Sex-specific effects of spironolactone on blood pressure in gonadectomized male and female Wistar rats

A low-salt diet is known to decrease and salt excess to increase blood pressure in humans and rodents. Sex steroids seem to play a role in salt dependent hypertension. However, little is known about sex differences in mineralocorticoid receptor blockade between male and female rats. The objective of the work was at first to investigate the effects of a low-salt vs. a high-salt diet on blood pressure without the influence of gonadal steroids in male and female rats. Second, to determine the sex-specific effects of mineralocorticoid receptor blockade by spironolactone in high-salt and low-salt fed gonadectomized male and female animals. Normotensive male and female Wistar rats were gonadectomized and put on a low (NaCl<0.03%) or high (NaCl=4%) salt diet. On each diet animals received spironolactone or placebo. Blood pressure was measured by tail-cuff-method; 24-h urine samples were collected in metabolic cages and blood was collected for hormonal measurements. High-salt diet significantly increased systolic blood pressure in both sexes. This effect could be blocked effectively by spironolactone only in male rats. Spironolactone treatment significantly increased aldosterone levels in males and females independent of the sodium content of the diet. High sodium diet significantly increased relative kidney weight, which was not altered by spironolactone treatment. Independently of gonadal steroids a high-salt diet increased blood pressure in gonadectomized male and female rats. Spironolactone lowered blood pressure only in male not in female rats on a high-salt diet clearly indicating sex-specific effects of the mineralo-corticoid antagonist spironolactone.     

Sodium balance, arterial pressure, and the role of the subfornical organ during chronic changes in dietary salt

The subfornical organ (SFO), one of the brain circumventricular organs, is known to mediate some of the central effects of angiotensin II related to sodium and water homeostasis. Because angiotensin II levels are altered with changes in chronic dietary salt intake, we reasoned that the actions of angiotensin II at the SFO might be involved in the regulation of arterial pressure during long-term alterations in dietary salt. The present study was designed to test the hypothesis that long-term control of arterial pressure during chronic changes in dietary salt intake requires an intact SFO. Male Sprague-Dawley rats were randomly selected for electrolytic lesion (SFOx, n = 8) or sham (n = 9) operation of the SFO. After a 1-wk recovery period, rats were instrumented with radio-telemetric blood pressure transducers for continuous 24-h measurement of mean arterial pressure (MAP) and heart rate (HR) and then were placed individually in metabolic cages. After another 1 wk of recovery, the rats were subjected to a 49-day protocol as follows: 1) a 7-day control period (1.0% NaCl diet), 2) 14 days of high-salt (4.0% NaCl) diet, 3) 7 days of normal-salt (1.0% NaCl) diet, 4) 14 days of low-salt (0.1% NaCl) diet, and 5) 7 days of recovery (1.0% NaCl diet). There were no significant differences in MAP or HR between SFOx and sham-operated rats throughout the protocol. These results do not support the hypothesis that the SFO is necessary for regulation of arterial pressure during chronic changes in dietary salt. However, SFOx rats demonstrated significantly less cumulative sodium balance than sham-operated rats on days 2-6 of the high-salt diet period. These data suggest that the SFO is important in the regulation of sodium homeostasis during chronic changes in salt intake.     

The importance of sodium and chloride ions for the development of DOCA-NaCl hypertension: a haemodynamic study

The role of sodium and its accompanying anion for the development of DOCA-salt hypertension was studied in uninephrectomized DOCA-treated weanling Wistar rats which were fed a diet containing either sodium chloride or sodium bicarbonate (170 mmol/kg). The blood pressure was increased in both groups of rats with sodium overload as compared to rats fed a low-salt diet only. A decreased cardiac output and substantially elevated systemic resistance were demonstrated in both groups of rats with high sodium intake in comparison with rats kept on a low-salt diet. However, these haemodynamic changes were more pronounced in rats with sodium chloride overload than in animals with a high sodium bicarbonate intake. On the other hand, the rigidity of major arteries which was estimated as the pulse pressure/stroke volume ratio, was increased only in rats fed a diet with sodium chloride but not in rats with sodium bicarbonate overload. Thus high sodium intake was responsible for the changes of systemic resistance in DOCA-treated animals and its action was only slightly augmented by a high chloride intake. In contrast to this, the chloride overload seemed to be essential for the induction of increased arterial rigidity.     

