Caroline Rugale

Simvastatin reverses target organ damage and oxidative stress in Angiotensin II hypertension: comparison with apocynin, tempol, and hydralazine.

The ability of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor simvastatin to reverse established cardiovascular and renal alterations and oxidative stress was assessed in angiotensin II (AngII) hypertension. Sprague-Dawley rats infused with AngII (200 ng/kg per minute for 17 days) were concomitantly treated or not for the last 7 days with simvastatin, apocynin, tempol, and hydralazine (60, 60, 30, and 15 mg/kg per day, respectively). Only hydralazine lowered AngII hypertension. Simvastatin and apocynin lowered cardiac hypertrophy by 52% and 54% and reversed the marked rise in albuminuria by 25% and 70%. Neither tempol nor hydralazine affected cardiac mass or albuminuria. None of the treatments modified the AngII-induced increase in carotid media thickness. The rise in cardiac superoxide anion production (lucigenin-enhanced chemiluminescence method) induced by AngII was reversed by all treatments. Enhanced plasma concentration of advanced oxidation protein products (spectrophotometry using chloramine T) was unaffected by simvastatin and tempol, but it was reversed by apocynin and hydralazine. Our results indicate that simvastatin reverse established cardiac and renal alterations in AngII hypertension independently of arterial pressure. It is suggested that oxidative stress participates in the maintenance of target organ damage and that antioxidant properties are involved in the beneficial influence of the statin.

Prevention and Reversal by Enalapril of Target Organ Damage in Angiotensin II Hypertension

Angiotensin-converting enzyme inhibitors (ACE-Is) prevent target organ damage in several models of hypertension. The aim of this study was to assess the influence of the ACE-I enalapril (10 mg/kg-1 per day, gavage) on the cardiovascular alterations and production of free radicals induced by chronic infusion of angiotensin II (Ang II, 200 ng/kg-1 per minute, SC) in Sprague-Dawley rats. Enalapril was given concomitantly for the 10 days of Ang II infusion (prevention) or from day 10 to 17 of Ang II infusion (intervention). The influence of the NADPH oxidase inhibitor apocynin (600 mg/L-1 in drinking water) was evaluated. mg/L-l in drinking water) was evaluated. Enalapril and apocynin had no effect on hypertension in the prevention and intervention studies. Enalapril prevented the increase in heart weight index (HWI), carotid cross-sectional area (CSA) and albuminuria induced by Ang II. Enalapril reduced HWI and albuminuria whereas CSA I was not affected in the intervention study. Apocynin had effects comparable to enalapril. Both enalapril and apocynin reduced the overproduction of superoxide anion by the left ventricle and rise in advanced oxidation protein products induced by C Ang II. Therefore, the antioxidant but not the antihypertensive effect of enalapril may participate in the prevention and treatment of the Ang II-induced cardiovascular and renal alterations.

Endogenous antioxidant defense induction by melon superoxide dismutase reduces cardiac hypertrophy in spontaneously hypertensive rats.

Abstract We assessed the influence of SODB, a melon superoxide dismutase (SOD), on left ventricular (LV) hypertrophy in SHR. SODB (4 or 40U SOD) was given orally for 4 or 28 days to SHR. For each treatment period, LV weight index (LVWI) and cardiomyocytes size were measured. SOD, glutathione peroxidase (GPx) and catalase expressions, and LV production and presence of superoxide anion were determined. Pro-inflammatory markers were also measured. SODB reduced LVWI and cardiomyocytes size after 4 or 28 days. Cardiac SOD and GPx increased by 30–40% with SODB. The presence but not production of superoxide anion was significantly reduced by SODB. No effect of SODB was detected on inflammatory status in any group. The beneficial effect of SODB on cardiac hypertrophy seems to be related to the stimulation of endogenous antioxidant defense, suggesting that SODB may be of interest as a dietary supplementation during conventional antihypertensive therapy.

Plasma Volume and Arterial Stiffness in the Cardiac Alterations Associated With Long-Term High Sodium Feeding in Rats

BACKGROUND Rats fed an early and long-term high-salt diet (HS, NaCl 8%) developed significant cardiovascular hypertrophy without major changes in blood pressure. The mechanism of this cardiac hypertrophy has not been yet elucidated. METHODS In the present work, we assessed the influence of volume overload and arterial stiffness on the structural and functional cardiac changes induced by a high salt feeding from weaning to 5 months of age in Sprague-Dawley rats. RESULTS Cardiac hypertrophy in HS rats was associated with clear augmentation in the size of left ventricular (LV) cardiomyocyte as compared with rats fed regular diet (NS). Echocardiography revealed a marked increase in relative wall thickness. Of note, no alteration of global and regional systolic and diastolic function was detected in HS rats. High sodium consumption was associated with a slight increase in aortic mean and pulse pressure (PP) without effect on pulse wave velocity (PWV) and elastic modulus. Plasma volume and central venous pressure were higher in HS than NS rats. Whereas plasma endothelin level was twofold higher in HS than in NS rats, LV endothelin level was similar in both groups. Treatment by the endothelin receptors blocker bosentan had no detectable effect on the changes induced by HS diet. CONCLUSIONS High sodium intake was associated with concentric cardiac hypertrophy without change of systolic and diastolic function. Aortic rigidity was not a determinant of cardiac hypertrophy. Beside a likely direct effect of sodium on cardiovascular system the slight increase in arterial pressure and plasma volume play a role.

