A Role of Inflammation and Immunity in Essential Hypertension-Modeled and Analyzed Using Petri Nets.

Recent studies have shown that the innate and adaptive immune system, together with low-grade inflammation, may play an important role in essential hypertension. In this work, to verify the importance of selected factors for the development of essential hypertension, we created a Petri net-based model and analyzed it. The analysis was based mainly on t-invariants, knockouts of selected fragments of the net and its simulations. The blockade of the renin-angiotensin (RAA) system revealed that the most significant effect on the emergence of essential hypertension has RAA activation. This blockade affects: (1) the formation of angiotensin II, (2) inflammatory process (by influencing C-reactive protein (CRP)), (3) the initiation of blood coagulation, (4) bradykinin generation via the kallikrein-kinin system, (5) activation of lymphocytes in hypertension, (6) the participation of TNF alpha in the activation of the acute phase response, and (7) activation of NADPH oxidase-a key enzyme of oxidative stress. On the other hand, we found that the blockade of the activation of the RAA system may not eliminate hypertension that can occur due to disturbances associated with the osmotically independent binding of Na in the interstitium. Moreover, we revealed that inflammation alone is not enough to trigger primary hypertension, but it can coexist with it. We believe that our research may contribute to a better understanding of the pathology of hypertension. It can help identify potential subprocesses, which blocking will allow better control of essential hypertension.

Mechanisms of blood pressure salt sensitivity: new insights from mathematical modeling.

Mathematical modeling is an important tool for understanding quantitative relationships among components of complex physiological systems and for testing competing hypotheses. We used HumMod, a large physiological model, to test hypotheses of blood pressure (BP) salt sensitivity. Systemic hemodynamics, renal, and neurohormonal responses to chronic changes in salt intake were examined during normal renal function, fixed low or high plasma angiotensin II (ANG II) levels, bilateral renal artery stenosis, increased renal sympathetic nerve activity (RSNA), and decreased nephron numbers. Simulations were run for 4 wk at salt intakes ranging from 30 to 1,000 mmol/day. Reducing functional kidney mass or fixing ANG II increased salt sensitivity. Salt sensitivity, associated with inability of ANG II to respond to changes in salt intake, occurred with smaller changes in renal blood flow but greater changes in glomerular filtration rate, renal sodium reabsorption, and total peripheral resistance (TPR). However, clamping TPR at normal or high levels had no major effect on salt sensitivity. There were no clear relationships between BP salt sensitivity and renal vascular resistance or extracellular fluid volume. Our robust mathematical model of cardiovascular, renal, endocrine, and sympathetic nervous system physiology supports the hypothesis that specific types of kidney dysfunction, associated with impaired regulation of ANG II or increased tubular sodium reabsorption, contribute to BP salt sensitivity. However, increased preglomerular resistance, increased RSNA, or inability to decrease TPR does not appear to influence salt sensitivity. This model provides a platform for testing competing concepts of long-term BP control during changes in salt intake.

High salt induces autocrine actions of ET-1 on inner medullary collecting duct NO production via upregulated ETB receptor expression.

The collecting duct endothelin-1 (ET-1), endothelin B (ETB) receptor, and nitric oxide synthase-1 (NOS1) pathways are critical for regulation of fluid-electrolyte balance and blood pressure control during high-salt feeding. ET-1, ETB receptor, and NOS1 are highly expressed in the inner medullary collecting duct (IMCD) and vasa recta, suggesting that there may be cross talk or paracrine signaling between the vasa recta and IMCD. The purpose of this study was to test the hypothesis that endothelial cell-derived ET-1 (paracrine) and collecting duct-derived ET-1 (autocrine) promote IMCD nitric oxide (NO) production through activation of the ETB receptor during high-salt feeding. We determined that after 7 days of a high-salt diet (HS7), there was a shift to 100% ETB expression in IMCDs, as well as a twofold increase in nitrite production (a metabolite of NO), and this increase could be prevented by acute inhibition of the ETB receptor. ETB receptor blockade or NOS1 inhibition also prevented the ET-1-dependent decrease in ion transport from primary IMCDs, as determined by transepithelial resistance. IMCD were also isolated from vascular endothelial ET-1 knockout mice (VEETKO), collecting duct ET-1 KO (CDET-1KO), and flox controls. Nitrite production by IMCD from VEETKO and flox mice was similarly increased twofold with HS7. However, IMCD NO production from CDET-1KO mice was significantly blunted with HS7 compared with flox control. Taken together, these data indicate that during high-salt feeding, the autocrine actions of ET-1 via upregulation of the ETB receptor are critical for IMCD NO production, facilitating inhibition of ion reabsorption.