Elevated salt intake impairs dilation of rat skeletal muscle resistance arteries via ANG II suppression

Vasodilator responses were assessed in resistance arteries (100-200 microm) isolated from the gracilis muscle of normotensive rats after changes in dietary salt intake. Sprague-Dawley rats were maintained on either a high-salt (HS) diet (4.0% NaCl) or a low-salt (LS) diet (0.4% NaCl) for 4-8 wk (chronic) or 3 days (short-term) with water ad libitum. One group of short-term HS rats received a continuous intravenous infusion of a low dose (5 ng x kg(-1) x min(-1)) of ANG II to prevent the ANG II suppression that occurs with HS diet. Short-term and chronic HS diet eliminated arterial dilation in response to ACh and reduced PO(2) (30-40 mmHg) and the stable prostacyclin analog iloprost. ANG II infusion preserved the response to these vasodilator stimuli in short-term HS animals. Dilator responses to sodium nitroprusside and forskolin were unaffected by HS diet. These findings suggest that ANG II suppression during HS diet impairs vascular relaxation mechanisms upstream from the cAMP and cGMP second messenger systems.     

Salt-induced ANG II suppression impairs the response of cerebral artery smooth muscle cells to prostacyclin

Recent studies have demonstrated that cerebral arteries from rats fed a high-salt (HS) diet exhibit impaired vasodilation and altered electrophysiological response to reduction in PO2. The present study examined whether an increase in salt intake alters the response of vascular smooth muscle cells (VSMC) to prostacyclin, a crucial mediator of hypoxic dilation in cerebral arteries. VSMC were isolated from cerebral arteries of male Sprague-Dawley rats maintained on an HS (4% NaCl) or a low-salt diet (0.4% NaCl) for 3 days. The stable prostacyclin analog iloprost (10 ng/ml) inhibited serotonin (0.1-10 microM)-induced contractions and the increase in intracellular Ca2+ concentration ([Ca2+]i) in VSMC isolated from arteries of animals fed the low-salt diet. In contrast, iloprost had no effect on serotonin-induced contractions and increases in [Ca2+]i in VSMC isolated from arteries of rats fed the HS diet. Preventing the fall in ANG in rats fed the HS diet by infusion of a low dose of ANG II (5 ng.kg(-1).min(-1) i.v.) restored the inhibitory effect of iloprost on serotonin-induced contractions and increases in [Ca2+]i in VSMC from animals fed the HS diet. These effects were reversed by AT1 receptor blockade with losartan. These results indicate that ANG II suppression secondary to elevated dietary salt intake impairs vascular relaxation and Ca2+ regulation by prostacyclin.     

Renal denervation chronically lowers arterial pressure independent of dietary sodium intake in normal rats

The present study was designed to test the hypothesis that renal nerves chronically modulate arterial pressure (AP) under basal conditions and during changes in dietary salt intake. To test this hypothesis, continuous telemetric recording of AP in intact (sham) and renal denervated (RDNX) Sprague-Dawley rats was performed and the effect of increasing and decreasing dietary salt intake on AP was determined. In protocol 1, 24-h AP, sodium, and water balances were measured in RDNX (n = 11) and sham (n = 9) rats during 5 days of normal (0.4% NaCl) and 10 days of high (4.0% NaCl) salt intake, followed by a 3-day recovery period (0.4% NaCl). Protocol 2 was similar with the exception that salt intake was decreased to 0.04% NaCl for 10 days after the 5-day period of normal salt (0.04% NaCl) intake (RDNX; n = 6, sham; n = 5). In protocol 1, AP was lower in RDNX (91 +/- 1 mmHg) compared with sham (101 +/- 2 mmHg) rats during the 5-day 0.4% NaCl control period. During the 10 days of high salt intake, AP increased <5 mmHg in both groups so that the difference between sham and RDNX rats remained constant. In protocol 2, AP was also lower in RDNX (93 +/- 2 mmHg) compared with sham (105 +/- 4 mmHg) rats during the 5-day 0.4% NaCl control period, and AP did not change in response to 10 days of a low-salt diet in either group. Overall, there were no between-group differences in sodium or water balance in either protocol. We conclude that renal nerves support basal levels of AP, irrespective of dietary sodium intake in normal rats.     

