Galectin-3 inhibition prevents adipose tissue remodelling in obesity.

Extracellular matrix remodelling of the adipose tissue has a pivotal role in the pathophysiology of obesity. Galectin-3 (Gal-3) is increased in obesity and mediates inflammation and fibrosis in the cardiovascular system. However, the effects of Gal-3 on adipose tissue remodelling associated with obesity remain unclear. Male Wistar rats were fed either a high-fat diet (33.5% fat) or a standard diet (3.5% fat) for 6 weeks. Half of the animals of each group were treated with the pharmacological inhibitor of Gal-3, modified citrus pectin (MCP; 100 mg kg(-1) per day) in the drinking water. In adipose tissue, obese animals presented an increase in Gal-3 levels that were accompanied by an increase in pericellular collagen. Obese rats exhibited higher adipose tissue inflammation, as well as enhanced differentiation degree of the adipocytes. Treatment with MCP prevented all the above effects. In mature 3T3-L1 adipocytes, Gal-3 (10(-8 )m) treatment increased fibrosis, inflammatory and differentiation markers. In conclusion, Gal-3 emerges as a potential therapeutic target in adipose tissue remodelling associated with obesity and could have an important role in the development of metabolic alterations associated with obesity.

Red wine intake but not other alcoholic beverages increases total antioxidant capacity and improves pro-inflammatory profile after an oral fat diet in healthy volunteers / El consumo de vino tinto pero no otras bebidas alcohólicas aumenta la capacidad antioxidante y mejora el perfil pro-inflamatorio después de una dieta rica en grasas oral en voluntarios sanos

Introduction. Different alcoholic beverages exert different effects on inflammation and oxidative stress but these results are controversial and scanty in some aspects. We analyze the effect of different alcoholic beverages after a fat-enriched diet on lipid profile, inflammatory factors and oxidative stress in healthy people in a controlled environment. Methods. We have performed a cross-over design in five different weeks. Sixteen healthy volunteers have received the same oral fat-enriched diet (1486kcal/m2) and a daily total amount of 16g/m2 of alcohol, of different beverages (red wine, vodka, brandy or rum) and equivalent caloric intakes as sugar with water in the control group. We have measured the levels of serum lipids, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNFα), interleukin 6 (IL-6), soluble phospholipase A2 (sPLA2), lipid peroxidation (LPO) and total antioxidant capacity (TAC). Results. Red wine intake was associated with decreased of mean concentrations of hsCRP, TNFα and IL-6 induced by fat-enriched diet (p<0.05); nevertheless, sPLA2 concentrations were not significantly modified. After a fat-enriched diet added with red wine, TAC increased as compared to the same diet supplemented with rum, brandy, vodka or the control (water with sugar) (p<0.05). Conclusions. Moderate red wine intake, but not other alcoholic beverages, decreased pro-inflammatory factors and increased total antioxidant capacity despite a fat-enriched diet intake in healthy young volunteers (AU)

Introducción. El efecto de las bebidas alcohólicas sobre la inflamación y el estrés oxidativo es variable y solo parcialmente conocido. Objetivo: analizar el efecto de diferentes bebidas alcohólicas sobre el perfil lipídico, factores de inflamación y estrés oxidativo en personas sanas con ingesta de una dieta enriquecida en grasas. Métodos. Se diseñó un estudio cruzado durante cinco semanas. Dieciséis voluntarios sanos recibieron la misma dieta enriquecida con grasa oral (1.486kcal/m2) más 16g/m2 de alcohol diarios, consumido como vino tinto, vodka, brandy o ron, o un equivalente calórico en el grupo control (azúcar y agua). Se midieron lípidos en suero, proteína C reactiva de alta sensibilidad (PCR-as), factor de necrosis tumoral (TNF) α, interleucina 6 (IL-6), fosfolipasa A2 soluble (sPLA2), la peroxidación lipídica (LPO) y la capacidad antioxidante total (TAC). Resultados. La ingesta de vino tinto se asoció con una disminución significativa de las concentraciones de PCR-as, TNFα e IL-6, inducida por una dieta rica en grasas (p <0,05). Las concentraciones de sPLA2 no se modificaron. El consumo de vino tinto, aún con una dieta rica en grasas, aumentó la capacidad antioxidante total comparada con el ron, brandy, vodka o el control (agua con azúcar) (p <0,05). Conclusiones. La ingesta moderada de vino tinto, pero no de otras bebidas alcohólicas, disminuyó las concentraciones de factores proinflamatorios y aumentó la capacidad antioxidante total, a pesar de la dieta enriquecida en grasa en voluntarios jóvenes sanos (AU)

