RESUMO
Many studies have shown that risk factors that are independent of blood pressure (BP) can contribute to the development of cardiac hypertrophy (CH). Among these factors, high-salt (HS) intake was prominent. Although some studies have attempted to elucidate the role of salt in the development of this disease, the mechanisms by which salt acts are not yet fully understood. Thus, the aim of this study was to better understand the mechanisms of CH and interstitial fibrosis (IF) caused by HS intake. Male Wistar rats were divided into 5 groups according to diet [normal salt (NS; 1.27% NaCl) or HS (8% NaCl)] and treatment [losartan (LOS) (HS+LOS group), hydralazine (HZ) (HS+HZ group), or N-acetylcysteine (NAC) (HS+NAC group)], which was given in the drinking water. Tail-cuff BP, transverse diameter of the cardiomyocyte, IF, angiotensin II type 1 receptor (AT1) gene and protein expression, serum aldosterone, cardiac angiotensin II, cardiac thiobarbituric acid-reactive substances, and binding of conformation-specific anti-AT1 and anti-angiotensin II type 2 receptor (AT2) antibodies in the 2 ventricles were measured. Based on the left ventricle transverse diameter data, the primary finding was the occurrence of significant BP-independent CH in the HS+HZ group (96% of the HS group) and a partial or total prevention of such hypertrophy via treatment with NAC or LOS (81% and 67% of the HS group, respectively). The significant total or partial prevention of IF using all 3 treatments (HS+HZ, 27%; HS+LOS, 27%; and HS+NAC, 58% of the HS group, respectively), and an increase in the AT1 gene and protein expression and activity in groups that developed CH, confirmed that CH occurred via the AT1 in this experimental model. Thus, this study unveiled some relevant previously unknown mechanisms of CH induced by chronic HS intake in Wistar rats. The link of oxidative stress with CH in our experimental model is very interesting and stimulates further evaluation for its full comprehension.
Assuntos
Cardiomegalia/patologia , Miócitos Cardíacos/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Acetilcisteína/farmacologia , Aldosterona/sangue , Angiotensina II/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Frequência Cardíaca , Hematócrito , Hidralazina/farmacologia , Losartan/farmacologia , Masculino , Miócitos Cardíacos/metabolismo , Potássio/sangue , Potássio/urina , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sódio/sangue , Sódio/urina , Cloreto de Sódio na Dieta/administração & dosagem , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
BACKGROUND: Dietary sodium is a well-known risk factor for cardiovascular and renal disease; however, direct evidence of the longitudinal changes that occur with aging, and the influence of dietary sodium on the age-associated alterations are scarce. METHODS: C57BL/6 mice were maintained for 13 months on a low (LS, 0.02 % Na+), normal (NS, 0.3 % Na+) or high (HS, 1.6 % Na+) salt diet. We assessed 1) the longitudinal trajectories for two markers of cardiovascular and renal dysfunction (blood pressure (BP) and albuminuria), as well as hormonal changes, and 2) end-of-study cardiac and renal parameters. RESULTS: The effect of aging on BP and kidney damage did not reach significance levels in the LS group; however, relative to baseline, there were significant increases in these parameters for animals maintained on NS and HS diets, starting as early as month 7 and month 5, respectively. Furthermore, changes in albuminuria preceded the changes in BP relative to baseline, irrespective of the diet. Circulating aldosterone and plasma renin activity displayed the expected decreasing trends with age and dietary sodium loading. As compared to LS - higher dietary sodium consumption associated with increasing trends in left ventricular mass and volume indices, consistent with an eccentric dilated phenotype. Functional and molecular markers of kidney dysfunction displayed similar trends with increasing long-term sodium levels: higher renovascular resistance, increased glomerular volumes, as well as higher levels of renal angiotensin II type 1 and mineralocorticoid receptors, and lower renal Klotho levels. CONCLUSION: Our study provides a timeline for the development of cardiorenal dysfunction with aging, and documents that increasing dietary salt accelerates the age-induced phenotypes. In addition, we propose albuminuria as a prognostic biomarker for the future development of hypertension. Last, we identified functional and molecular markers of renal dysfunction that associate with long-term dietary salt loading.
