Body Composition,Intraerythrocyte Sodium Content,Volume Regulation and Blood Pressure during Moderate Sodium Restriction in Hypertensive Men

ABSTRACT. Eleven moderately obese middle-aged male outpatients with untreated mild hypertension reduced their sodium intake by about 120 mmol per day during 4–6 weeks. Diastolic blood pressure was then significantly reduced in comparison with a matched control group. The reduction of urinary sodium excretion was significantly correlated to the change in mean arterial pressure. Mean body mass showed a small significant decrease, although there were no significant changes in total body water or body fat as determined from measurements of ⁴⁰K and tritiated water. Nor did mean extracellular water or plasma volume (Evan's blue) show any significant change. The decrease in urinary sodium excretion was associated with increases in plasma renin activity and urinary aldosterone excretion, while a sympathetic nervous natriuretic index (urinary dopamine to noradrenaline excretion ratio) decreased. The low sodium diet period was followed by a period of energy reduction as well as sodium restriction for 15 weeks. Mean body mass was then reduced by about 8 kg. The systolic but not the diastolic blood pressure showed a significant decrease. The intraerythrocyte content of water, sodium and potassium did not change significantly during any of the diet periods. We conclude that moderate sodium restriction lowered the blood pressure and affected the renin-aldosterone and sympathetic nervous system to retain sodium which might explain the constancy of the plasma volume.     

Effects of sodium intake, furosemide, and infusion of atrial natriuretic peptide on the urinary and metabolic clearances of arginine vasopressin in normal subjects

Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) have important influences on water and electrolyte metabolism, and studies on the interactions between these hormones may have important implications. We have investigated the effects of sodium intake, furosemide, and infusion of ANP on the urinary and metabolic (nonurinary) clearances of AVP in hydrated normal subjects. On a high sodium diet there was an increase in urine volume, sodium excretion, osmolal clearance, plasma ANP concentration, and urinary clearance and fractional excretion of AVP, with a decrease in PRA. The infusion of furosemide increased urine volume, sodium excretion, osmolal clearance, and PRA, but decreased circulating ANP levels and urinary clearance and fractional excretion of AVP. Since there was a positive correlation between circulating ANP and urinary clearance of AVP in these experiments, we infused human alpha ANP in physiological amounts and found increases in the urinary and metabolic (nonurinary) clearances of AVP. The changes in urinary clearance of AVP in all three experiments occurred even in relation to creatinine clearance. These observations demonstrate that urinary clearance of AVP does not correlate with urine volume, sodium or solute excretion, or PRA. The observations support a physiological role for ANP in modulating the renal action of AVP, probably at the level of the renal tubules, and indicate a need for caution when using plasma or urinary AVP as an indicator of AVP release from the neurohypophysis.     

Relationships of the renin-angiotensin-aldosterone system and sodium balance to blood pressure regulation in chronic renal failure of polycystic kidney disease

In 5 patients with polycystic kidney disease and creatinine clearances ranging from 4 to 40 ml/min, relationships between changes in blood pressure, sodium balance, body fluid compartments, plasma renin activity (PRA), urinary aldosterone excretion, and plasma aldosterone concentrations were studied during periods of low, medium, and high sodium intake. Total body water (TBW), total exchangeable body sodium (TEBS), and extracellular volume (ECV) were measured by isotope dilution techniques, plasma volume with Evan's blue dye, and PRA and aldosterone by radioimmunoassay. Low sodium intake reduced kidney function, blood pressure, and serum sodium, while PRA reached its highest levels. Subsequent increases in sodium intake improved kidney function and increased blood pressure. Plasma volume increased slightly and ECV markedly, while PRA dropped to 15% of the value noted after the low sodium intake. TBW and TEBS showed inconsistent changes. Aldosterone changes correlated closely with PRA. Blood pressure showed a negative correlation with PRA, but a positive one with body weight and cumulative sodium balance, and with plasma and extracellular volumes. It is suggested that whereas renin and aldosterone are involved in the maintenance of circulatory homeostasis during sodium loss, sodium retention causes an increase in blood pressure by concomitant changes in body fluids.     