Renal endothelin in chronic angiotensin II hypertension

To determine the influence of chronic ANG II infusion on urinary, plasma, and renal tissue levels of immunoreactive endothelin (ET), ANG II (65 ng/min) or saline vehicle was delivered via osmotic minipump in male Sprague-Dawley rats given either a high-salt diet (10% NaCl) or normal-salt diet (0.8% NaCl). High-salt diet alone caused a slight but not statistically significant increase (7 +/- 1%) in mean arterial pressure (MAP). MAP was significantly increased in ANG II-infused rats (41 +/- 10%), and the increase in MAP was significantly greater in ANG II rats given a high-salt diet (59 +/- 1%) compared with the increase observed in rats given a high-salt diet alone or ANG II infusion and normal-salt diet. After a 2-wk treatment, urinary excretion of immunoreactive ET was significantly increased by approximately 50% in ANG II-infused animals and by over 250% in rats on high-salt diet, with or without ANG II infusion. ANG II infusion combined with high-salt diet significantly increased immunoreactive ET content in the cortex and outer medulla, but this effect was not observed in other groups. In contrast, high-salt diet, with or without ANG II infusion, significantly decreased immunoreactive ET content within the inner medulla. These data indicate that chronic elevations in ANG II levels and sodium intake differentially affect ET levels within the kidney and provide further support for the hypothesis that the hypertensive effects of ANG II may be due to interaction with the renal ET system.     

Mechanisms of pressure-diuresis and pressure-natriuresis in Dahl salt-resistant and Dahl salt-sensitive rats

ABSTRACT: BACKGROUND: Data on blood flow regulation, renal filtration, and urine output in salt-sensitive Dahl S rats fed on high-salt (hypertensive) and low-salt (prehypertensive) diets and salt-resistant Dahl R rats fed on high-salt diets were analyzed using a mathematical model of renal blood flow regulation, glomerular filtration, and solute transport in a nephron. RESULTS: The mechanism of pressure-diuresis and pressure-natriuresis that emerges from simulation of the integrated systems is that relatively small increases in glomerular filtration that follow from increases in renal arterial pressure cause relatively large increases in urine and sodium output. Furthermore, analysis reveals the minimal differences between the experimental cases necessary to explain the observed data. It is determined that differences in renal afferent and efferent arterial resistance are able to explain all of the qualitative differences in observed flows, filtration rates, and glomerular pressure as well as the differences in the pressure-natriuresis and pressure-diuresis relationships in the three groups. The model is able to satisfactorily explain data from all three groups without varying parameters associated with glomerular filtration or solute transport in the nephron component of the model. CONCLUSIONS: Thus the differences between the experimental groups are explained solely in terms of difference in blood flow regulation. This finding is consistent with the hypothesis that, if a shift in the pressure-natriuresis relationship is the primary cause of elevated arterial pressure in the Dahl S rat, then alternation in how renal afferent and efferent arterial resistances are regulated represents the primary cause of chronic hypertension in the Dahl S rat.     