Assuntos
Hipertensão , Nefropatias , Sódio na Dieta , Animais , Camundongos , Albuminúria , Pressão Sanguínea , Rim , Camundongos Endogâmicos C57BL , Cloreto de Sódio na DietaRESUMO
Intracellular peptides generated by the proteasome and oligopeptidases have been suggested to function in signal transduction and to improve insulin resistance in mice fed a high-caloric diet. The aim of this study was to identify specific intracellular peptides in the adipose tissue of Wistar rats that could be associated with the physiological and therapeutic control of glucose uptake. Using semiquantitative mass spectrometry and LC/MS/MS analyses, we identified ten peptides in the epididymal adipose tissue of the Wistar rats; three of these peptides were present at increased levels in rats that were fed a high-caloric Western diet (WD) compared with rats fed a control diet (CD). The results of affinity chromatography suggested that in the cytoplasm of epididymal adipose tissue from either WD or CD rats, distinctive proteins bind to these peptides. However, despite the observed increase in the WD animals, the evaluated peptides increased insulin-stimulated glucose uptake in 3T3-L1 adipocytes treated with palmitate. Thus, intracellular peptides from the adipose tissue of Wistar rats can bind to specific proteins and facilitate insulin-induced glucose uptake in 3T3-L1 adipocytes.
Assuntos
Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Glucose/metabolismo , Resistência à Insulina , Peptídeos/análise , Peptídeos/metabolismo , Células 3T3 , Adipócitos/citologia , Adipócitos/metabolismo , Sequência de Aminoácidos , Animais , Cromatografia de Afinidade , Cromatografia Líquida , Ingestão de Energia , Insulina/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Ácido Palmítico/metabolismo , Ligação Proteica , Proteínas/metabolismo , Ratos , Ratos Wistar , Espectrometria de Massas em TandemRESUMO
High salt intake is a known cardiovascular risk factor and is associated with cardiac alterations. To better understand this effect, male Wistar rats were fed a normal (NSD: 1.3% NaCl), high 4 (HSD4: 4%), or high 8 (HSD8: 8%) salt diet from weaning until 18 wk of age. The HSD8 group was subdivided into HSD8, HSD8+HZ (15 mg . kg(-1) . d(-1) hydralazine in the drinking water), and HSD8+LOS (20 mg . kg(-1) . d(-1) losartan in the drinking water) groups. The cardiomyocyte diameter was greater in the HSD4 and HSD8 groups than in the HSD8+LOS and NSD groups. Interstitial fibrosis was greater in the HSD4 and HSD8 groups than in the HSD8+HZ and NSD groups. Hydralazine prevented high blood pressure (BP) and fibrosis, but not cardiomyocyte hypertrophy. Losartan prevented high BP and cardiomyocyte hypertrophy, but not fibrosis. Angiotensin II type 1 receptor (AT(1)) protein expression in both ventricles was greater in the HSD8 group than in the NSD group. Losartan, but not hydralazine, prevented this effect. Compared with the NSD group, the binding of an AT(1) conformation-specific antibody that recognizes the activated form of the receptor was lower in both ventricles in all other groups. Losartan further lowered the binding of the anti-AT(1) antibody in both ventricles compared with all other experimental groups. Angiotensin II was greater in both ventricles in all groups compared with the NSD group. Myocardial structural alterations in response to HSD are independent of the effect on BP. Salt-induced cardiomyocyte hypertrophy and interstitial fibrosis possibly are due to different mechanisms. Evidence from the present study suggests that salt-induced AT(1) receptor internalization is probably due to angiotensin II binding.
Assuntos
Pressão Sanguínea/fisiologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/fisiopatologia , Miocárdio/patologia , Cloreto de Sódio na Dieta/administração & dosagem , Aldosterona/sangue , Angiotensina II/análise , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Cardiomegalia/patologia , Colágeno Tipo I/análise , Colágeno Tipo III/análise , Modelos Animais de Doenças , Ingestão de Líquidos , Ingestão de Alimentos , Ecocardiografia , Fibrose , Expressão Gênica , Ventrículos do Coração/química , Ventrículos do Coração/patologia , Hidralazina/administração & dosagem , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Losartan/administração & dosagem , Masculino , Potássio/sangue , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/análise , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/fisiologia , Receptor Tipo 2 de Angiotensina/análise , Renina/sangue , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , Sódio/sangue , Sódio/urina , Fator de Crescimento Transformador beta/análise , UrinaRESUMO
Low birth weight has been associated with increased obesity in adulthood. It has been shown that dietary salt restriction during intrauterine life induces low birth weight and insulin resistance in adult Wistar rats. The present study had a two-fold objective: to evaluate the effects that low salt intake during pregnancy and lactation has on the amount and distribution of adipose tissue; and to determine whether the phenotypic changes in fat mass in this model are associated with alterations in the activity of the renin-angiotensin system. Maternal salt restriction was found to reduce birth weight in male and female offspring. In adulthood, the female offspring of dams fed the low-salt diet presented higher adiposity indices than those seen in the offspring of dams fed a normal-salt diet. This was attributed to the fact that adipose tissue mass (retroperitoneal but not gonadal, mesenteric or inguinal) was greater in those rats than in the offspring of dams fed a normal diet. The adult offspring of dams fed the low-salt diet, compared to those dams fed a normal-salt diet, presented the following: plasma leptin levels higher in males and lower in females; plasma renin activity higher in males but not in females; and no differences in body weight, mean arterial blood pressure or serum angiotensin-converting enzyme activity. Therefore, low salt intake during pregnancy might lead to the programming of obesity in adult female offspring.