The syndrome of inappropriate antidiuretic hormone secretion (SIADH): pathophysiologic mechanisms in solute and volume regulation.

1. Studies on eight patients were performed to clarify the mechanism(s) of altered sodium metabolism and volume regulation in SIADH. The mechanism controlling water excretion was also studied to determine whether there is evidence that altered osmoregulation may be the basis for inappropriate ADH secretion in some patients. 2. These studies show that cumulative sodium balance and aldosterone secretion rates in patients with SIADH are negatively correlated with water intake. There is also a negative correlation between aldosterone secretion and urinary sodium excretion. In the absence of normal urine diluting ability, this increased excretion of sodium becomes a mechanism that allows an increased quantity of water to be excreted despite the persistence of an ADH effect on the renal tubules. 3. Within the range of hyponatremia observed in our studies, changes in serum sodium concentration were accounted for by changes in solute and water balance. One patient, who was potassium deficient during the studies, retained large quantities of sodium and potassium that could not be accounted for by an increase in either serum osmolality or body weight. These observations suggest that intracellular osmotically active solute is either lost or "inactivated" in some manner as intracellular potassium is replenished. 4. Marked impairment of urine diluting ability was demonstrated in all patients. However, two patients with SIADH associated with pulmonary tuberculosis exhibited graded responses to water loading, which suggests that ADH secretion may have been suppressed as serum osmolality was progressively reduced. Whether this can be attributed to a basic alteration or "re-setting" or osmoreceptor function, or is merely an indication that greater than normal reductions of serum osmolality are required to inhibit potent nonosmotic stimuli, remains to be determined.     

The effect of changes in dietary sodium content on complaints and clinical parameters of volume depletion in patients with a permanent ileostomy

In seven patients with an ileostomy the volume and electrolyte composition of ileal effluent and urine were studied at the end of 7-day periods on a free diet (mean total sodium excretion 180 mmol/day) and on diets with a fixed sodium content ranging from 120 to 350 mmol/day. At the same time, complaints were scored and the plasma aldosterone concentration, renal aldosterone excretion, and ileal transmucosal potential difference were determined. On a free diet, all of the patients had one or more complaints. These tended to disappear when intake was increased. Changes in dietary sodium led to only minor changes in the volume and composition of the ileal effluent. Significant associations were found between sodium intake and complaints, the urinary sodium/potassium ratio, plasma aldosterone concentration, and aldosterone excretion. The ileal transmucosal potential difference showed the same tendency. Mean sodium intake on a free diet appeared to be suboptimal. The well-being of many ileostomists can be improved by increasing the dietary sodium intake to a level higher than 250 mmol/day.     

Water and electrolyte balance in adrenalectomized rats with diabetes insipidus (Brattleboro strain) given antidiuretic hormone

Vasopressin [antidiuretic hormone (ADH) as pitressin tannate in oil] was injected daily into male Brattleboro rats with hypothalamic diabetes insipidus before and after adrenalectomy. Body weight increased after ADH treatment. Urine volume, water intake, and excretion of osmotically free water fell as urinary osmolarity increased; all stabilized after 5–6 days. Total solute, sodium, calcium, and magnesium excretory rates also diminished. After adrenalectomy, body weight, food and water intakes, and urine volumes were reduced compared with those of sham-operated ADH-injected animals. The proportion of the dietary intakes of sodium, potassium, calcium, magnesium, and chloride appearing in the urine all increased initially after adrenalectomy. Seven days after operation, plasma sodium concentration and muscle sodium content were reduced; plasma potassium concentration and muscle water content were also higher than in sham-operated animals. The pattern of adrenal insufficiency observed in these ADH-injected rats was similar to that previously found in adrenalectomized normal, but not diabetic, rats. Vasopressin clearly influeces some of the characteristic features of adrenalectomized animals.     