Red wine intake but not other alcoholic beverages increases total antioxidant capacity and improves pro-inflammatory profile after an oral fat diet in healthy volunteers.

INTRODUCTION: Different alcoholic beverages exert different effects on inflammation and oxidative stress but these results are controversial and scanty in some aspects. We analyze the effect of different alcoholic beverages after a fat-enriched diet on lipid profile, inflammatory factors and oxidative stress in healthy people in a controlled environment. METHODS: We have performed a cross-over design in five different weeks. Sixteen healthy volunteers have received the same oral fat-enriched diet (1486kcal/m(2)) and a daily total amount of 16g/m(2) of alcohol, of different beverages (red wine, vodka, brandy or rum) and equivalent caloric intakes as sugar with water in the control group. We have measured the levels of serum lipids, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNFα), interleukin 6 (IL-6), soluble phospholipase A2 (sPLA2), lipid peroxidation (LPO) and total antioxidant capacity (TAC). RESULTS: Red wine intake was associated with decreased of mean concentrations of hsCRP, TNFα and IL-6 induced by fat-enriched diet (p<0.05); nevertheless, sPLA2 concentrations were not significantly modified. After a fat-enriched diet added with red wine, TAC increased as compared to the same diet supplemented with rum, brandy, vodka or the control (water with sugar) (p<0.05). CONCLUSIONS: Moderate red wine intake, but not other alcoholic beverages, decreased pro-inflammatory factors and increased total antioxidant capacity despite a fat-enriched diet intake in healthy young volunteers.

Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Toll-like receptor 4 (TLR4) signalling contributes to inflammatory cardiovascular diseases, but its role in hypertension and the associated vascular damage is not known. We investigated whether TLR4 activation contributed to angiotensin II (AngII)-induced hypertension and the associated vascular structural, mechanical and functional alterations. EXPERIMENTAL APPROACH: AngII was infused (1.44 mg · kg(-1) · day(-1), s.c.) for 2 weeks in C57BL6 mice, treated with a neutralizing anti-TLR4 antibody or IgG (1 µg · day(-1); systolic BP (SBP) and aortic cytokine levels were measured. Structural, mechanical and contractile properties of aortic and mesenteric arterial segments were measured with myography and histology. RT-PCR and Western blotting were used to analyse these tissues and cultured vascular smooth muscle cells (VSMC) from hypertensive rats (SHR). KEY RESULTS: Aortic TLR4 mRNA levels were raised by AngII infusion. Anti-TLR4 antibody treatment of AngII-treated mice normalised: (i) increased SBP and TNF-α, IL-6 and CCL2 levels; (ii) vascular structural and mechanical changes; (iii) altered aortic phenylephrine- and ACh-induced responses; (iv) increased NOX-1 mRNA levels, superoxide anion production and NAD(P)H oxidase activity and effects of catalase, apocynin, ML-171 and Mito-TEMPO on vascular responses; and (v) reduced NO release and effects of L-NAME on phenylephrine-induced contraction. In VSMC, the MyD88 inhibitor ST-2825 reduced AngII-induced NAD(P)H oxidase activity. The TLR4 inhibitor CLI-095 reduced AngII-induced increased phospho-JNK1/2 and p65 NF-κB subunit nuclear protein expression. CONCLUSIONS AND IMPLICATIONS: TLR4 up-regulation by AngII contributed to the inflammation, endothelial dysfunction, vascular remodelling and stiffness associated with hypertension by mechanisms involving oxidative stress. MyD88-dependent activation and JNK/NF-κB signalling pathways participated in these alterations.

Leptin, a mediator of cardiac damage associated with obesity.

