Increase of postheparin plasma-lipoprotein-lipase activity in ventromedial-hypothalamic obesity in rats

Postheparin plasma-lipoprotein lipase (LPL) and hepatic triglyceride lipase (H-TGL) were investigated in rats 1 week after ventromedial-hypothalamic lesions. The enzyme activities were measured using radio-labelled triolein as a substrate. Two lipases were measured separately using specific antiserum prepared against H-TGL. VMH-lesioned rats fed ad lib. showed an increase in plasma LPL with normal H-TGL activity and an elevation of plasma insulin. There was a positive correlation between plasma-LPL activity and insulin levels in VMH-lesioned rats. When rats were examined after overnight fast, VMH-lesioned rats again showed an increase in plasma LPL with normal H-TGL activity and an elevation of plasma insulin. There was also a positive correlation between plasma LPL activity and insulin levels. In order to examine the effect of insulin, rats were treated with daily doses of 3 units of insulin for 1 week. Rats fed ad lib. were insulin treatment showed an increase in plasma LPL with normal H-TGL activity. These results indicate that hyperinsulinemia which was produced by VMH lesions may increase postheparin plasma-LPL activity. We speculate that this increase in plasma-LPL activity mainly reflects that of adipose tissue. The increase of LPL activity can accelerate fat deposition into adipose tissue, contributing to one of the factors causing hypothalamic obesity.     

Central alpha-adrenoceptors during the development of hypertension in rats on high and low salt intake

Our purpose was to investigate the binding characteristics of central alpha-adrenoceptors during the early stages of the development of hypertension in rats on high and low salt (NaCl) intake. We measured alpha 1-[( 3H]prazosin) and alpha 2-[( 3H]rauwolscine) binding in membranes of the hypothalamus and medulla oblongata of six groups of young Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and subtotally nephrectomized WKY (SN) rats with mean arterial blood pressure (MAP) ranging from normotensive to hypertensive levels after 1 week of salt restriction or loading. In the hypothalamus the SN-high salt rats and both SHR groups had elevated alpha 1-number but there was no change in alpha 2-number. Moreover, MAP was positively correlated with mean hypothalamic alpha 1-number in the six groups. In the medulla oblongata alpha 1-number was unaffected. However, high salt diet influenced medullary alpha 2-binding in the opposite manner in WKY rats versus SN rats and SHR. In these latter groups the affinity was increased and the number decreased in response to high salt intake. Furthermore, a positive correlation between MAP and mean alpha 1:alpha 2 ratio existed in both the hypothalamus and the medulla of the six groups. The data suggest that hypothalamic alpha 1-binding capacity was increased in SHR due principally to a genetic condition which is mimicked by salt loading in the SN rats. Medullary alpha 2-adrenoceptors of WKY, which remained normotensive despite salt loading, responded differently to high salt intake than those of the SN and SHR, whose blood pressure rose significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Perinatal salt intake alters blood pressure and salt balance in hypertensive rats

Blood pressure and the rate of excretion of an oral salt load were examined in spontaneously hypertensive rats of the Okamoto strain after exposure in utero and during suckling to a high salt (3% NaCl, wt/wt), low salt (0.1%), control salt (0.8%), or high potassium (2.2% KCl, wt/wt) [corrected] maternal diet. After weaning, all offspring were given a diet containing 0.8% NaCl. There were small but significant differences in growth rate among offspring groups over the 60 weeks of observation, with rats exposed to perinatal low salt and high salt diet being lighter than those given control or high potassium diet. There were positive, significant correlations between body weight and blood pressure in all dietary groups at 8 weeks of age but not 16 or 24 weeks. Rats exposed to perinatal low salt diet had significantly lower blood pressures than the other three groups, which had similar blood pressures. Low salt rats also exhibited an exaggerated natriuresis after a single, oral salt load (0.15 M saline, 1% body weight) compared with the other three diet groups, which were not different from each other. High potassium rats had a reduced kaliuresis and diuresis after the salt load when compared with the other three groups. At 60 weeks of age, rats that received perinatal low salt diet had significantly heavier adrenal glands when compared with the other groups, and the high potassium group had significantly elevated plasma renin concentrations. Thus, maternal electrolyte intake during the perinatal phase may alter body fluid homeostasis in genetically susceptible individuals at maturity.     