Direct renal effects of a fructose-enriched diet: interaction with high salt intake.

Consumption of fructose has increased during the last 50 years. Excessive fructose consumption has a detrimental effect on mammalian health but the mechanisms remain unclear. In humans, a direct relationship exists between dietary intake of added sugars and increased risk for cardiovascular disease mortality (52). While the causes for this are unclear, we recently showed that fructose provided in the drinking water induces a salt-dependent increase in blood pressure in Sprague-Dawley rats in a matter of days (6). However, little is known about the effects of fructose in renal salt handling and whether combined intake of high fructose and salt can lead to salt-sensitive hypertension before the development of metabolic abnormalities. The long-term (more than 4 wk) adverse effects of fructose intake on renal function are not just due to fructose but are also secondary to alterations in metabolism which may have an impact on renal function. This minireview focuses on the acute effect of fructose intake and its effect on salt regulation, as they affect blood pressure.

Clinical application of the second morning urine method for estimating salt intake in patients with hypertension.

Estimation of salt intake by cumbersome 24-h urine collection is not suitable for individual patients because of substantial daily variation in intake. We developed the second morning urine (SMU) method for monitoring daily salt intake in healthy subjects by calculating the daily creatinine excretion and measuring the ratio of sodium to creatinine in the SMU specimen. To determine whether the SMU method was applicable to hypertensive patients, we tested it in hospitalized patients under an equilibrated sodium balance as a model population. This review focuses on application of the SMU method in hypertensive patients with mild target organ damage.

Mechanism of salt-sensitive hypertension: focus on adrenal and sympathetic nervous systems.

A central role for the kidney among the systems contributing to BP regulation and the development of hypertension has been proposed. Both the aldosterone/mineralocorticoid receptor pathway and the renal sympathetic nervous system have important roles in the regulation of renal excretory function and BP control, but the mechanisms underlying these processes have remained unclear. However, recent studies revealed the activation of two pathways in salt-sensitive hypertension. Notably, Rac1, a member of the Rho-family of small GTP binding proteins, was identified as a novel ligand-independent modulator of mineralocorticoid receptor activity. Furthermore, these studies point to crucial roles for the Rac1-mineralocorticoid receptor-NCC/ENaC and the renal ß-adrenergic stimulant-glucocorticoid receptor-WNK4-NCC pathways in certain rodent models of salt-sensitive hypertension. The nuclear mineralocorticoid and glucocorticoid receptors may contribute to impaired renal excretory function and the resulting salt-sensitive hypertension by increasing sodium reabsorption at different tubular segments. This review provides an in-depth discussion of the evidence supporting these conclusions and considers the significance with regard to treating salt-sensitive hypertension and salt-induced cardiorenal injury.

Circadian regulation of electrolyte absorption in the rat colon.