Elevated dietary salt suppresses renin secretion but not thirst evoked by arterial hypotension in rats

Increased dietary salt intake was used as a nonpharmacological tool to blunt hypotension-induced increases in plasma renin activity (PRA) in order to evaluate the contribution of the renin-angiotensin system (RAS) to hypotension-induced thirst. Rats were maintained on 8% NaCl (high) or 1% NaCl (standard) diet for at least 2 wk, and then arterial hypotension was produced by administration of the arteriolar vasodilator diazoxide. Despite marked reductions in PRA, rats maintained on the high-salt diet drank similar amounts of water, displayed similar latencies to drink, and had similar degrees of hypotension compared with rats maintained on the standard diet. Furthermore, blockade of ANG II production by an intravenous infusion of the angiotensin-converting enzyme inhibitor captopril attenuated the hypotension-induced water intake similarly in rats fed standard and high-salt diet. Additional experiments showed that increases in dietary salt did not alter thirst stimulated by the acetylcholine agonist carbachol administered into the lateral ventricle; however, increases in dietary salt did enhance thirst evoked by central ANG II. Collectively, the present findings suggest that hypotension-evoked thirst in rats fed a high-salt diet is dependent on the peripheral RAS despite marked reductions in PRA.     

Angiotensin II infusion restores stimulated angiogenesis in the skeletal muscle of rats on a high-salt diet

Elevated dietary salt intake has previously been demonstrated to have dramatic effects on microvascular structure and function. The purpose of this study was to determine whether a high-salt diet modulates physiological angiogenesis in skeletal muscle. Male Sprague-Dawley rats were placed on a control diet (0.4% NaCl by weight) or a high-salt diet (4.0% NaCl) before implantation of a chronic electrical stimulator. After seven consecutive days of unilateral hindlimb muscle stimulation, animals on control diets demonstrated a significant increase in microvessel density in the tibialis anterior muscle of the stimulated hindlimb relative to the contralateral control leg. High salt-fed rats demonstrated a complete inhibition of this angiogenic response, as well as a significant reduction in plasma ANG II levels compared with those of control animals. To investigate the role of ANG II suppression on the inhibitory effect of high-salt diets, a group of rats that were fed high salt were chronically infused with ANG II at a low dose. Maintenance of ANG II levels restored stimulated angiogenesis to control levels in animals fed a high-salt diet. Western blot analysis indicated that inhibition of angiogenesis in high salt-fed rats was not due to changes in VEGF or VEGF receptor type 1 protein expression in response to stimulation; however, the degree to which VEGF receptor 2 protein increased with stimulation was significantly lower in high salt-fed animals. This study demonstrates an inhibitory effect of high salt intake on stimulated angiogenesis and suggests a critical role for ANG II suppression in mediating this antiangiogenic effect.     

Oxytocin, water intake, and food sodium availability in male rats

This study examined the effect of subcutaneous administration of the neurohormone oxytocin on water intake of ad lib-fed (with or without sodium availability in the diet) and food-deprived animals. Results of the first experiment showed that oxytocin increased water intake and urine excretion in food-deprived but not in ad lib-fed animals. However, oxytocin treatment did not modify the reduced water "balance" (fluid intake minus urine volume) resulting from food deprivation or the daily food intake (Experiment 1). The dose-dependent polydipsic effect of oxytocin on food-deprived rats was always preceded by an increase in sodium and fluid urine excretion (Experiment 2). Oxytocin also increased the water intake of animals fed ad lib with a low sodium diet (Experiment 3). These results suggest that the effect of oxytocin on water intake is dependent on the presence or absence of sodium in the diet and that the excretion of sodium is the main mechanism of oxytocinergic polydipsia in food-deprived male rats.     

Heme oxygenase-derived carbon monoxide promotes arteriolar endothelial dysfunction and contributes to salt-induced hypertension in Dahl salt-sensitive rats