Disorders of body water homeostasis in critical illness.

Disorders of sodium and water homeostasis are among the most commonly encountered disturbances in the critical care setting, because many disease states cause defects in the complex mechanisms that control the intake and output of water and solute. Because body water is the primary determinant of extracellular fluid osmolality, disorders of body water balance can be categorized into hypoosmolar and hyperosmolar disorders depending on the presence of an excess or a deficiency of body water relative to body solute. Because the main constituent of plasma osmolality is sodium, hypoosmolar and hyperosmolar disease states are generally characterized hy hyponatremia and hypernatremia, respectively. After a brief review of normal water metabolism, this article focuses on the diagnosis and treatment of hyponatremia and hypernatremia in the critical care setting.     

The Sodium Intake Modifies the Renin-Aldosterone and Blood Pressure Changes Associated with Moderately Low Energy Diets

ABSTRACT. Thirty middle-aged, moderately obese men with untreated mild hypertension were allocated to two groups of 15 men each. Both groups were placed on energy-reduced diets (5.1 MJ/day) for 9–11 weeks which resulted in similar losses of body mass (8.5 kg). In group I the low energy diet was supplemented with sodium chloride leading to no change in urinary sodium excretion. During dieting there were significant reductions of plasma renin activity (PRA) and urinary excretion of noradrenaline and aldosterone. Heart rate but not mean arterial pressure (MAP) decreased significantly. Then followed a period of sodium restriction which resulted in a significant decrease in MAP and an increase in aldosterone excretion. In group II there was a reduction of sodium intake by about 80 mmol as judged from determinations of urinary sodium excretion. In this group the energy restriction was not accompanied by any changes in PRA or urinary excretion of aldosterone, whereas urinary noradrenaline excretion, heart rate and MAP decreased significantly. Urinary adrenaline excretion remained unchanged. It is concluded that the hypotensive response to moderate energy and sodium reduction cannot be explained by changes in the renin-aldosterone system.     

Sodium intake affects urinary albumin excretion especially in overweight subjects

OBJECTIVES: To examine the relationship between sodium intake and urinary albumin excretion, being an established risk marker for later cardiovascular morbidity and mortality. DESIGN: Cross-sectional cohort study using linear regression analysis. Setting. University hospital outpatient clinic. SUBJECTS: A cohort drawn from the general population, consisting of 7850 subjects 28-75 years of age, all inhabitants of the city of Groningen, the Netherlands. The cohort is enriched for the presence of subjects with elevated urinary albumin concentration. RESULTS: The results show a positive relationship between dietary sodium intake and urinary albumin excretion. The association was independent of other cardiovascular risk factors (such as sex, age, blood pressure, body mass index (BMI), waist-to-hip ratio, serum cholesterol, plasma glucose and smoking) and other food constituents (calcium, potassium and protein). The relationship between sodium intake and urinary albumin excretion was steeper in subjects with a higher BMI compared with a lower BMI. CONCLUSIONS: Sodium intake is positively related to urinary albumin excretion. This relation is more pronounced in subjects with a higher BMI. These results suggest that high sodium intake may unfavourably influences cardiovascular prognosis especially in overweight and obese subjects.     