The intestinal transport of nutrients exhibits distinct diurnal rhythmicity, and the enterocytes harbor a circadian clock. However, temporal regulation of the genes involved in colonic ion transport, i.e., ion transporters and channels operating in absorption and secretion, remains poorly understood. To address this issue, we assessed the 24-h profiles of expression of genes encoding the sodium pump (subunits Atp1a1 and Atp1b1), channels (α-, ß-, and γ-subunits of Enac and Cftr), transporters (Dra, Ae1, Nkcc1, Kcc1, and Nhe3), and the Na(+)/H(+) exchanger (NHE) regulatory factor (Nherf1) in rat colonic mucosa. Furthermore, we investigated temporal changes in the spatial localization of the clock genes Per1, Per2, and Bmal1 and the genes encoding ion transporters and channels along the crypt axis. In rats fed ad libitum, the expression of Atp1a1, γEnac, Dra, Ae1, Nhe3, and Nherf1 showed circadian variation with maximal expression at circadian time 12, i.e., at the beginning of the subjective night. The peak γEnac expression coincided with the rise in plasma aldosterone. Restricted feeding phase advanced the expression of Dra, Ae1, Nherf, and γEnac and decreased expression of Atp1a1. The genes Atp1b1, Cftr, αEnac, ßEnac, Nkcc1, and Kcc1 did not show any diurnal variations in mRNA levels. A low-salt diet upregulated the expression of ßEnac and γEnac during the subjective night but did not affect expression of αEnac. Similarly, colonic electrogenic Na(+) transport was much higher during the subjective night than the subjective day. These findings indicate that the transporters and channels operating in NaCl absorption undergo diurnal regulation and suggest a role of an intestinal clock in the coordination of colonic NaCl absorption.

[Impaired gustatory sensitivity of the tongue to table salt as a risk factor of arterial hypertension].

The study included 630 patients with verified diagnosis of arterial hypertension (AH) in whom 24 hr AP monitoring was performed, threshold gustatory sensitivity of the tongue to table salt (TGS) measured, and habit to add salt to the cooked food evaluated. Measurement of Na in daily urine of 442 patients was followed by estimation of salt consumption. The results were compared with those obtained in 100 patients with newly diagnosed AH. The control group comprised 288 subjects. TGS in AH patients was significantly higher than in controls and directly related to clinical features of the disease, high AP values, age, smoking habits, hypercholesterolemia, abdominal-type obesity, and hereditary predisposition. TGS positively correlated with daily urinary excretion of NaCl (r = 0.4-0.7; p < 0.05-0.01). High TGS decreased under effect of hypotensive therapy.

Epoxy Fatty Acids: From Salt Regulation to Kidney and Cardiovascular Therapeutics: 2019 Lewis K. Dahl Memorial Lecture.

Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.

Mechanisms of disease: WNK-ing at the mechanism of salt-sensitive hypertension.

Potassium deficiency is associated with an increased prevalence of hypertension. Increasing potassium intake lowers blood pressure via an unknown mechanism. WNK (with no lysine) kinases are a novel family of large serine/threonine protein kinases. A large deletion from the first intron of the WNK1 gene results in increased levels of expression of WNK1 and causes Gordon's syndrome, of which hypertension and hyperkalemia are features. WNK1 activates the Na(+)/Cl(-) cotransporter NCC and the epithelial Na(+) channel ENaC, and inhibits the renal K(+) channel ROMK. Enhanced Na(+) reabsorption and inhibition of K(+) secretion resulting from increased WNK1 expression probably contribute to hypertension and hyperkalemia in Gordon's syndrome. Here, we review the role of dietary K(+) deficiency in the pathogenesis of salt-sensitive hypertension and summarize recent findings indicating that WNK1 might mediate renal Na(+) retention and hypertension in K(+) deficiency.

Validation of spot urine in predicting 24-h sodium excretion at the individual level.

Background: Evidence for the effect of dietary sodium intake on the risk of cardiovascular disease has been controversial. One of the main explanations for the conflicting results lies in the great variability associated with measurement methods for sodium intake. Spot urine collection is a convenient method commonly used for sodium estimation, but its validity for predicting 24-h urinary sodium excretion at the individual level has not been well evaluated among the general population.Objective: The aim of this study was to evaluate the validity of the Kawasaki, the International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT), and the Tanaka formulas in predicting 24-h urinary sodium excretion by using spot urine samples in Chinese adults.Design: We analyzed the relative and absolute differences and misclassification at the individual level from 3 commonly used methods for estimating sodium intake among 141 Chinese community residents.Results: The mean measured 24-h sodium excretion was 220.8 mmol/d. The median (95% CIs) differences between measured sodium and those estimated from the Kawasaki, INTERSALT, and Tanaka methods were 6.4 mmol/d (-17.5, 36.8 mmol/d), -67.3 mmol/d (-96.5, -46.9 mmol/d), and -42.9 mmol/d (-59.1, -24.8 mmol/d), respectively. The proportions of relative differences >40% with the Kawasaki, INTERSALT, and Tanaka methods were 31.2%, 41.1%, and 22.0%, respectively; and the absolute difference for the 3 methods was >51.3 mmol/d (3 g salt) in approximately half of the participants. The misclassification rate was 63.1% for the Kawasaki method, 78.7% for the INTERSALT method, and 66.0% for the Tanaka method at the individual level.Conclusion: The results from our study do not support the use of spot urine to estimate 24-h urinary sodium excretion at the individual level because of its poor performance with respect to misclassification. This trial was registered at www.chictr.org.cn as ChiCTR-IOR-16010278.