Assuntos
Adiposidade/fisiologia , Dieta Hipossódica/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/etiologia , Tecido Adiposo/crescimento & desenvolvimento , Animais , Pressão Sanguínea/fisiologia , Feminino , Leptina/sangue , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/enzimologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Renina/sangue , Renina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Fatores Sexuais , Cloreto de Sódio na Dieta/administração & dosagemRESUMO
BACKGROUND: This study evaluated the effect of chronic sucrose feeding on hemodynamic parameters and renal sympathetic nervous activity. In addition, angiotensin I, II, and 1-7 levels were determined in plasma, heart, kidney, and the epididymal adipose tissue. METHODS: Male Wistar rats were treated for 30 days with 20% sucrose solution (n = 21) or tap water (n = 19) and food ad libitum. Blood pressure, cardiac output, and total peripheral resistance were recorded at the end of the 30-day treatment period. Sympathetic and angiotensinergic systems were evaluated by acute hexamethonium and captopril administration; plasma and tissue (heart, kidney, and epididymal adipose tissue) angiotensins were measured by high-performance liquid chromatography; and angiotensin-converting enzyme activity was determined by continuous fluorescent assay. Plasma renin activity and plasma levels of insulin and leptin were evaluated by radioimmunoassay. RESULTS: Chronic sucrose feeding was associated with increased blood pressure (BP) (129 +/- 1 v 102 +/- 3 mm Hg) and circulating insulin (171%) and leptin (356%) levels when compared with the control group. The sucrose group also showed a 27% higher renal sympathetic nervous activity. The depressor response to hexamethonium was similar in both groups, whereas captopril caused a more pronounced decrease in BP in the sucrose group than in controls (-40 +/- 2 v -11 +/- 2 mm Hg), possibly reflecting the higher plasma renin activity and plasma content of angiotensin II and renal angiotensin II in sucrose rats. CONCLUSIONS: These findings suggest a specific renal renin-angiotensin-sympathetic activation as a potential mechanism for the cardiovascular changes in response to chronic sucrose feeding.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Sacarose Alimentar/efeitos adversos , Hipertensão/etiologia , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/fisiologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Angiotensinas/metabolismo , Animais , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Captopril/farmacologia , Débito Cardíaco/fisiologia , Hexametônio/farmacologia , Hipertensão/fisiopatologia , Insulina/sangue , Rim/efeitos dos fármacos , Rim/fisiologia , Leptina/sangue , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Renina/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , Sódio/sangue , Sódio/urina , Sistema Nervoso Simpático/efeitos dos fármacos , Resistência Vascular/fisiologiaRESUMO
This study investigated the influence of sodium restriction and antihypertensive drugs on atherogenesis utilizing hypertensive (H) low-density lipoprotein-receptor knockout mice treated or not with losartan (Los) or hydralazine (Hyd) and fed low-sodium (LS) or normal-sodium (NS) chow. Despite reducing the blood pressure (BP) of H-LS mice, the LS diet caused arterial lipid infiltration due to increased plasma total cholesterol (TC) and triglycerides (TG). Los and Hyd reduced the BP of H-LS mice, and Los effectively prevented arterial injury, likely by reducing plasma TG and nonesterified fatty acids. Aortic lipid infiltration was lower in Los-treated H-LS mice (H-LS+Los) than in normotensive (N)-LS and H-LS mice. Aortic angiotensin II type 1 (AT1) receptor content was greater in H-NS than H-LS mice and in H-LS+Hyd than H-LS+Los mice. Carboxymethyl-lysine (CML) and receptor for advanced glycation end products (RAGE) immunostaining was greater in H-LS than H-NS mice. CML and RAGE levels were lower in LS animals treated with antihypertensive drugs, and Hyd enhanced the AT1 receptor level. Hyd also increased the gene expression of F4/80 but not tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-10, intercellular adhesion molecule-1 or cluster of differentiation 66. The novelty of the current study is that in a murine model of simultaneous hypertension and hyperlipidemia, the pleiotropic effect of chronic, severe sodium restriction elicited aortic damage even with reduced BP. These negative effects on the arterial wall were reduced by AT1 receptor antagonism, demonstrating the influence of angiotensin II in atherogenesis induced by a severely LS diet.