Obesity and excess of adipose tissue are associated with the development of cardiovascular risk factors such as diabetes, hypertension, and hyperlipidemia. At the cardiac level, various morphological adaptations in cardiac structure and function occur in obese individuals. Different mechanisms linking obesity to these modifications have been postulated. Adipose tissue and epicardial fat releases a large number of cytokines and bioactive mediators such as leptin. Leptin circulates in proportion to body fat mass, thus serving as a satiety signal and informing central metabolic control centers as to the status of peripheral energy stores. It participates in numerous other functions both peripherally and centrally, as indicated by the wide distribution of leptin and the different isoforms of its receptor in different tissues including the heart. This hormone has distinct effects on the reproductive, cardiovascular, and immune systems; however, its role in the heart could mediate wide physiological effects observed in obese individuals. Oxidative stress is associated with obesity and may be considered to be a unifying mechanism in the development of obesity-related comorbidities. It has been reported that obesity may induce systemic oxidative stress; in turn, oxidative stress is associated with an irregular production of adipokines. We herein review the current knowledge of cardiac effects of leptin and the possible mechanisms that are involved, including oxidative stress that plays a major role in the development of cardiovascular damage.

Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease.

Myocarditis and dilated cardiomyopathy (DCM) are inflammatory diseases of the myocardium, for which appropriate treatment remains a major clinical challenge. Oleanolic acid (OA), a natural triterpene widely distributed in food and medicinal plants, possesses a large range of biological effects with beneficial properties for health and disease prevention. Several experimental approaches have shown its cardioprotective actions, and OA has recently been proven effective for treating Th1 cell-mediated inflammatory diseases; however, its effect on inflammatory heart disorders, including myocarditis, has not yet been addressed. Therefore, the present study was undertaken to determine the effectiveness of OA in prevention and treatment of experimental autoimmune myocarditis (EAM). The utility of OA was evaluated in vivo through their administration to cardiac α-myosin (MyHc-α614-629)-immunized BALB/c mice from day 0 or day 21 post-immunization to the end of the experiment, and in vitro through their addition to stimulated-cardiac cells. Prophylactic and therapeutic administration of OA dramatically decreased disease severity: the heart weight/body weight ratio as well as plasma levels of brain natriuretic peptide and myosin-specific autoantibodies production were significantly reduced in OA-treated EAM animals, compared with untreated ones. Histological heart analysis showed that OA-treatment diminished cell infiltration, fibrosis and dystrophic calcifications. OA also decreased proliferation of cardiac fibroblast in vitro and attenuated calcium and collagen deposition induced by relevant cytokines of active myocarditis. Furthermore, in OA-treated EAM mice the number of Treg cells and the production of IL-10 and IL-35 were markedly increased, while proinflammatory and profibrotic cytokines were significantly reduced. We demonstrate that OA ameliorates both developing and established EAM by promoting an antiinflammatory cytokine profile and by interfering with the generation of cardiac-specific autoantibodies, as well as through direct protective effects on cardiac cells. Therefore, we envision this natural product as novel helpful tool for intervention in inflammatory cardiomyopathies including myocarditis.

The potential role of leptin in the vascular remodeling associated with obesity.