High Salt Intake Is Independently Associated With Hypertensive Target Organ Damage.

The authors tested the hypothesis that high salt intake is associated with hypertensive target organ damage (TOD) independent of blood pressure (BP), and oxidative stress is a modifying factor of this association. A total of 369 community-dwelling Japanese adults (mean age, 67.5 years; 56.6% women) were examined in this observational study. At the patients' annual health check-ups, urinary salt excretion (U-SALT), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and albumin-creatinine ratio (UACR) were measured from first morning urine. U-SALT (ß=0.14, P=.016) and 8-OHdG (ß=0.13, P=.018) were both independently associated with logUACR. U-SALT was associated with TOD independent of BP level, and oxidative stress may be a modifying factor in the association between high salt intake and TOD. The elevation of 8-OHdG may be involved in the pathophysiology of TOD induced by salt intake.

Patients with severe bowel malabsorption do not have changes in iodine status.

OBJECTIVE: We evaluated the influence of intestinal malabsorption on iodine status in patients who had short gut syndrome and received total parenteral nutrition (group I) compared with control subjects who had eutrophia (group II) and patients who had other illnesses but normal digestive tracts (group III). METHODS: Twenty-seven subjects were studied. Iodine intake was determined by the measurement of iodine in ingested food and in parenteral nutrition solutions. Urinary iodine excretion was measured by the Sandell-Kalthoff reaction. Urinary creatinine, anthropometric, and thyroid hormone functions were also determined. RESULTS: Daily iodine intakes were 658 +/- 125 (mean +/- standard deviation), 573 +/- 204, and 629 +/- 208 microg for groups I, II, and III, respectively. Daily urinary iodine excretion levels were 399 +/- 308, 439 +/- 192, and 370 +/- 268 microg and ratios of urinary iodine (micrograms) to creatinine (grams) were 614 +/- 349, 354 +/- 142, and 483 +/- 292, respectively. There were no statistically significant differences across groups. CONCLUSION: In Brazil the iodine provided by food, including iodized salt, has been sufficient to maintain iodine status in patients with short gut syndrome.

Role of female sex hormones in the development and reversal of dahl hypertension.

