The influence of the HMG-CoA reductase inhibitor simvastatin was assessed on the cardiovascular alterations and production of free radicals associated with chronic angiotensin II (Ang II) infusion. Simvastatin (60 mg/kg per day PO) or placebo were given concomitantly for 10 days in Sprague-Dawley rats infused with Ang II (200 ng/kg per minute SC, osmotic pump). In addition, simvastatin or placebo was also given in vehicle-infused rats. Tail-cuff pressure and albuminuria were measured before and at the end of the treatment period. Cardiac weight, carotid structure, production of reactive oxygen species (ROS, by chemiluminescence) by polymorphonuclear leukocytes and aortic wall as well as protein and lipid oxidation products were determined at the end of the study. Ang II increased tail-cuff pressure by 56±12 mm Hg and simvastatin blunted the development of hypertension by ≈70% (19±5 mm Hg). Increases in heart weight index and carotid cross-sectional area induced by Ang II were obliterated by simvastatin (3.18±0.09 versus 3.46±0.11 mg/g body wt and 0.125±0.010 versus 0.177±0.010 mm ² , respectively). The Ang II–induced increases in leukocyte and aortic production of ROS as well as protein and lipid oxidation products were prevented by simvastatin. No effect of simvastatin was detected in non–Ang II–infused rats. These results indicate that simvastatin prevented the development of hypertension and cardiovascular hypertrophy together with inhibition of the induced angiotensin II production of ROS. Therefore, inhibition of HMG CoA reductase by statins may have a beneficial effect on cardiovascular alterations through its antioxidant action in experimental Ang II–dependent hypertension.

—Angiotensin II (Ang II) stimulates the release and gene expression of endothelin-1 in isolated vascular smooth muscle cells. In 47 Sprague-Dawley rats, we assessed the influence of concomitant treatment by the mixed ET_A/ET_Bendothelin receptor antagonist bosentan (30 mg/kg per day, gavage) on the effect of a 10-day infusion of Ang II (200 ng/kg per minute, SC, osmotic pump) on arterial pressure, renal hemodynamics (microsphere method), albuminuria, cardiac weight, and carotid structure. Ang II increased systolic arterial pressure (SAP) by 49±7 mm Hg. Although bosentan alone did not affect SAP, the development of Ang II–induced hypertension was entirely prevented by the endothelin antagonist. In addition, the reduction in renal blood flow induced by Ang II (4.9±0.3 versus 7.4±0.2 mL · min⁻¹· g⁻¹in control rats) was prevented by concomitant administration of bosentan (8.8±0.8 mL · min⁻¹· g⁻¹). The marked increase in albuminuria observed in rats infused with Ang II (2524±961 versus 91±6 μg/24 h in control rats) was prevented by bosentan. Similarly, bosentan abolished the increase in heart weight index (from 2.96±0.03 to 3.41±0.08 mg/g body weight) and carotid media thickness (from 73±14 to 108±6 μm) induced by Ang II infusion. Of interest, the dipsogenic action of Ang II was not influenced by bosentan. In conclusion, endogenous endothelin contributes to the cardiovascular and renal effects of Ang II.

The influence of dietary sodium restriction and angiotensin II blockade on hypertension induced by a 25-day period of administration of the inhibitor of nitric oxide synthesis NG-nitro-L-arginine-methyl ester (10 mg/kg twice daily by gavage) was assessed in Wistar rats fed a normal or low sodium diet. In addition, the angiotensin II receptor blocker losartan (30 mg/kg once daily by gavage) was administered before and during NG-nitro-L-arginine-methyl ester in rats fed the normal sodium diet. At the end of the studies, conscious systolic arterial pressure increased similarly in NG-nitro-L-arginine-methyl ester-treated groups maintained on normal or low sodium intake. Moreover, a 25% reduction in cardiac output due to a decrease in stroke volume was observed in both groups. A slight but significant cardiac hypertrophic response was observed in hypertensive rats irrespective of sodium intake. At the completion of studies, plasma renin activity was similar to corresponding controls in the hypertensive groups on normal or low sodium intake. Losartan totally prevented the development of hypertension as well as the decrease in stroke volume and cardiac hypertrophy associated with NG-nitro-L-arginine-methyl ester treatment in rats on normal sodium intake. In conclusion, hypertension resulting from long-term blockade of nitric oxide synthesis was not affected by dietary sodium restriction. A crucial role for the renin-angiotensin system was demonstrated in this new model of hypertension.

The influence of a low-sodium (LS) diet was assessed on the cardiac and renal alterations and pro-oxidant effect associated with a 10-day infusion of angiotensin II (200 or 400 ng · kg⁻¹· min⁻¹, osmotic pumps). Tail-cuff pressure (TCP), albuminuria, and renal blood flow were determined at the end of the experiments. Heart weight index (HWI) and production of superoxide anion (O[ ]·) by the left ventricle and H₂O₂by the aorta was measured with the use of bioluminescence. Although the final TCP was similar in LS and normal sodium (NS) rats infused with high and low doses of angiotensin II, respectively, the increase in HWI was prevented by the LS diet. Sodium restriction reduced the rise in albuminuria without a change in the renal effect of angiotensin II. The increased production of O[ ]· and H₂O₂observed in NS rats was abrogated in LS rats. The beneficial influence of dietary sodium restriction on target organ damage induced by angiotensin II is independent of arterial pressure reduction and possibly related to attenuation of the prooxidant effect of the peptide.

Heart failure is the most frequent cardiac complication of chronic kidney disease (CKD). Biomarkers help identify high-risk patients. Natriuretic peptides (BNP and NT-proBNP) are largely used for monitoring patients with cardiac failure but are highly dependent on glomerular filtration rate (GFR). Soluble suppression of tumorigenicity 2 (sST2) biomarker is well identified in risk stratification of cardiovascular (CV) events in heart failure. Furthermore, sST2 is included in a bioclinical score to stratify mortality risk. The aims of this study were to evaluate (i) the interest of circulating sST2 level in heart dysfunction and (ii) the bioclinical score (Barcelona Bio-Heart Failure risk calculator) to predict the risk of composite outcome (major adverse coronary events) and mortality in the CKD population. A retrospective study was carried out on 218 CKD patients enrolled from 2004 to 2015 at Montpellier University Hospital. sST2 was measured by ELISA (Presage ST2® kit). GFR was estimated by the CKD-EPI equation (eGFR). Indices of cardiac parameters were performed by cardiac echography. No patient had reduced ejection fraction. 112 patients had left ventricular hypertrophy, and 184 presented cardiac dysfunction, with structural, functional abnormalities or both. sST2 was independent of age and eGFR (ρ=0.05, p=0.44, and ρ=−0.07, p=0.3, respectively). Regarding echocardiogram data, sST2 was correlated with left ventricular mass index (ρ=0.16, p=0.02), left atrial diameter (ρ=0.14, p=0.04), and volume index (ρ=0.13, p=0.05). sST2 alone did not change risk prediction of death and/or CV events compared to natriuretic peptides. Included in the Barcelona Bio-Heart Failure (BCN Bio-HF) score, sST2 added value and better stratified the risk of CV events and/or death in CKD patients (p<0.0001). To conclude, sST2 was associated with cardiac remodeling independently of eGFR, unlike other cardiac biomarkers. Added to the BCN Bio-HF score, the risk stratification of death and/or CV events in nondialyzed CKD patients was highly improved.