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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 9 4180-4185
Copyright © 2003 by The Endocrine Society

Salt Loading Affects Cortisol Metabolism in Normotensive Subjects: Relationships with Salt Sensitivity

Michiel N. Kerstens, Frank G. H. van der Kleij, Arnold H. Boonstra, Wim J. Sluiter, Jan Koerts, Gerjan Navis and Robin P. F. Dullaart

Departments of Endocrinology (M.N.K., W.J.S., R.P.F.D.) and Nephrology (F.G.H.V.D.K., A.H.B., G.N.) and Laboratory Center (J.K.), University Hospital Groningen, 9700 RB Groningen, The Netherlands

Address all correspondence and requests for reprints to: M. N. Kerstens, M.D., Department of Endocrinology, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: m.n.kerstens{at}int.azg.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We studied cortisol metabolism together with insulin sensitivity [homeostatic model assessment (HOMA)] and renal hemodynamics in 19 salt-resistant (sr) and nine salt-sensitive (ss) normotensive subjects after a low- and high-salt diet. Results are described as high- vs. low-salt diet. Sum of urinary cortisol metabolite excretion ({sum}metabolites) increased in sr subjects (3.8 ± 1.6 vs. 3.1 ± 1.1 µg/min per square meter, P < 0.05) and decreased in ss subjects (2.3 ± 1.0 vs. 2.9 ± 1.1 µg/min per square meter, P < 0.05). Plasma 0830 h cortisol decreased in sr subjects but did not change significantly in ss subjects. In all subjects, the absolute blood pressure change correlated negatively with the percentage change in {sum}metabolites (P < 0.05) and positively with the percentage change in renal vascular resistance (P < 0.05). {sum}metabolites during high-salt diet correlated negatively with the percentage changes in plasma 0830 h cortisol (P < 0.05) and renal vascular resistance (P = 0.05). HOMA did not change in either group, but the percentage change in HOMA correlated positively with the percentage change in plasma cortisol (P = 0.001) and negatively with the percentage change in {sum}metabolites (P < 0.01). Parameters of 11ß-hydroxysteroid dehydrogenase activity were not different between groups and did not change. In conclusion, these data suggest that cortisol elimination is affected differently after salt loading in sr and ss subjects. Changes in circulating cortisol might contribute to individual sodium-induced alterations in insulin sensitivity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
BASED ON THE blood pressure change after salt loading, individuals can be classified as salt-sensitive (ss) and salt-resistant (sr), although it should be noted that salt sensitivity is a continuous trait (1). Whereas traditionally most studies in salt sensitivity focus on hypertensive subjects, recent data support its importance in normotensive subjects, in whom the ssphenotype carries an increased risk for development of hypertension and is associated with an increased mortality (2). The exact mechanism underlying salt sensitivity has not been elucidated, but it has been related to several metabolic, vascular, and genetic factors (3).

There might also be a link between salt sensitivity and cortisol metabolism. One study suggested that hypertensive patients with the highest urinary excretion of free cortisol had the smallest blood pressure response to salt loading (4). In healthy subjects, dietary salt loading increases and sodium restriction decreases urinary free cortisol excretion (5, 6, 7). However, cortisol elimination can be more comprehensively determined by measurement of urinary cortisol metabolite excretion (8). So far, the possible relationship between salt sensitivity and total urinary cortisol metabolite excretion has not been studied in normotensive individuals. Moreover, sodium intake has been proposed to affect cortisol metabolism by modification of the activity of 11ß-hydroxysteroid dehydrogenase (11ßHSD), an enzyme that catalyzes the interconversion between cortisol and its inactive metabolite cortisone (8). In humans two isozymes exist, with 11ßHSD type 1 activating cortisone to cortisol and 11ßHSD type 2 inactivating cortisol to cortisone. In kidney, 11ßHSD type 2 acts as a gatekeeper for the mineralocorticoid receptor, protecting it from inappropriate stimulation by cortisol. The only available study so far (9) showed that variation in sodium intake does not modify the 11ßHSD setpoint, but it was suggested that the activity of 11ßHSD type 2 is lower in ssthan in sr normotensive subjects.

Previous studies have reported variable effects of salt loading on insulin sensitivity (3, 10, 11, 12). If cortisol metabolism does change after salt loading, it would be of interest to know whether such changes are associated with variations in insulin sensitivity.