Female sex hormones protect against the development of Dahl hypertension mediated by increases in dietary sodium. The role of female sex hormones in the reversal of Dahl hypertension mediated by decreases in dietary sodium is unknown. The goal of this study was to identify sex differences in the reversal of Dahl hypertension and the associated changes in water and electrolyte homeostasis. Male (M, n=8), female (F, n=8), and ovariectomized female (OVX, n=9) Dahl salt-sensitive rats were instrumented with an abdominal radiotelemetry device for 24-hour monitoring of blood pressure (BP) and heart rate. Daily measurements of food intake, water intake, and urine output were recorded as diet was changed from a low-sodium diet (0.15% NaCl) to a diet containing 8% NaCl. The diet was then changed back to 0.15% NaCl. The responses to changes in the salt diet were compared with responses observed in rats (M, n=4; F, n=4; OVX, n=4) that were maintained on 0.15% NaCl during the experiment. Sex differences in BP were observed when M, F, and OVX rats were fed 8% NaCl diet for 2 weeks (152+/-4, 141+/-3, and 154+/-5 mm Hg, respectively). BP was significantly greater (P<0.05) in M and OVX rats than in F rats. Fluid balance (water intake minus urine volume) and sodium balance (sodium intake minus sodium excretion) were similar in all groups on the 8% NaCl diet. BP in time-control M, F, and OVX rats was 121+/-3, 130+/-4, and 162+/-11 mm Hg, respectively. Compared with time-control groups, differences in BP while rats were eating the 8% NaCl diet were observed in M and F rats but not OVX rats. Reinstatement of an NaCl-deficient diet reversed the hypertension in M and F but not OVX rats (124+/-4, 124+/-2, and 145+/-5 mm Hg, respectively). The changes in dietary sodium caused similar changes in renal handling of sodium and water in all groups of rats; therefore, the effect on blood pressure was independent of renal excretory function. The inability to reverse the hypertension by decreasing sodium intake in OVX rats and the development of spontaneous hypertension in OVX females maintained on a low-sodium diet indicates that removal of the female sex hormones predisposes the animal to the development of hypertension that is sodium independent. We conclude that female sex hormones protect Dahl S rats against the development of sodium-dependent and -independent hypertension.

Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential hypertension.

We evaluated the association between salt-sensitive hypertension and 3 different genetic polymorphisms of the renin-angiotensin system. Fifty patients with essential hypertension were classified as salt sensitive or salt resistant, depending on the presence or absence of a significant increase (P<0.05) in 24-hour ambulatory mean blood pressure (BP) after high salt intake. The insertion/deletion (I/D) angiotensin-converting enzyme (ACE) gene, the M235T angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 (AT1) receptor gene polymorphisms were determined with the use of standard polymerase chain reaction methods. Twenty-four (48%) patients with significantly increased (P<0.05) 24-hour mean BP with high salt intake (from 107.3+/-9.4 to 114.8+/-10.6 mm Hg) were classified as salt sensitive. In the remaining 26 patients (52%), high salt intake did not significantly modify 24-hour mean BP (from 107.6+/-10 to 107. 8+/-9 mm Hg), and they were classified as having salt-resistant hypertension. We did not find any significant association between either M235T AGT or A1166C AT1 receptor genotypes and the BP response to high salt intake. However, patients with essential hypertension homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake (9. 8+/-8.1 mm Hg for systolic BP and 5.2+/-4.2 mm Hg for diastolic BP) than that observed in patients homozygous for the deletion allele (DD) (1.2+/-5.9 mm Hg for systolic BP; P=0.0118 and -0.2+/-4.2 mm Hg for diastolic BP; P=0.0274). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension also was significantly higher (P=0.012) in II (67%) and DI patients (62%) compared with DD hypertensives (19%). We conclude that a significant association exists between the I/D polymorphism of the ACE gene and salt-sensitive hypertension. Patients with II and DI genotypes have significantly higher prevalence of salt sensitivity than DD hypertensives.

Dual fortification of salt with iodine and micronized ferric pyrophosphate: a randomized, double-blind, controlled trial.

BACKGROUND: In many developing countries, children are at high risk for both goiter and anemia. In areas of subsistence farming in rural Africa, salt is one of the few regularly purchased food items and could be a good fortification vehicle for iodine and iron, provided that a stable yet bioavailable iron fortificant is used. OBJECTIVE: We tested the efficacy of salt dual-fortified with iodine and micronized ferric pyrophosphate for reducing the prevalence of iodine and iron deficiencies in children. DESIGN: In rural northern Morocco, we fortified local salt with 25 microg I (as potassium iodate)/g salt and 2 mg Fe (as micronized ferric pyrophosphate; mean particle size = 2.5 microm)/g salt. After storage and acceptability trials, we compared the efficacy of the dual-fortified salt (DFS) with that of iodized salt in a 10-mo, randomized, double-blind trial in iodine-deficient 6-15-y-old children (n = 158) with a high prevalence of anemia. RESULTS: After storage for 6 mo, there were no significant differences in iodine content or color lightness between the DFS and iodized salt. During the efficacy trial, the DFS provided approximately 18 mg Fe/d; iron absorption was estimated to be approximately 2%. After 10 mo of treatment in the DFS group, mean hemoglobin increased by 16 g/L (P < 0.01), iron status and body iron stores increased significantly (P < 0.01), and the prevalence of iron deficiency anemia decreased from 30% at baseline to 5% (P < 0.001). In both groups, urinary iodine (P < 0.001) and thyroid volume (P < 0.01) improved significantly from baseline. CONCLUSION: A DFS containing iodine and micronized ferric pyrophosphate can be an effective fortification strategy in rural Africa.