Vascular tissues express heme oxygenase (HO), which metabolizes heme to form carbon monoxide (CO). Heme-derived CO inhibits nitric oxide synthase and promotes endothelium-dependent vasoconstriction. After 4 wk of high-salt diet, Dahl salt-sensitive (Dahl-S) rats display hypertension, increased vascular HO-1 expression, and attenuated vasodilator responses to ACh that can be completely restored by acute treatment with an inhibitor of HO. In this study, we examined the temporal development of HO-mediated endothelial dysfunction in isolated pressurized first-order gracilis muscle arterioles, identified the HO product responsible, and studied the blood pressure effects of HO inhibition in Dahl-S rats on a high-salt diet. Male Dahl-S rats (5-6 wk) were placed on high-salt (8% NaCl) or low-salt (0.3% NaCl) diets for 0-4 wk. Blood pressure increased gradually, and responses to an endothelium-dependent vasodilator, ACh, decreased gradually with the length of high-salt diet. Flow-induced dilation was abolished in hypertensive Dahl-S rats. Acute in vitro pretreatment with an inhibitor of HO, chromium mesoporphyrin (CrMP), restored endothelium-dependent vasodilation and abolished the differences between groups. The HO product CO prevented the restoration of endothelium-dependent dilation by CrMP. Furthermore, administration of an HO inhibitor lowered blood pressure in Dahl-S rats with salt-induced hypertension but did not do so in low-salt control rats. These results suggest that hypertension and HO-mediated endothelial dysfunction develop gradually and simultaneously in Dahl-S rats on high-salt diets. They also suggest that HO-derived CO underlies the impaired endothelial dysfunction and contributes to hypertension in Dahl-S rats on high-salt diets.     

Protein intake conditions the diuresis seen after relief of bilateral ureteral obstruction in the rat

Natriuresis and diuresis occur in experimental animals after release of bilateral ureteral obstruction. Accumulation of urea and/or other natriuretic factors during the interval of complete obstruction may play a role in the ensuing postobstructive diuresis. The present experiments examine the potential role of dietary protein intake in conditioning the magnitude of the postobstructive diuresis after unilateral release of bilateral ureteral obstruction of 24-hr duration in the rat. Rats were fed isocaloric diets containing high (40% casein) or low (6% casein) protein for 4 weeks prior to obstruction. Rats fed a high protein diet had greater urine flows and fractional excretion of sodium and potassium after relief of obstruction than rats fed a low protein diet. Increased excretion of urea accounted for only part of the greater diuresis seen in rats fed a high protein diet. Hence, greater accumulation of other natriuretic factors during the period of obstruction in rats fed a high protein diet must play a role in the increased diuresis seen in this group of animals after release of obstruction.     

Loss of renal medullary endothelin B receptor function during salt deprivation is regulated by angiotensin II

We have recently demonstrated that chronic infusion of exogenous ANG II, which induces blood pressure elevation, attenuates renal medullary endothelin B (ET(B)) receptor function in rats. Moreover, this was associated with a reduction of ET(B) receptor expression in the renal inner medulla. The aim of this present work was to investigate the effect of a physiological increase in endogenous ANG II (low-salt diet) on the renal ET system, including ET(B) receptor function. We hypothesized that endogenous ANG II reduces renal medullary ET(B) receptor function during low-salt intake. Rats were placed on a low-salt diet (0.01-0.02% NaCl) for 2 wk to allow an increase in endogenous ANG II. In rats on normal-salt chow, the stimulation of renal medullary ET(B) receptor by ET(B) receptor agonist sarafotoxin 6c (S6c) causes an increase in water (3.6 ± 0.4 from baseline vs. 10.5 ± 1.3 μl/min following S6c infusion; P < 0.05) and sodium excretion (0.38 ± 0.06 vs. 1.23 ± 0.17 μmol/min; P < 0.05). The low-salt diet reduced the ET(B)-dependent diuresis (4.5 ± 0.5 vs. 6.1 ± 0.9 μl/min) and natriuresis (0.40 ± 0.11 vs. 0.46 ± 0.12 μmol/min) in response to acute intramedullary infusion of S6c. Chronic treatment with candesartan restored renal medullary ET(B) receptor function; urine flow was 7.1 ± 0.9 vs. 15.9 ± 1.7 μl/min (P < 0.05), and sodium excretion was 0.4 ± 0.1 vs. 1.1 ± 0.1 μmol/min (P < 0.05) before and after intramedullary S6c infusion, respectively. Receptor binding assays determined that the sodium-depleted diet resulted in a similar level of ET(B) receptor binding in renal inner medulla compared with rats on a normal-salt diet. Candesartan reduced renal inner medullary ET(B) receptor binding (1,414 ± 95 vs. 862 ± 50 fmol/mg; P < 0.05). We conclude that endogenous ANG II attenuates renal medullary ET(B) receptor function to conserve sodium during salt deprivation independently of receptor expression.     

Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

Infusion of angiotensin II (ANG II) causes salt-sensitive hypertension. It is unclear whether this is due to the body's inability to suppress ANG II during increased salt intake or, rather, an elevated basal level of plasma ANG II itself. To distinguish between these mechanisms, Sprague-Dawley rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of drugs, respectively. The sensitivity of arterial pressure to salt was measured in four groups with the following treatments: 1) saline control (Con, n = 12); 2) administration of the angiotensin-converting enzyme inhibitor enalapril to block endogenous ANG II (ANG-Lo, n = 10); 3) administration of enalapril and 5 ng.kg(-1).min(-1) ANG II to clamp plasma ANG II at normal levels (ANG-Norm, n = 10); and 4) administration of enalapril and 20 ng.kg(-1).min(-1) ANG II to clamp ANG II at high levels (ANG-Hi, n = 10). Rats ingested a 0.4% NaCl diet for 3 days and then a 4.0% NaCl diet for 11 days. Arterial pressure of rats fed the 0.4% NaCl diet was lower in ANG-Lo (84 +/- 2 mmHg) compared with Con (101 +/- 3 mmHg) and ANG-Norm (98 +/- 4 mmHg) groups, whereas ANG-Hi rats were hypertensive (145 +/- 4 mmHg). Salt sensitivity was expressed as the change in arterial pressure divided by the change in sodium intake on the last day of the 4.0% NaCl diet. Salt sensitivity (in mmHg/meq Na) was lowest in Con rats (0.0 +/- 0.1) and progressed from ANG-Lo (0.8 +/- 0.2) to ANG-Norm (1.5 +/- 0.5) to ANG-Hi (3.5 +/- 0.5) rats. We conclude that the major determinant of salt sensitivity of arterial pressure is the basal level of plasma ANG II rather than the responsiveness of the renin-angiotensin system.     

Flavonoid-induced reduction of ENaC expression in the kidney of Dahl salt-sensitive hypertensive rat

Flavonoid, a plant extract, exhibits various biological actions. Dietary flavonoid intake is reported to reduce an elevated blood pressure, however the mechanism is unknown. The epithelial Na+ channel (ENaC) in the kidney plays a key role in the regulation of blood pressure by contributing to the Na+ reabsorption in renal tubules. Thus, we investigated the effect of quercetin, a flavonoid, on ENaC mRNA expression in the kidney of hypertensive Dahl salt-sensitive rats. Dahl salt-sensitive rats of 8 weeks were acclimated for 1 week in a metabolic cage and were subsequently kept for 4 weeks under four different conditions: (1) normal salt diet (0.3% NaCl), (2) normal salt diet with quercetin (10 mg/kg/day), (3) high-salt diet (8% NaCl), and (4) high-salt diet with quercetin. Quercetin diminished the alphaENaC mRNA expression in the kidney associated with reduction of the systolic blood pressure elevated by high-salt diet, suggesting that one of the mechanisms of the flavonoid's antihypertensive effect on salt-sensitive hypertension would be mediated through downregulation of ENaC expression in the kidney.     