Relation of urinary urea to blood pressure: interaction with urinary sodium

A previous study reported that urinary markers of protein intake are inversely related to blood pressure via unknown mechanisms. In man and rats, protein intake affects renal function and increases renal sodium excretion. The present study investigates the relation between markers of protein intake and blood pressure and the possible role of sodium in this relation. Blood pressure status, overnight urinary urea as index of protein intake, urinary and plasma sodium, and other variables were measured in a population sample of 3705 men and women, aged 25-74 years, without high plasma creatinine. Urinary urea was inversely related to blood pressure and hypertension: in multivariate analyses, 6.5 mmol/h higher urinary urea (about one s.d. in men and women) was related to 4.25 mm Hg lower systolic blood pressure (95% confidence interval = 1.34-8.49), and to 0.65 lower risk of hypertension (95% CI 0.34-0.87). An interaction was found between overnight urinary sodium and the relation of urinary urea to blood pressure: the relation was significant only in persons with overnight urinary sodium above the median. Urinary urea was significantly and inversely also related to plasma sodium. Data confirm an inverse relation to blood pressure of protein intake as measured by urinary urea. The possibility of sodium-related mechanisms is supported by the interaction of urinary sodium with the relation and by the inverse association of urinary urea with plasma sodium. The hypothesis is made that high protein intake could counteract sodium-dependent blood pressure rise via stimulation of renal sodium excretion.     

Sodium sensitive and sodium retaining hypertension

The differences between sodium sensitive and sodium retaining hypertension were theoretically considered using a water tank model of body fluid volume-blood pressure regulation. If an outlet valve is attached to a tank with a base area corresponding to the reciprocal of total peripheral resistance (TPR) and water is poured into this tank at a rate corresponding to the amount of Na+ intake, then equilibrium should be achieved at a certain water level, volume and output from the outlet, which represent mean arterial pressure (MAP), cardiac output (CO) and urinary Na+ excretion. The height of the outlet from the tank bottom and the size cross-sectional area, of the outlet correspond to the x-intercept and slope of the renal function (pressure-natriuresis) curve, respectively. In both nonsodium sensitive hypertension, due to the shift of the curve toward a higher blood pressure level (elevated height of the outlet) without change in the slope (size of the outlet), and sodium sensitive hypertension, due to the depressed slope of the curve (reduced outlet size), not only MAP (water level) but also CO (water volume) are increased, resulting in sodium retaining hypertension, if TPR (reciprocal of base area) remained unchanged, while CO is relatively unchanged, resulting in nonsodium retaining hypertension, if TPR is elevated. Thus, the MAP and its sensitivity to sodium intake is determined by the renal function curve. Since body fluid volume is determined by both the renal function curve and TPR, however, changes in TPR during the development of hypertension is a major factor in determining whether or not the body fluid volume has to change only a small amount or a large amount. Therefore, the sodium sensitivity of blood pressure and sodium retention must be considered separately.     

Changes in adrenal responsiveness and potassium balance with shifts in sodium intake

Dietary sodium modulates the aldosterone response to angiotensin, but available evidence does not indicate whether there is a gradual change in adrenal responsiveness with intermediate sodium intakes or a sharp shift from a low to a high responsive level at some threshold sodium intake. Nine normal subjects received angiotensin II infusions while in balance on five levels of sodium intake over two orders of magnitude, 3 to 300 mEq sodium per day. Basal plasma renin activity, plasma aldosterone and plasma angiotensin II concentrations gradually fell as dietary sodium intake increased. The adrenal was quite sensitive to the state of sodium balance since a shift in sodium intake of as little as 20 mEq (e.g. 10 to 30 mEq/day) induced a significant change in basal plasma aldosterone. Adrenal responsiveness to infused angiotensin varied inversely with the log of urinary sodium excretion over the entire range of sodium intake, indicating that there is a gradual modulation of adrenal responsiveness with changes in dietary sodium. In addition, despite a constant dietary potassium intake, serum potassium gradually fell from 4.55 +/- .06 to 3.98 +/- .07 mEq/l, (P less than 0.02), as sodium intake increased, partly due to increased urinary potassium excretion (mean cumulative potassium loss of 129 mEq). Thus, changes in potassium balance may be important in modulating the sodium-associated variation in aldosterone secretion.     