BACKGROUND/OBJECTIVES: Extracellular matrix (ECM) participates in the vascular remodeling associated with obesity. We investigated the effects of leptin on the production of ECM components in primary cultured vascular smooth muscle cells (VSMCs) and whether leptin could be a mediator of obesity-induced vascular remodeling. METHODS: T he effects of leptin (100 ng ml(-1)) on ECM components and superoxide anion production (O(2)(.-)) were evaluated in presence or absence of the antioxidant melatonin (10(-)(3) mmol l(-1)) or the inhibitor of phosphatidylinositol 3'-kinase (PI3K), LY294002 (2 × 10(-)(4) mmol l(-1)) in VSMCs from adult rats in order to explore the role of both oxidative stress and the participation of PI3K/Akt pathway in the effects of leptin. ECM components and O(2)(.-) were quantified in the aortic media of male Wistar rats fed a high-fat diet (HFD; 33.5% fat), or a standard diet (CT; 3.5% fat) for 6 weeks. RESULTS: In VSMCs, leptin enhanced gene and protein levels of collagen I, fibronectin, transforming growth factor (TGF)-ß and connective tissue growth factor (CTGF) but did not change those of collagen III and galectin-3. Leptin also increased O(2)(.-) and Akt phosphorylation in VSMCs. These effects were prevented by the presence of either melatonin or LY294002, except O(2)(.-) production in the case of PI3K inhibition. The increase in body weight in HFD rats was accompanied by aorta thickening due to an increase in media area. The aortic fibrosis observed in HFD rats was associated with high levels of leptin, collagen type I, fibronectin, TGF-ß, CTGF, phosphorylated Akt and O(2)(.-). Aortic leptin levels were positively correlated with total collagen, collagen I, TGF-ß and CTGF levels. No differences were observed in the levels of collagen III, elastin or galectin-3 between both the groups. CONCLUSIONS: Leptin could participate in the vascular remodeling and stiffness associated with obesity by ECM production in VSMCs through the activation of oxidative stress-PI3K/Akt pathway and the production of the profibrotic factors TGF-ß and CTGF.

Factors involved in rosuvastatin induction of insulin sensitization in rats fed a high fat diet.

BACKGROUND AND AIM: To investigate whether rosuvastatin can improve insulin sensitivity in overweight rats having a high fat diet (HFD). The potential mechanisms involved in this action were evaluated, including SIRT-1, other factors involved in glucose metabolism and stress signaling pathways. METHODS AND RESULTS: Male Wistar rats (n = 30) were divided into three groups: (i) rats fed a standard diet (3.5% fat); (ii) rats fed a HFD (33.5% fat); and (iii) rats fed a HFD and treated with rosuvastatin (15 mg/kg/day). Evolution: 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Plasma levels of cholesterol, triglycerides, VLDL, glucose and insulin and leptin/adiponectin ratio were higher in HFD rats, and rosuvastatin treatment reduced them. SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 protein levels in white adipose tissue (WAT) were lower, and JNK was higher in HFD rats compared to controls. Rosuvastatin treatment normalized expression of these mediators. Endothelium-dependent relaxation was reduced in mesenteric rings from HFD rats compared to controls and rosuvastatin enhanced it in HFD rats. CONCLUSION: Rosuvastatin treatment reduced insulin resistance without affecting body weight or WAT loss in HFD rats. Reduction of leptin and JNK, and enhancement of SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 expression in WAT could contribute to insulin sensitization. Normalization of SIRT-1 expression in WAT could be considered a key novel mechanism that aids in explaining the beneficial effects of rosuvastatin on the amelioration of glucose metabolism and the arrangement of multiple signaling pathways participating in insulin resistance in overweight HFD rats.

Relevance of vascular peroxisome proliferator-activated receptor γ coactivator-1α to molecular alterations in atherosclerosis.

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is emerging as a novel factor that plays a critical role in integrating signalling pathways in the control of cellular and systemic metabolism. We investigated the role of vascular expression of PGC-1α and related factors, such as sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ (PPARγ) and adiponectin, during the atherosclerotic process. Endothelial function, vascular superoxide anion production and inflammatory mediators were also evaluated. This study was carried out in male New Zealand rabbits fed a diet containing 0.5% cholesterol and 14% coconut oil for 8 weeks. Animals developed mixed dyslipidaemia and atherosclerotic lesions, which were associated with endothelial dysfunction, aortic overproduction of superoxide anions and inflammation. Expression of PGC-1α, SIRT1, PPARγ and adiponectin was reduced (P<0.05) in aorta from atherosclerotic rabbits. Levels of PGC-1α were correlated negatively (P<0.05) with total cholesterol levels, aortic superoxide anion production and tumour necrosis factor-α expression, and positively (P<0.05) with maximal relaxation in response to acetylcholine. The observed results suggest that PGC-1α could be considered to be a link between the main atherosclerotic processes (endothelial dysfunction, oxidation and inflammation) and alterations of other factors involved in vascular wall integrity, such as SIRT1, PPARγ and adiponectin.

