The aim of this study was to evaluate whether the amelioration of endothelial dysfunction with candesartan, an AT1 angiotensin II antagonist, in spontaneously hypertensive rats (SHR) was associated with modification of the hepatic redox system.
SHR (n = 18; 22 weeks old) were treated or not with candesartan (2 mg kg-1 day-1) for 8 weeks. Wistar Kyoto rats (WKY; n = 8) of the same age were used as a normotensive reference group. At the end of the treatment period, systolic arterial pressure (SAP) was measured. Rats were killed by decapitation, and vascular reactivity to acetylcholine (ACh; 10-10-10-7 M), sodium nitroprusside (SNP; 10-10-10-7 M) and acetylcholine + L-NAME (ACh + L-NAME; 10-8-10-5 M) was studied in aortic rings. Hepatic levels of malonyl dialdehyde (MDA), GSH/GSSG ratio, glutathione peroxidase (GSHPx) and glutathione reductase (GSHRed) were measured in liver homogenates using specific assays. Aortic eNOS expression was measured with Northern blot analysis. All the experiments were carried out following recommendations from the institutional animal care and use committee, according to the guidelines for ethical care of experimental animals of the European Union. Dose-response curves were compared by multivariate analysis of variance for repeated measures (MANOVA) using the SPSS 10.0 program. All other data were analysed using a one-way analysis of variance, followed by a Newman-Keuls test if differences were noted. The null hypothesis was rejected when the P value was less than 0.05.
SAP was higher (P < 0.05) in SHR than in WKY and was reduced (P < 0.05) by candesartan. ACh relaxations were smaller (P < 0.05) and contractions induced by ACh + L-NAME were greater (P < 0.05) in SHR than in WKY. Treatment with candesartan enhanced (P < 0.05) ACh relaxations and reduced (P < 0.05) endothelium-dependent contractions. MDA levels were higher (P < 0.05) and GSH/GSSG ratio and GSHPx were lower (P < 0.05) in SHR than WKY. Candesartan reduced (P < 0.05) MDA and increased (P < 0.05) GSH/GSSG ratio without affecting either GSHPx or GSHRed. Expression of eNOS mRNA was similar in WKY and SHR, and candesartan increased (P < 0.05) it in SHR
Amelioration of hepatic antioxidant defence, as well as enhancement of eNOS gene expression and reduction of endothelium-dependent contractions, produced by candesartan could contribute to improve endothelial dysfunction in SHR. The results further support the role of AII in the functional vascular alterations produced by hypertension.