Assuntos
Aterosclerose/etiologia , Pressão Sanguínea , Dieta Hipossódica , Hiperlipidemias/complicações , Hipertensão/prevenção & controle , Animais , Hipertensão/complicações , Camundongos , Camundongos Knockout , Receptores de LDL/genéticaRESUMO
METHODS: Female Wistar rats were exposed to filtered air (F) or to concentrated fine particulate matter (P) for 15 days. After mating, the rats were divided into four groups and again exposed to F or P (FF, FP, PF, PP) beginning on day 6 of pregnancy. At embryonic day 19, the placenta was collected. The placental structure, the protein and gene expression of TGFß1, VEGF-A, and its receptor Flk-1 and RAS were evaluated by indirect ELISA and quantitative real-time PCR. RESULTS: Exposure to P decreased the placental mass, size, and surface area as well as the TGFß1, VEGF-A and Flk-1 content. In the maternal portion of the placenta, angiotensin II (AngII) and its receptors AT1 (AT1R) and AT2 (AT2R) were decreased in the PF and PP groups. In the fetal portion of the placenta, AngII in the FP, PF and PP groups and AT2R in the PF and PP groups were decreased, but AT1R was increased in the FP group. VEGF-A gene expression was lower in the PP group than in the FF group. CONCLUSIONS: Exposure to pollutants before and/or during pregnancy alters some characteristics of the placenta, indicating a possible impairment of trophoblast invasion and placental angiogenesis with possible consequences for the maternal-fetal interaction, such as a limitation of fetal nutrition and growth.
Assuntos
Exposição Ambiental , Material Particulado/metabolismo , Placenta/anatomia & histologia , Sistema Renina-Angiotensina , Animais , Feminino , Expressão Gênica , Placenta/metabolismo , Gravidez , Ratos , Ratos WistarRESUMO
Intracellular peptides generated by limited proteolysis are likely to function inside and outside cells and could represent new possibilities for drug development. Here, we used several conformational-sensitive antibodies targeting G-protein coupled receptors to screen for novel pharmacological active peptides. We find that one of these peptides, DITADDEPLT activates cannabinoid type 1 receptors. Single amino acid modifications identified a novel peptide, DIIADDEPLT (Pep19), with slightly better inverse agonist activity at cannabinoid type 1 receptors. Pep19 induced uncoupling protein 1 expression in both white adipose tissue and 3T3-L1 differentiated adipocytes; in the latter, Pep19 activates pERK1/2 and AKT signaling pathways. Uncoupling protein 1 expression induced by Pep19 in 3T3-L1 differentiated adipocytes is blocked by AM251, a cannabinoid type 1 receptors antagonist. Oral administration of Pep19 into diet-induced obese Wistar rats significantly reduces adiposity index, whole body weight, glucose, triacylglycerol, cholesterol and blood pressure, without altering heart rate; changes in the number and size of adipocytes were also observed. Pep19 has no central nervous system effects as suggested by the lack of brain c-Fos expression, cell toxicity, induction of the cannabinoid tetrad, depressive- and anxiety-like behaviors. Therefore, Pep19 has several advantages over previously identified peripherally active cannabinoid compounds, and could have clinical applications.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Obesidade/tratamento farmacológico , Peptídeos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Células 3T3-L1 , Adipócitos/patologia , Tecido Adiposo Branco/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/metabolismo , Obesidade/patologia , Peptídeos/química , Peptídeos/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismoRESUMO
BACKGROUND: Salt restriction is recommended for hypertension treatment to reduce blood pressure, but its effect on some risk factors is still a matter of discussion. The aim of this study was to observe the effect of a long period of salt restriction or overload on blood pressure, left ventricular mass (LVM), kidney mass (KM), glucose tolerance, and plasma insulin. METHODS: Male Wistar rats were fed from weaning with a low-salt diet (LSD) or a high-salt diet (HSD) until 72 weeks of age. After 48 weeks, the diets were changed in half of the rats: HSD until 48 weeks and then LSD (LHSD) and LSD until 48 weeks and then HSD (HLSD). Body weight, blood pressure, electrolyte excretion, creatinine clearance, plasma renin activity, LVM, KM, and intravenous glucose tolerance test with insulin determinations were evaluated. RESULTS: Blood pressure, LVM and KM were higher on the HSD than on the LSD. Blood pressure was lower on the LHSD than on the HLSD. There were no differences in LVM and KM on the LHSD compared with the HLSD. The relationship between area under the curve (AUC) of insulin and glucose during the intravenous glucose tolerance test was higher on the LSD. No differences were detected in AUC between the two groups of rats whose diet were inverted with 48 weeks of age. CONCLUSIONS: A chronic HSD increases blood pressure, LVM, and KM and a chronic LSD increases plasma insulin in response to a glucose challenge in aging rats. The hypotensive effect of salt restriction is not modified by a previous long period on a HSD.