Angiotensin-(3-4) normalizes blood pressure, decreases Na+ and energy intake, but preserves urinary Na+ excretion in overweight hypertensive rats.

Hypertension, one of the most common and severe comorbidities of obesity and overweight, is a worldwide epidemic affecting over 30% of the population. We induced overweight in young male rats (aged 58 days) by exposure to a hypercaloric high lipid (HL) diet in which 70% of the calories originated from fat. The HL diet also contained 33 or 57% higher Na+ than the control (CTR) diet. Over the following weeks the HL rats gradually became overweight (490 ± 12 g vs 427 ± 7 g in the CTR group after 15 weeks) with high visceral fat. They developed elevated systolic blood pressure (SBP) (141 ± 1.9 mmHg), which was fully restored to CTR values (128 ± 1.1 mmHg) by oral administration of Ang-(3-4) (Val-Tyr), the shortest renin-angiotensin-derived peptide. The overweight rats had lower plasma Na+ concentration that augmented to CTR values by Ang-(3-4) treatment. Na+ ingestion was depressed by 40% as result of the Ang-(3-4) treatment, whereas the urinary excretion of Na+ (UNaV) remained unmodified. The preservation of UNaV after Ang-(3-4) treatment - despite the sharp decrease in the dietary Na+ intake - can be ascribed to the normalization of renal type 1 angiotensin II receptors and Na+-transporting ATPases, both up-regulated in overweight rats. These renal effects complete a counterregulatory action on elevated renin-angiotensin activity that allows the high SBP to be normalized and body Na+ homeostasis to be restored concomitantly in overweight rats.

Skin capillary density and microvascular reactivity in obese subjects with and without metabolic syndrome.

Obesity is associated with increased cardiovascular morbidity and mortality. We hypothesized that microvascular function may be impaired in obese subjects with metabolic syndrome (OB-MetSnd) compared to obese subjects without MetSnd (OB) and healthy subjects (HS). In this cross-sectional study, we evaluated skin capillary density (SCD) in OB-MetSnd (n=20, 12 women, BMI=36.5±1.1kg/m(2)), OB (n=25, 16 women, BMI=34.5±0.7kg/m(2)), and HS (n=30, 22 women, BMI=22.8±0.3kg/m(2)) groups. SCD was evaluated by intravital video-microscopy at rest and after post-occlusive reactive hyperemia (PORH) and venous congestion (VC). OB-MetSnd subjects exhibited significant differences in the values of MetSnd components and in leptin and HOMA-IR levels compared to OB and HS individuals. There were no differences in SCD among groups in resting conditions. The OB-MetSnd group failed to show a significant increase in the number of recruited capillaries during PORH and VC compared to the SCD evaluated at rest. A negative correlation of SCD with waist circumference, BMI, blood pressure, and HOMA-IR was observed after PORH and VC. When obese subjects were analyzed according to their HOMA-IR quartiles, a significant decrease in SCD was observed during POHR (P=0.02). Our findings showed that obese subjects have structural and functional alterations in skin microcirculation that are proportional to the increase in the degree of global and central obesity. In addition, in OB-MetSnd subjects, the cutaneous capillaries at rest are already maximally recruited, indicating an absence of functional capillary reserve. This may be related to the insulin resistance observed in OB-MetSnd individuals.

Hypoadiponectinemia is associated with prehypertension in obese individuals of multiethnic origin.

BACKGROUND: Considering that prehypertension is associated with an increase in cardiovascular risk, hypoadiponectinemia seems to be a predictor of hypertension. HYPOTHESIS: This study investigated whether adiponectin plasma levels are affected in Brazilian obese prehypertensives compared with those in normotensives and hypertensives. METHODS: The study involved 96 multiethnic obese subjects (mean age = 42.8-11.9 years; BMI = 35.7-7.3 kg/m(2)). Fasting plasma adiponectin and serum insulin were determined by radioimmunoassay. Insulin resistance was estimated by HOMA-IR. Blood pressure was recorded using a calibrated automated sphygmomanometer. RESULTS: Adiponectin concentrations were significantly lower in prehypertensives compared with those in normotensives, but hypertensives exhibited the lowest adiponectin concentrations of all. Regarding the values of HOMA-IR, both prehypertensives and hypertensives were significantly more insulin resistant when compared with normotensives. When normotensives and prehypertensives were classified according to the 50th percentile of adiponectin (< or = vs > 6.5 mg/ml) a logistic regression was performed to estimate the association of this adipokine with hypertension, the lower the plasma adiponectin values, the greater the association. A multivariate linear regression analysis adjusted for cardiometabolic factors showed that systolic blood pressure increased by 1.612 mm Hg for 1 microg/mL reduction in adiponectin plasma levels (P < 0.01). CONCLUSION: Our findings have shown that hypoadiponectinemia is associated with prehypertension in obese individuals of multiethnic origin.

Not all obese subjects of multiethnic origin are at similar risk for developing hypertension and type 2 diabetes.