Membrane ion transport in erythrocytes of salt hypertensive Dahl rats and their F2 hybrids: the importance of cholesterol.

The possible association of salt hypertension and altered lipid metabolism with abnormalities of particular systems transporting sodium and potassium has been studied in erythrocytes of Dahl rats and their F2 hybrids fed a high-salt diet since weaning. Our attention was paid to the Na(+)-K+ pump, Na(+)-K+ cotransport and especially to passive membrane permeability for Na+ and Rb+ (Na+ and Rb+ leak), because the Na+ leak was found to be dependent on the genotype, age and salt intake of Dahl rats, whereas the Rb+ leak was suggested to be a potential marker of salt sensitivity in Dahl and Sabra rats. Young male Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats kept on a low-salt (0.3% NaCl) or high-salt diet (8% NaCl) were used for the progenitor study. The subsequent genetic study was based on 135 young male SS/Jr x SR/Jr F2 hybrids fed a high-salt diet since weaning. Ouabain (5 mmol/l) and bumetanide (10 micromol/l) were used to distinguish the contribution of the Na(+)-K+ pump, Na(+)-K+ cotransport and passive membrane permeability to measured net Na+ fluxes and unidirectional Rb+ (K+) movements. Compared to normotensive SR/Jr animals, salt-loaded SS/Jr rats had higher blood pressure (BP), elevated erythrocyte Na+ content, and increased Na+ and Rb+ leaks together with enhanced Na+ and Rb+ transport mediated by the Na(+)-K+ pump and Na(+)-K+ cotransport system. Salt hypertensive Dahl rats were also characterized by elevated plasma levels of total cholesterol and triglycerides, which were positively associated with BP of F2 hybrids (r=0.27 and 0.24, p< 0.01). In F2 hybrids, mean arterial pressure correlated significantly with erythrocyte Na+ content (r=0.24, p<0.01) and ouabain-sensitive Na+ extrusion, but not with the passive membrane permeability for Na+ or Rb+ (r=-0.02 and 0.06, not significant). Both of the above-mentioned significant associations could partially be ascribed to the dependence of erythrocyte Na+ content and ouabain-sensitive Na+ extrusion on plasma cholesterol (r=0.18 and 0.21, p<0.05). Our results support the idea that abnormal lipid metabolism and/or altered Na+,K(+)-ATPase function play an important role in the pathogenesis of salt hypertension in salt-sensitive Dahl rats.

Mechanism of sodium load-induced hypertension in non-insulin dependent diabetes mellitus model rats: defective dopaminergic system to inhibit Na-K-ATPase activity in renal epithelial cells.

Obesity-related non-insulin dependent diabetes mellitus (NIDDM) is frequently accompanied by hypertension. The present study was designed to clarify this mechanism. We first determined the blood pressure in male Wistar fatty rats (WFR), one of the NIDDM model rats, and in Wistar lean rats (WLR) as the control, with a normal (0.7% NaCl) or high (7% NaCl) salt diet. We observed no difference in systolic and mean blood pressures between WFR and WLR. WFR, however, became extremely hypertensive as a result of ingesting the high salt diet. We next investigated the mechanism for sodium sensitivity in WFR. Although the urinary excretion of dopamine (DA), a potent natriuretic factor, which reflects the ability for renal DA production, was preserved in WFR, the sodium balance with the high salt diet was positive. Moreover, Na-K-ATPase activity in isolated proximal convoluted tubules (PCT) from WFR with a normal salt diet was significantly (p<0.05) higher than that from WLR. A high salt load produced a significant (p<0.05) decrease in Na-K-ATPase activity in WLR but not in WFR. Similarly, Na-K-ATPase activity in WLR with a normal salt diet was significantly (p<0.05) inhibited by DA (10(-5) M), but this was not true in WFR. Furthermore, urinary excretion of norepinephrine in WFR with a high salt diet was the highest among all the groups. These results indicate that WFR tend to develop salt-sensitive hypertension that could be caused by the excessive sodium retention occurring as the results of a defective dopaminergic system in the kidney that fails to inhibit Na-K-ATPase activity. Augmentation of the renal sympathetic nervous system may play some role in this setting.