Effect of eplerenone on hypertension-associated renal damage in rats: potential role of peroxisome proliferator activated receptor gamma (PPAR-γ).

UNLABELLED: Several factors, including mineralocorticoids, have been implicated in the renal damage associated with hypertension. Peroxisome proliferator activated receptor gamma (PPAR-γ) agonists improve renal damage associated with different pathologies. Therefore, our hypothesis was that mineralocorticoid receptor blockade ameliorates renal damage associated with hypertension and that this improvement may be mediated by PPAR-γ. Spontaneously hypertensive rats (SHR) were treated with either vehicle or eplerenone, a mineralocorticoid receptor antagonist, at two different doses: 30 and 100 mg/kg/day for 10 weeks. Age-matched Wistar Kyoto rats (WKY) were used as a normotensive reference group. SHR showed tubulointersticial fibrosis and mild tubular atrophy. These alterations were accompanied by increases in renal cortex gene expression of transforming growth factor beta (TGF-ß) connective tissue growth factor (CTGF) and phosphorylated Smad2 protein levels, factors involved in the fibrotic response. Interleukin 1-beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) gene expression were also increased. By contrast, lysyl oxidase (LOX) expression and PPAR-γ protein levels were decreased in SHR as compared with normotensive animals. Only the high dose of eplerenone was able to reduce blood pressure and partially prevent LOX down-regulation in SHR. Both eplerenone doses significantly ameliorated interstitial fibrosis and tubular atrophy, reduced TGF-ß, CTGF and cytokine gene expression, and decreased Smad2 activation, while normalizing PPAR-γ protein levels. CONCLUSIONS: Mineralocorticoid receptor activation participates in hypertension-associated renal damage. This effect seems to involve stimulation of both fibrotic and inflammatory processes mediated (at least in part) by a down-regulation of PPAR-γ that can favour an up-regulation of the TGF-ß/Smad signalling pathway.

Papel de la aldosterona en las alteraciones vasculares funcionales y en el proceso inflamatorio asociados a la hipertensión en ratas / Role of aldosterone in vascular functional alterations and the inflammatory process associated to hypertension in rats

Objetivos: Estudiar la participación de la aldosterona en la disfunción vascular, el proceso inflamatorio y estrés oxidativo vascular asociado a hipertensión. Material y método: Se utilizaron ratas (n = 16) espontáneamente hipertensas (SHR) de 22 semanas de edad. La mitad de las ratas fueron tratadas durante 10 semanas con eplerenona a una dosis de 30 mg/kg/día (E-30). Se utilizaron ratas (n = 8) normotensas (WKY) como grupo de referencia. La presión arterial se midió de manera indirecta en la arteria caudal de la cola de las ratas. Al final del tratamiento las ratas se sacrificaron y se pesaron los corazones. Se evaluó la función endotelial en anillos aórticos en respuesta a la acetilcolina. La expresión del ARN mensajero (ARNm) de las interleucinas 1 β y 6 (IL-1β e IL-6), del factor de necrosis tumoral α (TNF-α), de la enzima óxido nítrico endotelial (eNOS) y de la subunidad p22phox de la enzima NAD(P)H oxidasa se midió en la aorta de las ratas. Resultados: Las SHR presentaron unos valores de presión arterial sistólica mayores (p < 0,05) que las ratas controles WKY (199,8±4,2 frente a 125,3±2,0 mmHg). El tratamiento con eplerenona redujo (p < 0,05) ligeramente las cifras de presión arterial en las ratas hipertensas (E30; 181,0±2,0 mmHg). No hubo diferencias en el peso corporal de las ratas, sin embargo el peso relativo del corazón de las ratas hipertensas era significativamente mayor respecto a las ratas normotensas y se normalizó con el tratamiento con eplerenona. La relajación a acetilcolina estaba significativamente reducida en las ratas SHR así como la expresión vascular de la eNOS. Sin embargo, las ratas hipertensas presentaron una sobreexpresión vascular del ARNm de IL-1β, IL-6, TNF-α y p22phox respecto a las WKY (p < 0,05). El tratamiento con eplerenona normalizó la función endotelial en las ratas hipertensas; aumento la expresión del ARNm de eNOS y redujo la expresión vascular de las citocinas IL-1β, IL-6, TNF-α, así como de la p22phox. Conclusiones: La aldosterona participa en las alteraciones funcionales vasculares en las SHR reduciendo la biodisponibilidad de óxido nítrico, aumentando el estrés oxidativo y el proceso inflamatorio vascular(AU)