The effects of aprotinin, a kallikrein inhibitor, on renin release and urinary sodium excretion in mild essential hypertensives

The effects of aprotinin on renin release and renal function were evaluated in 24 male essential hypertensive patients, on unrestricted (n = 17) and on chronic low as well as on high sodium intake. Aprotinin (1 X 10(6) kallikrein inhibitor units) or saline (200 ml) were infused in all patients for 6 h. Blood samples were taken for plasma renin activity (PRA) and 6-h urine collections were obtained for active and inactive kallikrein, sodium and potassium excretion measurement. In patients on unrestricted sodium diet, aprotinin had no effect on blood pressure (BP), glomerular filtration rate, renal plasma flow, urinary sodium and potassium excretion. However, an inverse relationship was found between pretreatment urinary sodium excretion and the per cent reduction of the latter after aprotinin. A significant reduction in urinary sodium excretion was induced by aprotinin in patients on high sodium intake, whereas no change was observed in the same patients when on a low sodium diet. Aprotinin reduced the urinary excretion of active kallikrein by 81% and the active to total kallikrein ratio from 24 to 6%. Infusion of aprotinin induced a significant decline in active renin but did not modify inactive renin levels in patients on unrestricted sodium diet as well as in patients on low or high sodium intake. Our data suggest that the inhibition of kallikrein and/or other serine proteases by aprotinin can interfere with renal release of active renin and also support the hypothesis that the renal kallikrein system exerts a regulatory control on sodium excretion in salt replete hypertensives.     

IS THE ‘SODIUM INDEX’ A USEFUL WAY OF EXPRESSING CLINICAL PLASMA RENIN,ANGIOTENSIN AND ALDOSTERONE VALUES?

In normal subjects taking variously high, normal or low sodium diets, while potassium intake was maintained within the normal range, highly significant inverse relationships were demonstrated between 24 h urinary sodium output and the concurrent plasma concentrations of renin, angiotensin II and aldosterone. With linear coordinates, these relationships were described by rectangular hyperbolae. With logarithmic plots the relationships became rectilinear. When 24 h urinary sodium output was 75 mmol or higher, there was no worthwhile advantage in relating renin to sodium excretion; plasma angiotensin II and aldosterone, however, were significantly related inversely to urinary sodium in this range. When 24 h urinary sodium output was below 10 mmol, plasma renin, angjotensin II and aldosterone all varied over wide but elevated ranges and were not significantly related to urinary sodium excretion rates. We conclude that whereas estimations of urinary sodium may be of value in revealing latent aberrations of sodium intake, there is no distinct advantage in relating measurements of renin or angiotensin II to urinary sodium output if the diet is known to be within broad ‘normal’ limits. This should simplify the relevant blood sampling procedure under both ward and outpatient conditions. If plasma renin, angiotensin II and aldosterone are to be related to concurrent urinary sodium output, logarithmic, rather than linear, co-ordinates, are appropriate.     

Does a digoxin-like substance participate in vascular and pressure control during dietary sodium changes in patients with primary aldosteronism?

To evaluate the importance of an endogenous sodium pump inhibitor in the pathogenesis of low renin human hypertension, the urinary excretion of a digoxin-like immunoreactive substance (DLIS) was measured in eight patients with primary aldosteronism (n = 5, with adenomas) during two sequential 1-week periods of low- (20 mmol/l NaCl) and high- (200 mmol/l NaCl) sodium intake. DLIS excretion increased consistently during high-sodium intake while urinary aldosterone, plasma renin activity, cortisol and adrenocorticotropic hormone did not change. Although blood pressure showed a time-course parallel to that of the urinary DLIS, the blood pressure increments were not accompanied by evidence of vasoconstriction since forearm blood flow (plethysmographic technique) increased and forearm vascular resistances were reduced. Moreover, the reactivity of forearm arterioles to local norepinephrine was unchanged during the period of low- and high-salt intake, despite the fact that an endogenous sodium pump inhibitor should, supposedly, sensitize the responses to an adrenergic agonist. Finally, forearm vasoconstrictor responses to ouabain, a pharmacological Na+,K(+)-ATPase antagonist, were potentiated during the high-salt diet, a result not expected if an increased number of sodium pumps were occupied by an endogenous inhibitor. These results provide unequivocal evidence for a modulation by salt intake of the urinary excretion of a DLIS in patients with primary aldosteronism. This substance might participate in the regulation of body fluid volume in this syndrome and possibly in other physiological conditions. However, no evidence could be found for a cause--effect relationship between blood pressure and DLIS increments during high-salt intake, at least during the short-term course of the study.     