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Dieta Hipossódica , Coração/efeitos dos fármacos , Insulina/sangue , Cloreto de Sódio na Dieta/administração & dosagem , Cloreto de Sódio na Dieta/farmacologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Área Sob a Curva , Peso Corporal , Teste de Tolerância a Glucose , Ventrículos do Coração/efeitos dos fármacos , Resistência à Insulina , Rim/efeitos dos fármacos , Masculino , Miocárdio/patologia , Ratos , Ratos Wistar , Renina/sangueRESUMO
A low-salt (LS) diet during pregnancy has been linked to insulin resistance in adult offspring, at least in the experimental setting. However, it remains unclear if this effect is due to salt restriction during early or late pregnancy. To better understand this phenomenon, 12-week-old female Wistar rats were fed a LS or normal-salt (NS) diet during gestation or a LS diet during either the first (LS10) or second (LS20) half of gestation. Glucose tolerance test, HOMA-IR, gene expression analysis and DNA methylation measurements were conducted for the Insr, Igf1, Igf1r, Ins1 and Ins2 genes in the livers of neonates and in the liver, white adipose tissue and muscle of 20-week-old male offspring. Birth weight was lower in the LS20 and LS animals compared with the NS and LS10 rats. In the liver, the Igf1 levels in the LS10, LS20 and LS neonates were lower than those in the NS neonates. Methylation of the Insr, Igf1r, Ins1 and Ins2 genes was influenced in a variable manner by low salt intake during pregnancy. Increased liver Igf1 methylation was observed in the LS and LS20 neonates compared with their NS and LS10 counterparts. Glucose intolerance was observed in adult offspring as an effect of low salt intake over the duration of pregnancy. Compared to the NS animals, the HOMA-IR was higher in the 12-week-old LS and 20-week-old LS-10 rats. Based on these results, it appears that the reason a LS diet during pregnancy induces a low birth weight is its negative correlation with Igf1 DNA methylation in neonates.
Assuntos
Glicemia/efeitos dos fármacos , Metilação de DNA/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Cloreto de Sódio na Dieta/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Metilação de DNA/efeitos dos fármacos , Dieta Hipossódica , Jejum/sangue , Feminino , Teste de Tolerância a Glucose , Recém-Nascido de Baixo Peso , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Gravidez , Ratos , Ratos Wistar , Estatísticas não ParamétricasRESUMO
INTRODUCTION: Previous studies from our laboratory demonstrated that dietary salt overload and salt restriction during pregnancy were associated with cardiac and renal structural and/or functional alterations in adult offspring. The present study evaluated renal and cardiac structure and the local renin-angiotensin system in newborns from dams fed high-, normal- or low-salt diets during pregnancy. METHODS: Female Wistar rats were fed low- (LS, 0.15% NaCl), normal- (NS, 1.3% NaCl) or high- (HS, 8% NaCl) salt diets during pregnancy. Kidneys and hearts were collected from newborns (n = 6-8/group) during the first 24 hours after birth to evaluate possible changes in structure using stereology. Protein expression of renin-angiotensin system components was evaluated using an indirect enzyme-linked immunosorbent assay (ELISA). RESULTS: No differences between groups were observed in total renal volume, volume of renal compartments or number of glomeruli. The transverse diameter of the nuclei of cardiomyocytes was greater in HS than NS males in the left and right ventricles. Protein expression of the AT1 receptor was lower in the kidneys of the LS than in those of the NS and HS males but not females. Protein expression of the AT2 receptor was lower in the kidneys of the LS males and females than in those of the NS males and females. CONCLUSION: High salt intake during pregnancy induced left and right ventricular hypertrophy in male newborns. Salt restriction during pregnancy reduced the expression of renal angiotensin II receptors in newborns.