Objetives: To study the participation of aldosterone in the vascular dysfunction, inflammatory process and vascular oxidative stress associated to hypertension. Material and methods: Half of the group of 22 week-old spontaneously hypertensive rats (n=16) were treated with eplerenone (E-30; 30 mg/kg/day) for 10 weeks. Normotensive rats (WKY; n = 8) were used as reference group. Systolic arterial pressure (SAP) was measured by the tail-cuff method. Body weight and heart weight were measured at the end of the treatment. Endothelium-dependent relaxations, as well as vascular mRNA expression of interleukin 1 β and 6 (IL-1β and IL-6), tumor necrosis factor alpha (TNF-α), of endothelial nitric oxide synthase (eNOS), NAD(P)H oxidase subunit p22phox were studied in aorta from SHR untreated or treated with eplerenone. Results: SHR showed higher levels of systolic blood pressure (p < 0.05) as compare with control rats (199.8±4.2 vs. 125.33±2.0 mmHg). Although there were no differences in the body weight among the groups, hypertensive rats had a higher relative heart weight compare to normotensive rats and it was normalize with the treatment of eplerenone (p < 0.05). SHR showed higher vascular mRNA expression of IL-1β, IL-6, TNF-α and p22phox compared to WKY (p < 0.05). Treatment with eplerenone slightly reduced (p < 0.05) blood pressure in hypertensive rats (E30; 181.0±2.0 mmHg) and normalized acetylcholine relaxations. Eplerenone enhanced (p < 0.05) eNOS and reduced p22phox, IL-1β, IL-6, TNF-α of aortic mRNA expressions in SHR. Conclusions: In SHR, aldosterone participates in the functional vascular alterations through the diminution of nitric oxide availability and the enhancement of the inflammatory process and the increase of vascular oxidative stress(AU)

Low mercury concentrations cause oxidative stress and endothelial dysfunction in conductance and resistance arteries.

Increased cardiovascular risk after mercury exposure has been described, but the underlying mechanisms are not well explored. We analyzed the effects of chronic exposure to low mercury concentrations on endothelium-dependent responses in aorta and mesenteric resistance arteries (MRA). Wistar rats were treated with mercury chloride (1st dose 4.6 microg/kg, subsequent dose 0.07 microg.kg(-1).day(-1) im, 30 days) or vehicle. Blood levels at the end of treatment were 7.97 +/- 0.59 ng/ml. Mercury treatment: 1) did not affect systolic blood pressure; 2) increased phenylephrine-induced vasoconstriction; 3) reduced acetylcholine-induced vasodilatation; and 4) reduced in aorta and abolished in MRA the increased phenylephrine responses induced by either endothelium removal or the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 100 microM). Superoxide dismutase (SOD, 150 U/ml) and the NADPH oxidase inhibitor apocynin (0.3 mM) decreased the phenylephrine-induced contraction in aorta more in mercury-treated rats than controls. In MRA, SOD did not affect phenylephrine responses; however, when coincubated with l-NAME, the l-NAME effect on phenylephrine response was restored in mercury-treated rats. Both apocynin and SOD restored the impaired acetylcholine-induced vasodilatation in vessels from treated rats. Endothelial NOS expression did not change in aorta but was increased in MRA from mercury-treated rats. Vascular O2(-) production, plasmatic malondialdehyde levels, and total antioxidant status increased with the mercury treatment. In conclusion, chronic exposure to low concentrations of mercury promotes endothelial dysfunction as a result of the decreased NO bioavailability induced by increases in oxidative stress. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease.

Aldosterone and its blockade: a cardiovascular and renal perspective.