Hormonal Pattern During Development of Hypertension in Spontaneously Hypertensive Rats (SHR)

Urinary excretion of sodium, noradrenaline, dopa-mine, aldosterone, prostaglandin E². and plasma renin activity were determined in 7 and 16 weeks old spontaneously hypertensive rats (SHR) and in two normotensive control strains, ordinary Wistar control rats (NCR) and Wistar-Kyoto normotensive rats (WKR). Each group consisted of 10–11 rats. The animals were kept in metabolic cages. Experiments were performed on standard diet (5–8 mmol Na⁺/100 g food) and with an increased (15.6 and 56.0 mmol Na⁺/100 g food) salt intake.

At 7 weeks of age, when SHR are in a borderline phase of hypertension, they exhibited a decreased urinary sodium excretion, and an increased urinary noradrenaline excretion compared to controls. The latter might reflect an increased overall activity of the sympathetic nervous system. Urinary dopamine excretion was also increased probably mirroring a higher activity in a renal natriure-tic dopamine system. Plasma renin activity and urinary aldosterone excretion were depressed.

At 16 weeks of age, when SHR are in an early established phase of hypertension, urinary sodium excretion was still lower in SHR, while urinary noradrenaline and dopamine excretions had become normal compared to controls. Plasma renin activity and urinary aldosterone excretion remained depressed. Urinary PGE₂ excretion, only determined in this age group, was significantly higher in SHR.

When sodium intake was increased 8-10 times the difference in urinary sodium excretion was diminished and not significantly lower in SHR. The salt load caused a doubling of the urinary dopamine excretion, while the noradrenaline excretion was unchanged.

These findings might be compatible with the view that the decreased urinary sodium excretion in the young SHR would be caused by an increased sympathetic outflow to the kidneys promoting tubular sodium reabsorption while the increased urinary dopamine excretion is regarded as a compensatory mechanism to overcome the difficulties to excrete sufficient amounts of sodium.     

Urinary Excretion Patterns in Renal Failure Due to Malaria: The Effects of Phenoxybenzamine in Two Cases

Summary: Urinary solute excretion was studied in 4 patients with renal failure due to falciparum malaria with heavy parasitaemia. Two patterns of excretion were observed. The first pattern, noted in two patients, was characterised by a urine sodium below 10 mEq/L and a high osmotic urine and plasma ratio. The second pattern, observed in the other 2 patients, showed the urine sodium above 40 mEq/L and iso-osmotic urine. The creatinine clearance was much lower in the patients with the second urinary pattern. In all cases there was no evidence of dehydration or sodium depletion. Following phenoxybenzamine injection there was a significant increase in urine flow, creatinine and osmolar clearances and sodium excretion in the patients with the i first urinary pattern. The other 2 patients with the second urinary pattern showed no significant changes in urine flow, clearances and solute excretion. Renal failure in the first 2 patients is believed to be prerenal, being due to the temporary decrease in blood flow of the outer cortical nephrons secondary to vasoconstriction mediated by norepinephrine discharge from the sympathetic nervous system, which could be corrected by phenoxybenzamine. In the second group the urinary pattern was suggestive of acute tubular necrosis.     

Rapid blood pressure control with minoxidil: acute and chronic effects on blood pressure, sodium excretion, and the renin-aldosterone system.