Effect of Early Stage Kidney Disease on Cardiac Mass: Comparison to Post-Donation Renal Function

Background/Aim: In chronic renal failure the increase in cardiovascular risk is in part related to the high prevalence of left ventricular hypertrophy. The aim of the present monocentric retrospective study was to evaluate the influence of the presence of parenchymal kidney disease on left ventricular geometry in normotensive (arterial pressure <140/90 mm Hg) patients (KD+, n = 50, mean age 39 ± 19 years) with mild to moderate renal failure (stage 2-3 chronic kidney disease). Methods: Left ventricular geometry was estimated by echocardiography and compared to a group of healthy subjects with similarly reduced renal function as a consequence of renal donation (KD-, n = 63, mean age 52 ± 12 years). Results: Subjects with and without kidney disease had similar blood pressure, body mass index and isotopic glomerular filtration rate. Left ventricular mass (LVM) indexed to body surface area was greater in KD+ as compared to KD- subjects and the difference was more pronounced in women than in men. The increase in LVM in KD+ patients was associated with lower albuminemia and hematocrit, and a higher plasma renin activity and aldosterone as compared to KD- subjects. In multivariate analysis, kidney disease emerged as an important determinant of LVM index independently of age, gender and blood pressure. Conclusion: This observation suggests that the presence of kidney disease has an independent amplifying effect on LVM which could be related to volume overload and/or prohypertrophic factors such as aldosterone.

Carbon Monoxide Pollution Impairs Myocardial Perfusion Reserve: Implication of Coronary Endothelial Dysfunction

Chronic exposure to simulated urban CO pollution is reported to be associated with cardiac dysfunction. Despite the potential implication of myocardial perfusion alteration in the pathophysiology of CO pollution, the underlying mechanisms remain today still unknown. Therefore, the aim of this work was to evaluate the effects of prolonged exposure to simulated urban CO pollution on the regulation of myocardial perfusion. Cardiac hemodynamics and myocardial perfusion were assessed under basal conditions and during the infusion of a β-Adrenergic agonist. The effects of CO exposure on capillary density, coronary endothelium-dependent vasodilatation, eNOS expression and eNOS uncoupling were also evaluated. Our main results were that prolonged CO exposure was associated with a blunted myocardial perfusion response to a physiological stress responsible for an altered contractile reserve. The impairment of myocardial perfusion reserve was not accounted for a reduced capillary density but rather by an alteration in coronary endothelium-dependent vasorelaxation (−45% of maximal relaxation to ACh). In addition, though chronic CO exposure did not change eNOS expression, it significantly increased eNOS uncoupling. Therefore, the present work underlines the fact that chronic CO exposure, at levels found in urban air pollution, is associated with reduced myocardial perfusion reserve. This phenomenon is explained at the coronary-vessel level by deleterious effects of CO exposure on the endothelium NO-dependent vasorelaxation via eNOS uncoupling.

TIME-COURSE REDUCTION OF RENAL FUNCTION IN RATS ON HIGH SODIUM INTAKE: ACUTE REVERSAL BY POTASSIUM CANRENOATE

1 Time course of renal alterations associated with long‐term (since weaning) administration of a high sodium (HS, 8% NaCl) diet was assessed in Sprague‐Dawley rats. Reversal by acute administration of the mineralocorticoid receptor antagonist, potassium canrenoate (40 mg/kg, i.p.) or the type 1 angiotensin II receptor antagonist, losartan (10 mg/kg, i.v.), was evaluated at the age of 5 months (i.e. after 21 weeks of HS feeding). 2 High sodium intake had no detectable effect on blood pressure; however, albuminuria was always higher in the HS than control group. Glomerular filtration rate, renal plasma flow and filtration fraction decreased significantly after 12 weeks of HS diet by approximately 50, 30 and 20%, respectively. Canrenoate was effective and markedly reversed the renal hypofiltration associated with HS feeding without change in systemic blood pressure. In contrast, losartan reduced blood pressure and it was devoid of a beneficial effect on renal function. 3 The present observations indicate that hypofiltration and hypoperfusion of the kidney occurred progressively and require a long period of exposure to a high sodium intake. Albuminuria, which increased before detectable changes in renal function, may represent an early marker of renal dysfunction. The beneficial effect of acute administration of potassium canrenoate favours the participation of aldosterone, at least partially, in the sustained deterioration of renal function after 21 weeks of high sodium feeding.

Sodium restriction modulates innate immunity and prevents cardiac remodeling in a rat model of metabolic syndrome

In the view of the relationships between excessive sodium intake, immunity and target organ damage, we hypothesized that reduction in dietary sodium would be beneficial in the prevention of cardiac alterations through a restrained local immunity response in a rat model of metabolic syndrome. Sprague-Dawley rats were fed a 60% fructose diet with either a normal sodium (0.64% NaCl) or a low sodium content (<0.01% NaCl) for 8weeks. After 4weeks, rats were infused or not with angiotensin II (200ng·kg-1·min-1, sc) for 4weeks. Tail-cuff blood pressure was determined in conscious rats. Heart and left ventricle weight, cardiomyocyte size, and cardiac fibrosis were evaluated. We performed a transcriptomic analysis in order to identify differentially regulated cardiac mRNAs between normal and low sodium diets. We validated those results using qPCR and immunohistochemistry. Angiotensin II-induced blood pressure rise was blunted (~50%) in the low-sodium fed rats while cardiac hypertrophy and fibrosis were prevented. Transcriptomic analysis revealed 66 differentially regulated genes including 13 downregulated genes under the low sodium diet and implicated in the innate immune response. This was confirmed by reduced cardiac macrophages infiltration under the low sodium diet. Dietary sodium restriction prevents structural alterations of the heart of rats with fructose-induced insulin resistance and angiotensin II-hypertension. The reduction of cardiac inflammation and macrophage infiltration suggests that innate immunity has an important role in the beneficial effect of sodium restriction on cardiac remodeling.