Aldosterone not only contributes to salt and water homeostasis, but also exerts direct cardiovascular and renal effects. Numerous experimental and clinical studies indicate that aldosterone participate in cardiac alterations associated with hypertension, heart failure, diabetes and other pathological entities. It is important to mention that dietary salt is a key factor in aldosterone-mediated cardiovascular damage, since damage was more evident in animals on a high-salt diet than animals on a low salt diet. A pathophysiological action of aldosterone involves development of extracellular matrix and fibrosis, inflammation, stimulation of reactive oxygen species production, endothelial dysfunction, cell growth and proliferation. Many studies showed local extra-adrenal production of aldosterone in brain blood vessel, and the heart, which contribute in an important manner to the pathological actions of this mineralocorticoid. Several studies such as RALES, EPHESUS, 4E and others, recently showed that mineralocorticoid-receptor (MR) antagonists, alone or in combination with ACE inhibitors or ARBs, reduced the risk of progressive target organ damage and hospitalization in patients with hypertension and heart failure. These clinical benefits support the therapeutic usefulness of MR antagonists.

Effects of ovariectomy and growth hormone administration on body composition and vascular function and structure in old female rats.

UNLABELLED: Aging and estrogen-deprivation induce deleterious effects on body composition and vascular function in females. On the other hand, growth hormone (GH), whose production is reduced by age, exerts several vascular effects. The aim of this study was to investigate the effect of long-term estrogen deprivation and GH administration on body composition, vascular function and structure in aged female rats. METHODS: Twelve female Wistar rats were ovariectomized at 10 months of age. At 20 months of age, half of the ovariectomized rats were treated with GH for 4 weeks. The remaining ovariectomized rats animals and one group of six intact females were used as control groups. After the treatment period, animals were sacrificed and Specific Gravity Index (SGI) and periuterine fat weigh, as well as vascular reactivity and morphometry in aortic rings, were studied. RESULTS: No significant differences were found in SGI and periuterine fat weigh between ovariectomized and intact control rats. SGI was significantly increased by GH, and periuterine fat was reduced by the treatment. Dose-dependent relaxing responses to acetylcholine and isoproterenol were significantly diminished in ovariectomized rats as compared with intact animals, and GH treatment improved these responses. Ovariectomized animals showed significantly higher contracting responses to phenylephrine, acetylcholine + L-NAME and angiotensin-I than intact rats, and treatment with GH reduced them significantly. Media cross-sectional area was increased in ovariectomized rats as compared to intact animals, and GH reduced this area, but differences did not reach significance. CONCLUSION: GH has beneficial effects in body composition and endothelial function in old ovariectomized female rats.

Body composition and vascular effects of growth hormone administration in old female rats.

Aging is associated with alterations in cardiovascular system and changes in body composition. The aim of this study was to investigate the effect of GH on body composition, vascular function and structure in old female rats. Old (20 months) and adult (4 months) female Wistar rats were used. One group of old animals was treated with GH (2 mg/kg/day) for four weeks. Periuterine fat weight, specific gravity index (SGI), dose response to Acetylcholine, Isoprenaline, Phenylephrine and Acetylcholine in the presence of L-NAME and vascular morphology in aortic rings, were studied. Old rats showed increased fat weight and decreased SGI (p<0.05) as compared to adult animals. GH reduced fat weight (p<0.05) and tended to increase SGI (NS). Old rats showed impaired vasodilatation to Acetylcholine and Isoprenaline (p<0.05), and GH improved these responses (p<0.05). Contraction response to Phenylephrine was higher in old than in adults rats (p<0.05), but GH did not show any effect. Contraction induced by Acetylcholine+L-NAME was higher in old rats than in adults, and GH tended to reduce this response, although not significantly. Aortic media area was increased in old rats, and GH reduced this parameter (p<0.05). In conclusion, GH shows beneficial effects on body composition, vascular function and morphology in old female rats.

Alteraciones del endotelio en la hipertensión / Endothelial dysfunction in hypertension

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Efectos mecánicos y dinámicos de la hipertensión sobre el endotelio / Mechanical and dynamical effects of hypertension on endothelia

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Relevance of endothelium-derived hyperpolarizing factor in the effects of hypertension on rat coronary relaxations.

