOS), p22 phox , gp91 phox , NOX1, NOX4, copper/zinc-containing SOD, manganese superoxide dismutase (Mn-SOD), extracellular SOD and ACE were designed by Roche Diagnostics.…”

“…[1][2][3] Therefore, by blocking the binding of angiotensin II to angiotensin II type 1 receptors, angiotensin II receptor blockers (ARBs) not only reduce blood pressure, but they also have a powerful vascular protective effect. 4,5 On the other hand, angiotensin-converting enzyme (ACE) inhibitors, which work by inhibiting angiotensin II formation, have also been widely used in the clinical setting. Both ACE inhibitors and ARBs have shown greater ability to prevent organ damage than other antihypertensive drugs in clinical studies.…”