BACKGROUND: Whether insulin resistance and not obesity per se is the major contributor to clinical outcomes associated with obesity has not been fully established. This study evaluated in a group of obese Brazilians of multiethnic origin to what extent the prevalence of hypertension and other cardiometabolic risk factors varies as a function of the degree of insulin sensitivity. METHODS: The study involved 118 individuals (mean age of 44+/-12 years; BMI=38.6+/-7.9 kg/m(2)) without evidence of diabetes or cardiovascular disease. Insulin resistance was assessed by HOMA-IR index, which was used to stratify patients into tertiles. RESULTS: The mean HOMA-IR in tertile 1, the most insulin-sensitive group, was 2.7+/-0.8 and in tertile 3, the most insulin-resistant group, 9.1+/-2.4 (P<0.001). Mean arterial pressure showed a linear and significant variation across the HOMA-IR tertiles 1, 2, and 3 (94.3+/-11.7; 98.7+/-11.4; 105.0+/-12.4 mm Hg), as did fasting plasma glucose (93.6+/-12.1; 98.1+/-12.7; 100.0+/-11.0 mg/dL), uric acid (4.7+/-1.4; 5.9+/-1.9; 6.3+/-1.4 mg/dL), HDL-cholesterol (48.1+/-11.6; 46.5+/-10.5; 42.2+/-8.0 mg/dL), and plasma adiponectin (7.8+/-3.3; 7.0+/-2.8; 6.3+/-6.5 microg/mL), respectively. The results indicated that 27.5% of our patients had dysglicemia, 28.2% had hypertriglyceridemia, and 30.7% had arterial hypertension in the most insulin-sensitive tertile, when compared with 51%, 53.8% and 79.4%, respectively, in the most insulin-resistant tertile. A stepwise regression analysis showed that only HOMA-IR and age independently affected the risk for increased systolic blood pressure. CONCLUSION: In conclusion, our findings have shown that the risk of developing essential hypertension, type 2 diabetes, and cardiovascular disease is accentuated in obese individuals who are also more insulin resistant.

Association of a common variant of the leptin gene with blood pressure in an obese Brazilian population.

BACKGROUND: This study assessed in obese Brazilians subjects whether a common variant of leptin gene, -2548G>A, is associated with blood pressure changes. METHODS: A total of 140 subjects, 99 women; mean age of 45.2 +/- 12.4 years; body mass index (BMI) = 38.5 +/- 8.0 kg/m2 were included. Blood pressure was recorded using Dinamap 1846 (Critikon, Tampa, FL). Molecular analysis was made by use of PCR and restriction fragment-length polymorphism analysis. Plasma insulin and leptin concentrations were determined by radioimmunoassay. RESULTS: AA homozygotes, in comparison with the G-allele carriers, showed significant lower levels of systolic, diastolic, and mean arterial pressure (120 +/- 10 vs. 132 +/- 17 mm Hg, P = 0.01; 75 +/- 6 vs. 84 +/- 12 mm Hg, P = 0.009; 92 +/- 7 vs. 100 +/- 12 mm Hg, P = 0.007, respectively). The differences in blood pressure remained significant after adjusting for the influence of gender, age, obesity, and body fat distribution as well as for leptin, insulin, and homeostasis model assessment of insulin resistance. A stepwise regression analysis confirmed that the LEP AA genotype independently predicted blood pressure changes. On the other hand, in GG homozygotes, insulinemia showed a significant association with blood pressure values. This suggests that common LEP genotype carriers exhibiting high insulin levels, reflecting an insulin-resistant state, were particularly prone to higher blood pressure levels. CONCLUSIONS: Our results showing that higher blood pressure levels were found with the most prevalent -2548G>A genotype, whereas patients with the AA genotype seemed to be protected from hypertension, indicate that the -2548G>A polymorphism of LEP appears to be an important mediator of obesity hypertension.

Treatment of hypertension in individuals with the cardiometabolic syndrome: role of an angiotensin II receptor blocker, telmisartan.

Arterial hypertension is a global public health problem owing to its high prevalence and association with increased risk for cerebral, cardiac and renal events. Hypertension frequently clusters with other cardiometabolic risk factors, such as dysglycemia, low levels of high-density lipoprotein cholesterol and high triglyceride levels. These, along with other factors such as central obesity, increased inflammation, endothelial dysfunction and thrombosis, are components of the metabolic syndrome. All guidelines recommend that the first-line therapy in metabolic syndrome should be based on lifestyle modification, consisting of diet and moderate exercise for at least 30 min/day. Concerning drug treatment of hypertension associated with other cardiometabolic risk factors, many results of head-to-head studies have demonstrated a reduction in new-onset Type 2 diabetes in hypertensive patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, when compared with conventional antihypertensive therapy. The explanations of the different actions of both these drugs include several mechanisms related to pancreatic insulin release and insulin sensitivity improvement. Another mechanism by which the inhibition of the renin-angiotensin system may improve insulin sensitivity is through the partial peroxisome proliferator-activated receptor-gamma agonism of telmisartan. For that reason, telmisartan has been considered by some experts to be an antihypertensive agent that is particularly useful in the treatment of hypertension associated with cardiometabolic risk factors. The impact of the promising metabolic action exhibited by telmisartan on the outcome of hypertensive patients aggregating other cardiometabolic risk factors waits for adequately randomized and powered clinical trials.