Assuntos
Coração/anatomia & histologia , Rim/anatomia & histologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Cloreto de Sódio na Dieta/administração & dosagem , Cloreto de Sódio/química , Animais , Animais Recém-Nascidos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal , Dieta Hipossódica , Ensaio de Imunoadsorção Enzimática , Feminino , Hipertrofia Ventricular Direita , Miócitos Cardíacos/metabolismo , Gravidez , Prenhez , Ratos , Ratos Wistar , Renina/metabolismoRESUMO
AIMS: The goal of the current study was to evaluate the impact of maternal sodium intake during gestation on the systemic and renal renin-angiotensin-aldosterone-system (RAAS) of the adult offspring. MAIN METHODS: Female Wistar rats were fed high- (HSD-8.0% NaCl) or normal-sodium diets (NSD-1.3% NaCl) from 8 weeks of age until the delivery of their first litter. After birth, the offspring received NSD. Tail-cuff blood pressure (TcBP) was measured in the offspring between 6 and 12 weeks of age. At 12 weeks of age, the offspring were subjected to either one week of HSD or low sodium diet (LSD-0.16% NaCl) feeding to evaluate RAAS responsiveness or to acute saline overload to examine sodium excretory function. Plasma (PRA) and renal renin content (RRC), serum aldosterone (ALDO) levels, and renal cortical and medullary renin mRNA expression levels were evaluated at the end of the study. KEY FINDINGS: TcBP was higher among dams fed HSD, but no TcBP differences were observed among the offspring. Male offspring, however, exhibited increased TcBP after one week of HSD feeding, and this effect was independent of maternal diet. Increased RAAS responsiveness to the HSD and LSD was also observed in male offspring. The baseline levels of PRA, ALDO, and cortical and medullary renin gene expression were lower but the RRC levels were higher among HSD-fed male offspring (HSDoff). Conversely, female HSDoff showed reduced sodium excretion 4 h after saline overload compared with female NSDoff. SIGNIFICANCE: High maternal sodium intake is associated with gender-specific changes in RAAS responsiveness among adult offspring.
Assuntos
Efeitos Tardios da Exposição Pré-Natal , Sistema Renina-Angiotensina/efeitos dos fármacos , Sódio na Dieta/farmacologia , Envelhecimento/fisiologia , Aldosterona/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Dieta , Feminino , Hematócrito , Rim/efeitos dos fármacos , Rim/metabolismo , Córtex Renal/metabolismo , Medula Renal/metabolismo , Masculino , Reação em Cadeia da Polimerase , Gravidez , RNA Mensageiro/biossíntese , Ratos , Renina/biossíntese , Renina/metabolismo , Caracteres Sexuais , Sódio/sangue , Sódio/urinaRESUMO
OBJECTIVE: To get some additional insight on the mechanisms of the effect of salt intake on body weight. DESIGN AND METHODS: Rats were fed a low (LSD), normal (NSD), or high (HSD) salt diet. In a first set, body weight, tail-cuff blood pressure, fasting plasma thyroid-stimulating hormone, triiodothyronine, L-thyroxine, glucose, insulin, and angiotensin II were measured. Angiotensin II content was determined in white and brown adipose tissues. Uncoupling protein 1 expression was measured in brown adipose tissue. In a second set, body weight, food intake, energy balance, and plasma leptin were determined. In a third set of rats, motor activity and body weight were evaluated. RESULTS: Blood pressure increased on HSD. Body weight was similar among groups at weaning, but during adulthood it was lower on HSD and higher on LSD. Food intake, L-thyroxine concentration, uncoupling protein 1 expression and energy expenditure were higher in HSD rats, while non-fasting leptin concentration was lower in these groups compared to NSD and LSD animals. Plasma thyroid-stimulating hormone decreased on both HSD and LSD while plasma glucose and insulin were elevated only on LSD. A decrease in plasma angiotensin II was observed in HSD rats. On LSD, an increase in brown adipose tissue angiotensin II content was associated to decreased uncoupling protein 1 expression and energy expenditure. In this group, a low angiotensin II content in white adipose tissue was also found. Motor activity was not influenced by the dietary salt content. CONCLUSIONS: Chronic alteration in salt intake is associated with changes in body weight, food intake, hormonal profile, and energy expenditure and tissue angiotensin II content.
Assuntos
Peso Corporal/efeitos dos fármacos , Dieta Hipossódica , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Cloreto de Sódio na Dieta/administração & dosagem , Tecido Adiposo Marrom/metabolismo , Angiotensina II/metabolismo , Animais , Peso Corporal/fisiologia , Proteínas de Transporte/metabolismo , Relação Dose-Resposta a Droga , Ingestão de Alimentos/fisiologia , Ingestão de Energia/fisiologia , Metabolismo Energético/fisiologia , Hipertensão/dietoterapia , Canais Iônicos , Masculino , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Wistar , Hormônios Tireóideos/sangue , Fatores de Tempo , Proteína Desacopladora 1 , DesmameRESUMO
Modifications in chylomicron metabolism caused by antihypertensive drugs were investigated in hypertensive subjects because previous studies had indicated that diuretics and beta-blockers modify the plasma lipid concentrations through mechanisms that were not fully understood. A triglyceride-rich emulsion resembling lymph chylomicrons, labeled with (3H) triolein and (14C) cholesteryl oleate, was infused intravenously into mildly hypertensive patients after 8 weeks on placebo and subsequently on hydrochlorothiazide (n = 10) or propranolol (n = 8). The residence time of both radioactivities in plasma was utilized for the simultaneous calculation of the particle remnant removal rate and of the lipoprotein lipase activity expressed as a delipidation index = 1 - [(3H) triolein residence time/(14C) cholesteryl oleate residence time]. Treatment with hydrochlorothiazide diminished the delipidation rate value whereas propranolol mildly increased the removal rate of the remnant particle. These alterations of the chylomicron kinetics were not accompanied by changes in plasma triglycerides, glucose, and insulin concentration as measured in the fasting state. The impairment of the lipoprotein lipase activity by thiazides and the faster removal rate of the whole particle by propranolol could explain the reason why in previous clinical studies the simultaneous use of these drugs does not aggravate the hyperlipidemia known to be induced by thiazides alone.