Hypertension in children with obesity

The prevalence of obesity related hypertension has dramatically increased in children with the parallel increase in pediatric obesity. This pediatric health problem may adversely affect cardiovascular health in adult life. The pathogenesis of hypertension in obese children is not widely understood. We therefore undertake this review to raise public awareness. Early childhood parameters like birth weight and postnatal weight gain may play important roles in risk for obesity and obesity related hypertension later in childhood and adult life. Further information is required to confirm this origin of hypertension so that appropriate measures are taken in the peri-natal period. The role of sympathetic nervous system has now been well established as one of the principle mechanisms involved in obesity related hypertension. The Renin-Angiotensin system, insulin resistance due to obesity and as a part of metabolic syndrome along with imbalance in adipokines such as leptin and adiponectin, cause activation of the sympathetic system, vasoconstriction, endothelial dysfunction and sodium reabsorption among other perturbations. Multi-step interventions targeting these various mechanisms are required to break the cycle of obesity and metabolic syndrome. Vitamin D deficiency, sleep apnea due to airway obstruction and hyperuricemia may also play a significant role and should not be ignored in its early stages. Obesity is a risk factor for other co-morbid conditions like chronic kidney disease and fatty liver which further accentuate the risk of hypertension. Increased awareness is required to prevent, diagnose and treat obesity related hypertension among the pediatric population.     

Sympathetic activity and food intake of rats with ventromedial hypothalamic lesions

Following ventromedial hypothalamic lesions, food intake increased from 60 to slightly more than 77 kcal/day during the first 6 days. Body weight increased and sympathetic activity, as measured by the electrical firing rate of efferent nerves to interscapular brown adipose tissue, decreased significantly. During a 6-day period of intragastric overfeeding in which animals with hypothalamic lesions received 60 kcal for the first day and 80 kcal for the remaining 5 days, the VMH-lesioned animals gained significantly more weight than the intact, sham-lesioned controls. This difference in weight gain was paralleled by the increased weight of liver and white adipose tissue. The lesioned animals showed a highly significant reduction in sympathetic activity compared to the normal or slightly increased values observed in the sham-lesioned animals. These studies are consistent with the hypothesis that food-induced increases in sympathetic activity are modulated by the ventromedial hypothalamus.     

Hypertension and obesity

Obesity, as defined by bodily weight (body weight) and by bodily conformation-derived variables, accompanies hypertension in many patients. Both conditions are independent cardiovascular risk factors. In a formal survey carried out in the adult general population of Uruguay (LATIR Study, 575 adult and elderly subjects of whom 41.6% were males), we found the prevalence of hypertension to be 28.5% (95% CI: 24.9-32.4%) and that 74.4% of hypertensive individuals had a body mass index (BMI) higher than 25 kg/m(2) (95% CI: 67.0-80.8%). This association between obesity and hypertension forms part of a broader relationship between body weight and blood pressure (BP). In the general population, BP bears a positive linear correlation with BMI and waist-to-hip ratio over the continuous ranges of normal and unfavourable values of these three variables (r = 0.42, P < 0.001 for the correlation between BMI and mean BP, LATIR Study). Patients who present hypertension and obesity usually present other unfavourable conditions for cardiovascular prognosis, including changes in carbohydrate and lipid metabolism, hyperuricaemia, left ventricular hypertrophy, and/or the obstructive sleep apnoea syndrome. On average, hypertension is salt-sensitive in obese patients, and plasma volume and cardiac index are increased. Adequate control of body weight results in substantial reductions in total blood volume, cardiac output, BP and left ventricular mass, and in an amelioration or the disappearance of sleep apnoea. Adequate sodium intake restriction must form part of any diet prescribed to obese hypertensive patients. Various drug classes may be used to treat hypertension efficaciously in patients who also present obesity.     