Hypoadiponectinemia is associated with blood pressure increase in obese insulin-resistant individuals.

Adiponectin is a major adipocytokine and has been considered as an independent risk factor for arterial hypertension. Most studies on the subject have been restricted to biracial (white-black) and Asian groups. The present report examined whether adiponectin affects blood pressure in a sample of untreated obese Brazilians of multiethnic origin. Fasting plasma adiponectin and serum insulin were determined by radioimmunoassay. Insulin resistance was estimated by homeostatic model assessment of insulin resistance (HOMA-IR). Blood pressure was recorded using Dinamap 1846 (Critikon, Tampa, FL). Adiponectin was significantly lower in obese hypertensive individuals than in obese normotensive ones. Blood pressure, insulin, and HOMA-IR were significantly higher in obese hypertensive than in obese normotensive individuals. Plasma adiponectin was negatively associated with waist-to-hip ratio, blood pressure, insulin, and HOMA-IR. The comparison of obese individuals who markedly differed in their HOMA-IR (> vs 6. 5 microg/mL), a 3 x 2 analysis of variance showed an independent contribution of adiponectin in the variation of mean arterial pressure. These results support the notion that HOMA-IR and adiponectin independently predict blood pressure variation in obese insulin-resistant Brazilians.

Efeito do urapidil sobre a pressão arterial, hemodinâmica renal, metabolismo lipídico e glicídico / The effect of urapidil on blood pressure, renal hemodynamics, lipid and glucose metabolism

PURPOSE--To evaluate the effects of urapidil on blood pressure (BP), renal hemodynamics and lipid and glucose metabolism, in patients with mild-to-moderate uncomplicated essential hypertension. METHODS--Fifteen hypertensive patients, aged 38-64 year-old were studied by ambulatory blood pressure monitoring system (ABPM). It was also evaluated: 1) the creatinine clearance; 2) the effective renal plasma flow by use of a single plasma sample after injection of orthoiodohippurate; 3) the serum triglycerides, cholesterol, and HDL-cholesterol; 4) blood levels of glucose and insulin. The urapidil dose ranged from 60 to 180 mg/day, according to the individual response. RESULTS--The values after four weeks washout-placebo and active treatment with urapidil showed: the systolic/diastolic BP was reduced from 157.7 +/- 6/108.0 +/- 2 on placebo to 140.4 +/- 4/97.3 +/- 3 mmHg (p < 0.05/p < 0.01) after urapidil, respectively, whereas heart rate was unchanged. The percentage of elevated systolic and diastolic BP values during 24h (BP load) was reduced from 60.9 to 54.4 and from 60.8 to 50.3, respectively. Effective renal plasma flow, glomerular filtration rate, filtration fraction and renal vascular resistance were unaltered by treatment. Significant increase in HDL-cholesterol was observed (from 39.5 +/- 3.6 on placebo vs 49.2 +/- 4.8 mg/dl (p < 0.01) after urapidil. Total cholesterol, LDL-cholesterol and triglycerides levels were not modified with treatment. Circulating plasma glucose and insulin remained unchanged. CONCLUSION--Urapidil is an effective antihypertensive agent without deleterious effect on renal hemodynamics, lipid and glucose metabolism.

Objetivo − Avaliar os efeitos do urapidil sobre a pressão arterial, hemodinâmica renal, metabolismo lipídico e glicídico em portadores de hipertensão arterial sistêmica primária leve a moderada. Métodos − Foram analisados 15 pacientes hipertensos, com idades entre 38 e 64 anos, utilizando-se a técnica da monitorização ambulatorial da pressão arterial (MAPA) em 24h, avaliando-se, também, os clearances de creatinina e do hipuran radioativo, espectrofotometria de cristal sólido e as dosagens do colesterol e triglicérides séricos, do HDL-colesterol, da glicemia e insulina. As doses de urapidil variaram de 60 a 180mg/dia, administradas 2 ou 3 vezes, de acordo com cada caso. A avaliação durou pelo menos 6 semanas. Resultados − Os parâmetros analisados após 4 semanas de washout-placebo e tratamento com urapidil revelaram: 1) redução significante das pressões sistólica e diastólica (157,7±6 e 108±2 na fase placebo para 140,4±4 e 97,3±3mmHg, p<0,05; p<0,01, respectivamente); 2) o fluxo plasmático renal efetivo, ritmo de filtração glomerular, fração de filtração e resistência vascular renal não sofreram mudanças significantes; 3) aumento significante na concentração sérica das HDLcolesterol (39,5±3,6 para 49,2±4,8mg/dl, p<0,01), sem modificações nos níveis séricos do colesterol total, LDL colesterol e triglicérides; 4) as curvas glicêmicas e insulínicas não se alteraram. Conclusão − O urapidil reduziu a pressão arterial sem promover alterações na hemodinâmica renal, metabolismo lipídico e glicídico