OBJECTIVES: To evaluate the relative participation of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and prostanoids in the relaxing responses induced by acetylcholine and isoproterenol in isolated coronary arteries from adult Wistar- Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). DESIGN AND METHODS: Male adult WKY rats and SHR were used in the study. Segments from left coronary arteries (approximately 350-380 microm internal diameter and 2 mm long) were mounted in an isometric myograph and pre-contracted with serotonin. Dose-response curves to acetylcholine and isoproterenol were carried out in absence and presence of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (LNAME), the inhibitor of the cyclo-oxygenase, indomethacin and KCI. Areas under the respective dose-response curves were used to calculate the approximate relative participation of NO, EDHF and prostanoids. RESULTS: Relaxations to either acetylcholine or isoproterenol were lower in SHR than in WKY rats. In WKY rats, presence of LNAME diminished (P< 0.05) relaxation to acetylcholine from 10(-9) to 10(-6) mol/l, and induced a contracting response at 10(-5) and 10(-4) mol/l of acetylcholine. Addition of indomethacin did not significantly affect dose-related relaxation to acetylcholine 10(-9) to 10(-6) mol/l in WKY rats, and reduced (P < 0.05) the contracting response observed at 10(-5) mol/l of acetylcholine. In SHR, addition of LNAME markedly reduced (P< 0.05) acetylcholine relaxations, but did not produce any contracting effect. Addition of indomethacin on top of LNAME slightly (P< 0.05) enhanced relaxing response to acetylcholine in SHR. Presence of LNAME in the media diminished (P < 0.05) relaxation to isoproterenol in both WKY rats and SHR. Addition of indomethacin on top of LNAME increased (P< 0.05) isoproterenol-relaxing response to levels similar to and higher than control conditions in WKY rats and SHR, respectively. Addition of KCI blunted both acetylcholine- and isoproterenol-relaxations in both groups. CONCLUSIONS: NO and EDHF are the main endothelium-derived relaxing factors underlying acetylcholine and isoproterenol relaxations in rat coronary arteries, respectively. EDHF reduction, and not only NO reduction play a key role in the diminished coronary relaxations induced by acetylcholine and isoproterenol in SHR. An arachidonic acid derivative with contracting activity released by acetylcholine and isoproterenol in a differential manner, could oppose the relaxing actions of NO and EDHF.

Atorvastatin prevents glomerulosclerosis and renal endothelial dysfunction in hypercholesterolaemic rabbits.

BACKGROUND: Numerous studies have shown that elevated plasma cholesterol can exacerbate renal disease. However, the effect of lipids on renal structure and vascular function in normal kidneys is less well established. Therefore, the aim of this study was to evaluate the impact of hypercholesterolaemia on glomerular structure and vascular reactivity of segmental arteries in rabbits. In addition, we also studied whether or not atorvastatin can prevent these structural and vascular alterations in hypercholesterolaemic rabbits. METHODS: Male New Zealand rabbits were fed either a normal rabbit chow or a diet containing 1% cholesterol and treated or not with atorvastatin (1 mg/kg/day) for 12 weeks. Dose-response curves to acetylcholine (10(-9)-10(-4) mol/l) and sodium nitroprusside (10(-9)-10(-4) mol/l) were studied in segmental arteries in the presence or absence of the thromboxane A2/PGH2 receptor antagonist ifetroban (10(-5) mol/l). Glomerular size and structure were also evaluated. RESULTS: Compared with control animals, hypercholesterolaemic rabbits presented glomerular hypertrophy and several types of injuries (capillary collapse, hyalinosis and alterations of Bowman's capsule), suggesting diffuse glomerulosclerosis. Segmental arteries also showed relaxing responses to acetylcholine and sodium nitroprusside which were lower than and similar to, respectively, those of control animals. The presence of ifetroban improved the acetylcholine response only in hypercholesterolaemic rabbits. Atorvastatin treatment prevented vascular and most glomerular changes associated with hypercholesterolaemia even in the presence of very high cholesterol levels. CONCLUSIONS: Atorvastatin exerts a protective effect on renal damage associated with hypercholesterolaemia even in the presence of deleterious levels of plasma cholesterol.