Hypertension in obesity

AIM: To review various topics regarding the relationship between obesity and hypertension. DATA SUMMARY: Obesity is a widespread and increasingly prevalent condition associated with a large number of comorbid diseases, one of the most important of which is obesity-induced hypertension (HTN). The association between obesity and HTN has been well documented in most racial, ethnic and socio-economic groups, although the relationship between body mass index (BMI) and blood pressure values depends on age, gender, type of obesity and race differences. Obesity-induced HTN has some unique characteristics that differ from those observed in lean hypertensive patients. The hemodynamic profile of obese subjects is characterised by high cardiac output, high plasma and total blood volume, and inappropriately normal to total peripheral resistance. Clinically, hypertensive obese subjects are more likely to develop left ventricular hypertrophy and kidney damage than their lean counterparts. Various common factors are involved in establishing sodium retention and vascular resistance and may be critically influenced by the neurobiological/genetic mechanisms leading to obesity, in which insulin, leptin and the adrenergic system play major roles. Obesity is one of the main causes of therapeutic failure, and a number of studies have demonstrated that obese subjects need more antihypertensive drugs than sex and age-matched lean hypertensives. Long-term dietary treatment, consisting of a moderate restriction of energy and salt intake, is the most effective and safe treatment for obesity-associated HTN. The use of treatments other than calorie restriction should be considered with caution. Drugs that increase energy expenditure or reduce appetite may variably increase blood pressure (BP) and are unsuitable for hypertensive subjects. There do not seem to be any clear differences in the efficacy of the various antihypertensive drug classes. The clustering of cardiovascular risk factors other than HTN needs to be taken into account when choosing antihypertensive treatment for obese subjects. CONCLUSIONS: Obesity is a highly prevalent condition that causes or exacerbates many health problems including HTN. Combined interventions at different levels can help in losing weight and therefore reduce the cardiovascular risk, morbidity and mortality associated with obesity.     

Hypertension in obesity

Hypertension and obesity are major components of the cardiometabolic syndrome and are both on the rise worldwide, with enormous consequences on global health and the economy. The relationship between hypertension and obesity is multifaceted; the etiology is complex and it is not well elucidated. This article, reviews the current knowledge on obesity-related hypertension. Further understanding of the underlying mechanisms of this epidemic will be important in devising future treatment avenues.     

Mineralocorticoid regulation of salt intake is preserved in hippocampectomized rats

Considering the high concentration of binding sites for [3H]-aldosterone in the hippocampus, a relationship between these sites and the regulation of sodium appetite by aldosterone was investigated. After surgical hippocampectomy, rats showed an approximately 80% depletion of [3H]-aldosterone binding sites. In spite of this reduction, hippocampectomized rats developed a sodium appetite after adrenalectomy; this sodium appetite was suppressed by continuous administration of aldosterone, a response similar to the pattern found in normal rats. These results suggest that the hippocampus is not the main target of the effect of the hormone on salt intake.     

A gene expression analysis in rat kidney following high and low salt intake

BACKGROUND : The effects of salt intake on renal regulation have been investigated for decades. To find new pathways and to demonstrate the utility of oligonucleotide expression arrays, we studied whole kidneys. METHODS : Eight Sprague-Dawley rats were divided into two groups. One group received a 6% salt (by weight) diet, while the other group received a 0.3%, otherwise identical, salt diet for 7 days. The rats were sacrificed after 7 days and the left kidney was subjected to RNA extraction. Oligonucleotide expression arrays (Affymetrix) were used to determine downregulation and upregulation, comparing high with low salt intake. Four rats from each group were studied separately. RESULTS : The experiments were reproducible. Thirty genes were downregulated with the high-salt diet, while 35 genes were upregulated. The renin gene, beta-2 glycoprotein-1, retinol binding protein, annexin VI, and the PTP2C protein tyrosine phosphatase were among the downregulated genes. The angiotensin II receptor type 1B receptor, HMG-CoA reductase, B7 antigen, and the rat calcium channel beta subunit III were among the upregulated genes. Differentially regulated were the p55 subunit (upregulated) and the p50 subunit (downregulated) of the phosphatidyl inositol 3-kinase enzyme complex. We verified our results by selecting a high-salt downregulated gene (renin) and an upregulated gene (B7 antigen) and subjecting these genes to real-time polymerase chain reaction. The results were consistent. CONCLUSION : Oligonucleotide expression arrays can detect novel genes encoding for proteins not generally associated with responses to varied salt intake. Experiments of this nature have substantial limitations and require detailed verification. However, overall, the utility is promising.     