Diet and water-salt balance in rats

We compared parameters of water-salt balance in Wistar female rats fed normal chows during more than 2 weeks. Potassium content was 1.4-fold higher in diet I than in diet II, and sodium end water content was 3.3- and 7.5-fold higher in diet II than in diet I. Blood osmolality and concentration of Na+, K+, Mg2+ were equal in rats fed different chow. In water-loaded rats (5 ml of water/100 bw per os) fed different chow, urine flow rate did not differ, but solute-free water excretion was higher by 40.2% in the rats fed diet II vs. diet I. The sort of diet did not affect the renal sodium excretion during oral administration of 5 ml 0.9% NaCl per 100 g bw to rats. After vasopressin injection solute-free water reabsorption was 1.5-fold higher in rats fed diet II. Natriuretic and hydruretic effect of exenatide, glucagon-like peptide 1 mimetic, was weaker in rats fed diet I. The data obtained indicate that organism can effectively maintain blood parameters. The modulation of hormone regulatory effects on water and sodium balance was found to depend on the state of organism under diet consumed continuously.     

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.     

Effects of high-salt diet on CYP450-4A omega-hydroxylase expression and active tone in mesenteric resistance arteries

This study investigated the role of changes in the expression of the cytochrome P-450 4A (CYP450-4A) enzymes that produce 20-hydroxyeicosatetraenoic acid (20-HETE) in modulating the responses of rat mesenteric resistance arteries to norepinephrine (NE) and reduced Po(2) after short-term (3-day) changes in dietary salt intake. The CYP450-4A2, -4A3, and -4A8 isoforms were all detected by RT-PCR in arteries obtained from rats fed a high-salt (HS, 4% NaCl) diet, whereas only the CYP450-4A3 isoform was detected in vessels from rats fed a low-salt (LS, 0.4% NaCl) diet. Expression of the 51-kDa CYP450-4A protein was significantly increased by a HS diet. Inhibiting 20-HETE synthesis with 30 muM N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) reduced the vasoconstrictor response to NE in arteries obtained from rats fed either a LS or HS diet, but NE sensitivity after DDMS treatment was significantly lower in vessels from rats on a HS diet. DDMS treatment also restored the vasodilator response to reduced Po(2) that was impaired in arteries from rats on a HS diet. These findings suggest that 1) a HS diet increases the expression of CYP450-4A enzymes in the mesenteric vasculature, 2) 20-HETE contributes to the vasoconstrictor response to NE in mesenteric resistance arteries, 3) the contribution of 20-HETE to the vasoconstrictor response to NE is greater in rats fed a HS diet than in rats fed a LS diet, and 4) upregulation of the production of 20-HETE contributes to the impaired dilation of mesenteric resistance arteries in response to hypoxia in rats fed a HS diet.     

High dietary salt decreases antioxidant defenses in the liver of fructose-fed insulin-resistant rats

In this study we investigated the hypothesis that a high-salt diet to hyperinsulinemic rats might impair antioxidant defense owing to its involvement in the activation of sodium reabsorption to lead to higher oxidative stress. Rats were fed a standard (CON), a high-salt (HS), or a high-fructose (HF) diet for 10 weeks after which, 50% of the animals belonging to the HF group were switched to a regimen of high-fructose and high-salt diet (HFS) for 10 more weeks, while the other groups were fed with their respective diets. Animals were then euthanized and their blood and liver were examined. Fasting plasma glucose was found to be significantly higher (approximately 50%) in fructose-fed rats than in the control and HS rats, whereas fat liver also differed in these animals, producing steatosis. Feeding fructose-fed rats with the high-salt diet triggered hyperinsulinemia and lowered insulin sensitivity, which led to increased levels of serum sodium compared to the HS group. This resulted in membrane perturbation, which in the presence of steatosis potentially enhanced hepatic lipid peroxidation, thereby decreasing the level of antioxidant defenses, as shown by GSH/GSSG ratio (HFS rats, 7.098±2.1 versus CON rats, 13.2±6.1) and superoxide dismutase (HFS rats, 2.1±0.05 versus CON rats, 2.3±0.1%), and catalase (HFS rats, 526.6±88.6 versus CON rats, 745.8±228.7 U/mg ptn) activities. Our results indicate that consumption of a salt-rich diet by insulin-resistant rats may lead to regulation of sodium reabsorption, worsening hepatic lipid peroxidation associated with impaired antioxidant defenses.