Assuntos
Anti-Hipertensivos/uso terapêutico , Quilomícrons/metabolismo , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Propranolol/uso terapêutico , Adulto , Idoso , Ésteres do Colesterol/metabolismo , Ésteres do Colesterol/farmacocinética , Feminino , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Hipertensão/fisiopatologia , Lipídeos/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Trioleína/metabolismo , Trioleína/farmacocinéticaRESUMO
This study aimed at measuring the influence of a low salt diet on the development of experimental atherosclerosis in moderately hyperlipidemic mice. Experiments were carried out on LDL receptor (LDLR) knockout (KO) mice, or apolipoprotein E (apoE) KO mice on a low sodium chloride diet (LSD) as compared with a normal salt diet (NSD). On LSD, the rise of the plasma concentrations of TG and nonesterified fatty acid (NEFA) was, respectively, 19% and 34% in LDLR KO mice, and 21% and 35% in apoE KO mice, and that of plasma cholesterol was limited to the LDLR KO group alone (15%). Probably due to the apoE KO severe hypercholesterolemia, the arterial inner-wall fat storage was not influenced by the diet salt content and was far more abundant in the apoE KO than in the LDLR KO mice. However, in the less severe hypercholesterolemia of the LDLR KO mice, lipid deposits on the LSD were greater than on the NSD. Arterial fat storage correlated with NEFA concentrations in the LDLR KO mice alone (n = 14, P = 0.0065). Thus, dietary sodium chloride restriction enhances aortic wall lipid storage in moderately hyperlipidemic mice.
Assuntos
Aorta/metabolismo , Lipídeos/sangue , Receptores de LDL/deficiência , Cloreto de Sódio na Dieta/farmacologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Arteriosclerose/etiologia , Ácidos Graxos/sangue , Hiperlipidemias/sangue , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Receptores de LDL/genética , Triglicerídeos/sangueRESUMO
Several studies support the hypothesis that chronic diseases in adulthood might be triggered by events that occur during fetal development. This study examined the consequences of perinatal salt intake on blood pressure (BP) and carbohydrate and lipid metabolism in adult offspring of dams on high-salt [HSD; 8% (HSD2) or 4% (HSD1)], normal-salt (NSD; 1.3%), or low-salt (LSD; 0.15% NaCl) diet during pregnancy and lactation. At 12 wk of age, female Wistar rats were matched with adult male rats that were fed NSD. Weekly tail-cuff BP measurements were performed before, during, and after pregnancy. After weaning, the offspring received only NSD and were housed in metabolic cages for 24-h urine collection for sodium and potassium and nitrate and nitrite excretion measurements. At 12 wk of age, intra-arterial mean BP was measured, a euglycemic-hyperinsulinemic clamp was performed, and plasma lipids and nitrate and nitrite concentrations were determined. Tail-cuff BP was higher during pregnancy in HSD2 and HSD1 than in NSD and LSD dams. Mean BP (mm Hg) was also higher in the offspring of HSD2 (110 +/- 5) and HSD1 (107 +/- 5) compared with NSD (100 +/- 2) and LSD (92 +/- 2). Lower glucose uptake and higher plasma cholesterol and triacylglycerols were observed in male offspring from LSD dams (glucose uptake: HSD2 17 +/- 4, HSD1 15 +/- 3, NSD 11 +/- 3, LSD 4 +/- 1 mg . kg(-1) . min(-1); cholesterol: HSD2 62 +/- 6, HSD1 82 +/- 11, NSD 68 +/- 10, LSD 98 +/- 17 mg/dL; triacylglycerols: HSD2 47 +/- 15, HSD1 49 +/- 12, NSD 56 +/- 19, LSD 83 +/- 11 mg/dL). In conclusion, maternal salt intake during pregnancy and lactation has long-term influences on arterial pressure, insulin sensitivity, and plasma lipids of the adult offspring.