Reductions in caloric intake and early postnatal growth prevent glucose intolerance and obesity associated with low birthweight

Aims/hypothesis Low birthweight (LBW) and rapid postnatal weight gain, or catch-up growth, are independent risk factors for the development of obesity and diabetes during adult life. Individuals who are both small at birth and have postnatal catch-up growth are at the highest risk. We hypothesised that dietary interventions designed to attenuate catch-up growth in LBW subjects may have long-term beneficial consequences.Materials and methods We used our previously described mouse model of LBW-associated diabetes, created by restricting maternal food intake to 50% during the last week of gestation. Control (C) dams and dams that had been subjected to undernutrition (U) were then provided either chow ad libitum after delivery or 50% food restriction on a per-day basis from delivery until weaning. We designated the resulting four groups control-control (CC), undernutrition-control (UC), control-undernutriton (CU) and undernutrition-undernutrition (UU), indicating the prenatal and postnatal experimental conditions, respectively. Carbohydrate metabolism and adiposity were assessed prospectively in offspring until age 6 months.Results Males that were small at birth and exhibited early postnatal catch-up growth developed glucose intolerance and obesity by age 6 months. In contrast, LBW mice without catch-up growth (UU) remained smaller than controls (CC), and glucose intolerance and obesity was prevented. Similarly, mice with normal birthweight that had blunted catch-up growth (CU) were leaner and had better tolerance test than CC mice. Catch-up growth during the first week of life correlated better than birthweight with glucose, fat mass and glucose tolerance up to 6 months of age.Conclusions/interpretation Prevention of early catch-up growth reversed the development of glucose intolerance and obesity in our mouse model of LBW-associated diabetes.     

Osteoporosis and salt intake

AIM: Recently, it has been hypothesized that salt intake may be related to the risk of osteoporosis. The aim of this review was to summarize the evidence for such relationship and to discuss possible mechanisms. DATA SYNTHESIS: We performed a review of the scientific literature on osteoporosis, particularly its etiology, and then focussed on studies addressing the relation between salt intake on the one hand, and calcium balance, bone resorption, bone mineral density and fractures on the other. Although a relation between high salt intake and increased bone loss is biologically plausible, the most pertinent studies relating salt intake to bone mineral density are only suggestive of high salt consumption as a risk factor for osteoporosis. Unfortunately, studies on fracture risk and salt intake are lacking. CONCLUSION: The relationship between salt intake and osteoporosis is still controversial. A possible relation between salt intake and fracture risk should be addressed in future studies.     

High salt intake potentiates the renal vascular and glomerular damage caused by low doses of angiotensin II in uni-nephrectomized rats.

OBJECTIVE: We recently reported that the renin-angiotensin system plays an important role in the progression of vascular and kidney injuries, even in Dahl salt-sensitive rats with volume-dependent hypertension. In this study, we investigated whether a high-salt diet increases susceptibility to kidney injury induced by angiotensin II in normotensive, uni-nephrectomized Sprague-Dawley rats, which mimics the condition of salt-volume repletion and blunted renin-angiotensin system. METHODS: The rats were fed either a low-salt (0.3% NaCl) or a high-salt (4% NaCl) diet and divided into five groups: two control groups with a low-salt or a high-salt diet without angiotensin II infusion (saline infusion), and three angiotensin II groups (angiotensin II infusion, 10 or 50 ng/kg per min with high-salt diet, 50 ng/kg per min with low-salt diet, subcutaneously). The rats were kept on these regimes for 8 weeks. The blood pressure was measured every week. Functional and morphological alterations in the kidney were assessed at the end of the experiment RESULTS: There were no differences in the arterial blood pressures of the five experimental groups. However, angiotensin II infusion increased the weights of the heart and aortic walls in a dose-dependent manner in the high-salt groups. There was also a dose-dependent increase in proteinuria, N-acetyl-beta-D-glucosaminidase activity (NAG) excretion, and additional glomerular and arterial injuries in the kidney, associated with angiotensin II infusion in the high-salt groups. In the rats given a higher dose of angiotensin II, the high-salt diet significantly increased the weights of the heart and aortic walls and exacerbated the renal function and morphological injuries, compared to the low-salt group. High-salt diet alone increased the kidney and heart weights. However, it did not significantly influence the results of the morphological and functional study. On the other hand, angiotensin II infusion on a low-salt diet showed a trend towards glomerular damage; however, the effects were small and not significant. Similarly, there were few effects of angiotensin II infusion on morphology and functional study on a low-salt diet CONCLUSION: These data clearly show that a high-salt intake increases susceptibility of the kidney to injuries induced by low doses of angiotensin II in normotensive, uni-nephrectomized rats.     

