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Effect of AT1 receptor blockade on hepatic redox status in SHR: possible relevance for endothelial function?
Eva Cediel1, David Sanz-Rosa, M Pilar Oubina
1Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain.
Insights
Candesartan treatment improved endothelial dysfunction in spontaneously hypertensive rats by reducing blood pressure and enhancing nitric oxide synthase. The drug also modulated hepatic redox systems, suggesting a role for angiotensin II in hypertension-related vascular changes.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Oxidative Stress Research
Background:
- Endothelial dysfunction is a hallmark of hypertension, contributing to vascular complications.
- The role of hepatic redox systems in hypertension and their modulation by antihypertensive drugs requires further investigation.
Purpose of the Study:
- To investigate the effects of candesartan on endothelial dysfunction in spontaneously hypertensive rats (SHR).
- To determine if candesartan's amelioration of endothelial dysfunction is associated with modifications in the hepatic redox system.
- To explore the involvement of angiotensin II in hypertension-induced vascular and hepatic alterations.
Main Methods:
- Administration of candesartan (2 mg.kg-1.day-1 for 10 weeks) to spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY).
- Assessment of systolic arterial pressure (SAP), acetylcholine (ACh)-induced relaxations, and contractions induced by ACh + NG-nitro-l-arginine methyl ester (l-NAME).
- Measurement of aortic endothelial nitric oxide synthase (eNOS) mRNA and NAD(P)H oxidase p22phox subunit expression.
- Analysis of liver homogenates for malonyl dialdehyde (MDA) levels, reduced/oxidized glutathione ratio (GSH/GSSG), and glutathione peroxidase activity (GPx).
- Evaluation of vascular, lumen, and media areas.
Main Results:
- Candesartan reduced SAP in both SHR and WKY rats.
- ACh relaxations were enhanced, and ACh + l-NAME contractions were reduced by candesartan in SHR.
- Candesartan increased aortic eNOS mRNA expression in both strains and reduced p22phox expression in SHR.
- In SHR livers, candesartan decreased MDA levels and increased the GSH/GSSG ratio.
- Candesartan reduced media area in SHR without affecting vessel or lumen area.
Conclusions:
- Hypertension is linked to elevated vascular superoxide anions and alterations in the hepatic redox system, with angiotensin II playing a significant role.
- Candesartan effectively ameliorates endothelial dysfunction and vascular remodeling in hypertensive rats.
- The findings support a key role for angiotensin II via AT1 receptors in mediating hypertension-induced vascular alterations and suggest a broader impact on redox balance.
Abstract:
The study investigated whether the amelioration of endothelial dysfunction by candesartan (2 mg.kg-1.day-1; 10 wk) in spontaneously hypertensive rats (SHR) was associated with modification of hepatic redox system. Systolic arterial pressure (SAP) was higher (P < 0.05) in SHR than in Wistar-Kyoto rats (WKY) and was reduced (P < 0.05) by candesartan in both strains. Acetylcholine (ACh) relaxations were smaller (P < 0.05) and contractions induced by ACh + NG-nitro-l-arginine methyl ester (l-NAME) were greater (P < 0.05) in SHR than in WKY. Treatment with candesartan enhanced (P < 0.05) ACh relaxations in SHR and reduced (P < 0.05) ACh + l-NAME contractions in both strains. Expression of aortic endothelial nitric oxide synthase (eNOS) mRNA was similar in WKY and SHR, and candesartan increased (P < 0.05) it in both strains. Aortic mRNA expression of the subunit p22phox of NAD(P)H oxidase was higher (P < 0.05) in SHR than in WKY. Treatment with candesartan reduced (P < 0.05) p22phox expression only in SHR. Malonyl dialdehyde (MDA) levels were higher (P < 0.05), and the ratio reduced/oxidized glutathione (GSH/GSSG) as well as glutathione peroxidase activity (GPx) were lower (P < 0.05) in liver homogenates from SHR than from WKY. Candesartan reduced (P < 0.05) MDA and increased (P < 0.05) GSH/GSSG ratio without affecting GPx. Vessel, lumen, and media areas were bigger (P < 0.05) in SHR than in WKY. Candesartan treatment reduced (P < 0.05) media area in SHR without affecting vessel or lumen area. The results suggest that hypertension is not only associated with elevation of vascular superoxide anions but with alterations of the hepatic redox system, where ANG II is clearly involved. The results further support the key role of ANG II via AT1 receptors for the functional and structural vascular alterations produced by hypertension.