Changes in blood pressure, heart rate, electrolyte excretion, and the renin-angiotensin-aldosterone system were monitored before and after minoxidil was added to a regimen of a diuretic and propranolol hydrochloride in 12 severely hypertensive patients. None required more than 40 mg of minoxidil daily for control. On a constant intake, urinary sodium excretion decreased, while urinary potassium excretion remained stable. Heart rate, body weight, and plasma volume increased, while creatinine clearance did not change. Although plasma renin activity increased fourfold, the plasma aldosterone concentration did not increase. Six subjects were restudied after two months of minoxidil treatment. Although blood pressure control continued to be excellent in these subjects, plasma renin values and plasma volume had returned to pretreatment levels. These studies suggest that minoxidil rapidly and effectively lowers blood pressure. Although sodium retention accompanies minoxidil administration acutely, the effect is independent of aldosterone and may be transient.     

Low Response of Renin–Angiotensin System to Sodium Intake Intervention in Chinese Hypertensive Patients

The interactions of sodium balance and response of renin–angiotensin–aldosterone system are important for maintaining the hemodynamic stability in physiological conditions. However, the influence of short-term sodium intake intervention in the response of renin–angiotensin system (RAS) on hypertensive patients is still unclear. Thus, we conducted a clinical trial to investigate the effects of short-term sodium intake intervention on the response of RAS in hypertensive patients.One hundred twenty-five primary Chinese hypertensive patients were divided into high, moderate, and low sodium groups by 24-hour urinary sodium excretion (UNa⁺). All the patients received a 10-day dietary sodium intake intervention with standardized sodium (173.91mmol/day) and potassium (61.53mmol/day). Blood pressure, urinary sodium, urinary potassium, plasma sodium, potassium, creatinine, the levels of plasma renin activity, plasma angiotensin II concentrations (AT-II), and plasma aldosterone concentrations were detected before and after the intervention.Before the intervention, no differences were found in blood pressure and RAS among 3 groups. After standardized dietary sodium intake intervention, both UNa⁺ excretion and systolic pressure decreased in high-sodium group, while they increased in moderate and low-sodium groups. Intriguingly, there were no changes in the levels of plasma renin activity, AT-II, and plasma aldosterone concentrations among 3 groups during the intervention.The present study demonstrated that the influenced sodium excretion and blood pressure by short-term sodium intake intervention were independent of RAS quick response in Chinese hypertensive patients.     

Blood pressure, sodium intake, insulin resistance, and urinary nitrate excretion

The objective of this study was to investigate the relationships among various humoral factors thought to be involved in the regulation of blood pressure during high NaCl intake. Nineteen healthy subjects underwent sequential 5-day periods ingesting a low-sodium (25 mmol/d) or high-sodium (200 mmol/d) diet. Insulin resistance was assessed by the steady-state plasma glucose concentration at the end of a 3-hour insulin suppression test. Insulin resistance correlated inversely with natriuresis (P=0.04) and directly with increase in weight (P=0.03). The increase in mean arterial pressure associated with the high-sodium diet correlated directly with the gain in weight (P<0.05) and inversely with the increase in urinary nitrate excretion (P<0.0001). In a multiple regression model, more than 2/3 of the variance in mean arterial pressure was accounted for by the gain in weight and change in urinary nitrate excretion. The steady-state plasma glucose concentrations obtained with the 2 diets were similar, indicating that insulin resistance was unaffected by sodium intake. During high sodium intake, plasma renin activity and aldosterone decreased and plasma atrial natriuretic peptide increased; these changes did not correlate with the change in mean arterial pressure, insulin resistance, or change in urinary nitrate excretion. To the extent that urinary nitrate excretion reflects activity of the endogenous nitric oxide system, these results suggest that the salt sensitivity of mean arterial pressure may be related to blunted generation of endogenous nitric oxide. The results also demonstrate that insulin-resistant individuals have an impaired natriuretic response to high sodium intake.