Inhibition of hypertension and salt intake by oral taurine treatment in hypertensive rats

Effects of oral treatment with taurine on fluid intakes produced by renin were assessed in spontaneously hypertensive rats of the Okamoto strain (SHR). Renin injected into the preoptic area increased water intake and evoked salt (2.7% NaCl solution) intake, and angiotensin II injected into this area increased water intake, but not salt intake, in both SHR and control normotensive Wistar-Kyoto rats (WKY). The salt intake elicited by renin, but not water intake produced by renin or angiotensin II, was potentiated in SHR. These effects of renin and angiotensin II on fluid intakes were antagonized by previous administration of taurine or gamma-aminobutyric acid into the cerebral ventricles in both strains. When SHR received water containing 3% taurine from 32 to 105 days of age, development of hypertension was inhibited. Renin administered into the preoptic area at 105 days of age caused an increase in salt intake, but the increase was markedly inhibited by the oral administration of taurine as well. These results show that salt appetite produced by centrally administered renin is exaggerated in SHR and that development of hypertension as well as renin-induced salt appetite in SHR is inhibited by dietary taurine.     

Cardiac hypertrophy and cardiac renin-angiotensin system in Dahl rats on high salt intake

OBJECTIVE: On high salt intake, Dahl salt-sensitive rats develop cardiac hypertrophy disproportionate to the degree of hypertension. In the present studies, we assessed whether the cardiac hypertrophy induced by high salt depends on the development of hypertension per se, and leads to over-activity of the cardiac renin-angiotensin system (RAS). METHODS: Cardiac angiotensin converting enzyme (ACE) mRNA and activity, cardiac and plasma angiotensin I and II (AngI, II), as well as plasma renin activity (PRA) were assessed in Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats on high (1370 micromol/g food) or regular salt (120 micromol/g food) diet for 2-5 weeks. Cardiac ACE and hypertrophic response in Dahl S on high salt were also assessed after central blockade of sympathetic hyperactivity and hypertension. RESULTS: In Dahl S rats, ACE mRNA and activity of the left ventricle (LV) increased markedly after 4-5 weeks of high salt diet compared with Dahl S on the control diet and Dahl R on either diet Chronic intra-cerebroventricular treatment with Fab fragments blocking brain 'ouabain' prevented the hypertension by high salt in Dahl S rats but did not affect the salt-induced increases in LV weight or in LV ACE mRNA and activity. On regular salt diet, Dahl S rats demonstrated significantly lower cardiac AngI and AngII than Dahl R rats. However, high salt intake did not cause significant changes in cardiac AngI and II in either strain. On regular salt diet, PRA, plasma AngI and II were all significantly lower in Dahl S versus R. In Dahl S rats, high salt did not cause further decreases of the already low PRA or plasma AngI and II. CONCLUSIONS: These data indicate a low activity of both circulatory and cardiac RAS in Dahl S versus R rats. The marked cardiac hypertrophy and increase in cardiac ACE mRNA and activity induced by high salt in Dahl S do not depend on the increase in blood pressure. High salt intake did not increase cardiac AngII in Dahl S, suggesting that the increase in ACE mRNA and activity may be relevant for non-angiotensinergic mechanisms involved in cardiac hypertrophy.