Effect of sodium restriction on urinary excretion of cortisol and its metabolites in humans.

The adrenal gland is involved in the control of urinary sodium excretion mainly via the secretion of the mineralocorticoid aldosterone. Although under certain conditions glucocorticoid seem to be also involved in the regulation of sodium homeostasis, there are contradictory reports on the relationship between cortisol secretion and sodium intake. Given recent findings linking regulation of physiological activity of steroids to the activity of specific enzymatic pathways, we have examined changes in urinary excretion of cortisol and its metabolites in eight healthy volunteers on a low sodium diet. Urinary steroids were measured with specific radioimmunoassays after extraction and chromatography (F and E) or after dilution (THF and THE). Excretion of cortisol (124 +/-41 nmol/day) was significantly lower on Day 2 (86 +/- 27 nmol/day, p < 0.01) and Day 7 (85 +/- 25 nmol/day, p < 0.01) of sodium restriction. On the same samples calculated ratios of THF/F (55 +/- 15; 61 +/- 22; 68 +/- 21) and E/F (2.5 +/- 0.6; 2.8 +/- 1.4; 3.0 +/- 1.3) reflecting the activity of 5 beta-reductase and 11 beta-hydroxysteroid dehydrogenase, respectively, showed significant increases in the former on both Days 2 and 7 and for the latter only on Day 7. This study supports the notion that sodium restriction decreases urinary cortisol excretion and provides evidence that increased activity of 5 beta-reductase and lowered metabolism by 11 beta-HSD are presumably the mechanisms of this decrease.

Influence of dietary sodium on waterborne copper toxicity in rainbow trout, Oncorhynchus mykiss.

Juvenile rainbow trout were fed diets containing control (0.26 mmol/g) or elevated (1.3 mmol/g) dietary Na+ in combination with either background (19 nmol/L) or moderately elevated levels (55 or 118 nmol/L) of waterborne Cu for 21 d. Unidirectional waterborne Na+ uptake rates (measured with 22Na) were up to four orders of magnitude higher than those of Cu (measured with 64Cu). Chronic exposure to elevated dietary Na+ alone or in combination with elevated waterborne Cu decreased whole-body uptake rates of waterborne Na+ and Cu. Accumulation of new Cu and Na+ at the gills was positively and highly significantly correlated and responded to the experimental treatments in a similar fashion, suggesting that Na+ and Cu have common branchial uptake pathways and that dietary Na+ preexposure modifies these pathways. Chronic exposure to elevated waterborne Cu significantly increased Cu concentrations in the liver but caused only modest increases in total Cu concentrations in the whole body and gill. Chronic exposure to elevated dietary Na+ slightly decreased whole-body Cu concentration on day 14 and greatly reduced liver Cu concentration on days 14 and 21; new Cu accumulation in whole-body, gill, and internal organs was reduced on all days. Chronic exposure to elevated waterborne Cu or dietary Na+ alone reduced short-term gill Cu binding at low waterborne Cu concentrations. At high waterborne Cu concentrations, chronic exposure to elevated waterborne Cu had no effect, while elevated dietary Na+ increased Cu binding to the gills. Combined chronic exposure to elevated dietary Na+ and waterborne Cu decreased gill Cu binding over the entire range of Cu concentrations tested. Clearly, chronic exposure to elevated dietary Na+ and waterborne Cu appears to modify gill Cu-binding characteristics and may be important considerations in future development of a chronic biotic ligand model for Cu.