Assuntos
Hiperlipidemias/etiologia , Hiperlipidemias/fisiopatologia , Resistência à Insulina/fisiologia , Efeitos Tardios da Exposição Pré-Natal , Cloreto de Sódio na Dieta/farmacologia , Fatores Etários , Animais , Pressão Sanguínea , Peso Corporal , Dieta Hipossódica , Feminino , Lactação , Lipídeos/sangue , Nitratos/urina , Nitritos/urina , Gravidez , Ratos , Ratos WistarRESUMO
A hipertensão arterial é uma doença multifatorial decorrente da interação de aspectos ambientais e genéticos. Sabemos, também, que a hipertensão arterial é poligênica e sua apresentação fenotípica dependerá do gene ou do grupo de genes envolvidos em cada caso.Dentre a multifatoriedade da hipertensão arterial, o endotélio surge como um dos fatores mais importantes no controle do tônus vasomotor.O endotélio tem a capacidade de produzir substâncias vasodilatadoras e vasoconstritoras. É o equilíbrio entre essas substâncias que determinará o tônus vasomotor. Quando existe disfunção endotelial há maior aumento da produção de vasoconstritores ou menor produção da quantidade de substâncias vasodilatadoras. Isso acarreta aumento do tônus vasomotor e conseqüente aumento da pressão arterial.Vários são os medicamentos disponíveis no controle da pressão arterial.Neste artigo serão discutidos os mecanismos envolvidos no aumento da pressão arterial decorrentes de disfunção endotelial. Também serão abordados alguns aspectos relacionados com o efeito dos medicamentos anti-hipertensivos sobre a função endotelial...
Assuntos
Humanos , Endotélio , Sistemas Neurossecretores , Doenças Cardiovasculares/história , Hipertensão , Óxido NítricoRESUMO
O consumo crônico de dieta com conteúdo elevado de sal está associado com maior pressao arterial e mortalidade por doenças cardiovasculares. Baseado neste fenômeno, a restrição de sal na dieta tem sido recomendada como tratamento não medicamentoso para a hipertensão arterial sistêmica. Além dos benefícios de redução da pressão arterial e mortalidade cardiovascular durante este tratamento, outros efeitos conhecidos são as modificações no metabolismo da glicose e da insulina, ativação dos sistemas renina angiotensina e nervoso simpático e redução da atividade da via L-argininaláxido nítrico. Estudos clínicos e experimentais têm mostrado uma associação entre a restrição salina e resistência à insulina. Em estudos experimentais prévios verificou-se que o menor consumo de sal na dieta esteve associado à maiores insulinemias durante um teste de tolerância à glicose intravenoso, sem evidência de maior resistência à insulina medida em adipócitos isolados do tecido adiposo peri-epididimal de ratos Wistar. Em outros estudos, utilizando o "clamp" euglicêmico hiperinsulinêmico, verificou-se menor sensibilidade à insulina durante a restrição crônica de sal. Um outro achado foi uma maior meia vida da insulina. O maior peso corporal destes animais e a ativação dos sistemas renina angiotensina e nervoso simpático, além da menor atividade da via L-arginina / óxido nítrico, são possíveis mecanismos responsáveis pela redução da sensibilidade à insulina em resposta à restrição de sal na dieta. Em um outro estudo foi observado que o bloqueio agudo do sistema nervoso simpático com propranoiol e prazozin e a ativação da via L-argininaláxido nítrico melhoraram a sensibilidade à insulina durante o consumo prolongado de dieta hipossódica. Assim, a menor sensibilidade à insulina em resposta à restrição crônica de sal na dieta pode ser corrigida por inibidores do sistema nervoso simpático e por estimulação da via L-arginina / óxido nítrico.
Assuntos
Humanos , Dieta Hipossódica , Hipertensão/prevenção & controle , Resistência à Insulina , Cloreto de Sódio na DietaRESUMO
A pressão arterial varia com o tempo, tanto em indivíduos sadios como em portadores de hipertensão arterial. Esta variabilidade é controlada por mecanismos de regulação que mantêm a pressão dentro de limites estreitos. O único mecanismo de regulação da pressão arterial que é capaz de corrigir integralmente qualquer distúrbio que ocorra é o mecanismo renal denominado natriurese pressórica. Qualquer alteração funcional renal decorrente de patologias renais ou de modificações funcionais devidas a estímulos externos aos rins pode comprometer a natriurese pressórica e gerar aumentos da pressão mantidos cronicamente. A prevalência de hipertensão é de cerca de 90 por cento na presença de doenças renais crônicas. Nestas doenças renais, os seguintes mecanismos foram identificados como possíveis responsáveis pela manutenção de pressão arterial elevada: aumento da volemia, hiperatividade dos sistemas renina-angiotensina nervoso simpático, redução da atividade da via L-arginina- óxido nítrico, aumento de endotelina circulante etc.