Whereas metabolic factors might be involved in salt sensitivity, it has also been stated that salt sensitivity is a reflection of (subclinical) renal dysfunction, resulting from either renal function impairment or altered renal vascular reactivity to increased salt intake (13). In this respect it has been shown that the increase in effective renal plasma flow (ERPF) is blunted and renal vascular resistance (RVR) is increased after a high-sodium diet in ss, compared with sr individuals (13, 14). Similar differences in hemodynamic response between ss and sr subjects in response to a high-sodium diet have been suggested to occur in liver, the principal site of cortisol catabolism (15). In contrast to the liver, noninvasive measurement of renal hemodynamics can be performed relatively easy and is highly accurate.

We hypothesized that salt sensitivity in normotensive subjects is associated with sodium-induced alterations in cortisol metabolism. We, therefore, studied the effects of dietary sodium loading on cortisol metabolism in a group of healthy, normotensive subjects, divided into ss and sr subjects. In addition, insulin sensitivity and renal hemodynamics were determined in these subjects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and protocol

Twenty-eight healthy Caucasian subjects (21 males, 7 females) were studied. The study was approved by the local medical ethics committee, and all participants gave written informed consent. All subjects were normotensive, defined as a blood pressure less than 140/85 mm Hg. None of the subjects used medications, including oral contraceptives. Each participant was studied on two separate occasions, after having used in random order a low (50 meq/d) and a liberal (200 meq/d; further referred to as high) sodium diet for 1 wk, with an intake of 100 meq potassium daily (16). The diets were prescribed by a dietitian. To prevent changes in dietary habits, the diets were based on the personal food habits of each subject and fitted to the individual caloric needs. Differences in sodium intake were achieved by replacing sodium-rich food products with a low-sodium brand of the same product. Sodium supplements were used only by subjects in whom a high-sodium intake would otherwise have resulted in a change of dietary habits. Compliance was checked from 24-h urine collections 3 d before the actual experimental day. Female subjects were tested in the midluteal phase of the menstrual cycle. Glycyrrhizin-containing products were not allowed during the study. On d 7, 24-h urine was collected for analysis, and each participant visited our research unit at 0800 h on d 8, after an overnight fast. Completeness of 24-h urine collections was estimated by measurement of urinary creatinine. Blood samples were drawn after 30 min of supine rest. Body weight and height were measured and body mass index was calculated as weight divided by height squared. Blood pressure was recorded at 15-min intervals with an automated device (Dinamap, GE Medical Systems, Milwaukee, WI) with patients in semirecumbent position, and the mean of the values obtained between 1000 and 1200 h was used for analysis. Salt sensitivity was arbitrarily defined as an increase of mean arterial blood pressure (MAP) of 3 mm Hg or more during the high- vs. the low-sodium diet and salt resistance as a difference of less than 3 mm Hg (1, 9).

Glomerular filtration rate and ERPF were measured by constant infusion of 125I-iothalamate and 131I-hippuran, respectively (17). RVR was calculated as the ratio of MAP to ERPF.

Insulin sensitivity was analyzed by homeostatic model assessment (HOMA), according to the formula: fasting plasma glucose x fasting plasma insulin/22.5 (18).

Laboratory measurements

Serum and urine electrolytes were determined on a Mega Multi-Test analyzer (Merck, Darmstadt, Germany). Blood glucose was measured on a glucose analyzer (APEC Inc., Danvers, MA).

Venous blood samples for hormonal assays were collected in prechilled ethylenediamine tetraacetate-anticoagulated glass tubes, which were immediately centrifuged and frozen at -20 C until assay. Plasma-free insulin was measured by RIA after polyethylene-glycol precipitation (Novo Nordisk, Copenhagen, Denmark). Plasma renin activity was assayed by RIA measuring the generation of angiotensin-I (CIS-Bio International, Gif-sur-Yvette, France). Plasma cortisol and aldosterone were measured by in-house RIAs (19).

Urinary free cortisol (UFF) and free cortisone (UFE) were measured after differential extraction with organic solvents and affinity chromatography by RIA (19, 20). Urinary steroid metabolites were analyzed by gas chromatography (20, 21, 22). The overall setpoint of 11ßHSD activity in vivo was estimated as a urinary ratio: tetrahydrocortisol (THF) + allo-tetrahydrocortisol (allo-THF) to tetrahydrocortisone (THE) (8). The ratio of UFF to UFE was used as an index of 11ßHSD type 2 activity in vivo (23, 24, 25, 26). Cortisol elimination was calculated as the sum of urinary excretion of THF, allo-THF, THE, cortols, and cortolones, which in a steady-state situation equals cortisol production (27).

Statistical analysis

Data are presented as mean ± SD. Within-group changes in variables were evaluated by the paired-Wilcoxon test. Between-group differences in variables were compared by the Mann-Whitney U test. Bivariate relationships between parameters were evaluated by Spearman’s rank correlation analysis. Multiple stepwise regression analyses were performed to assess the independent association between variables. A two-sided value P < 0.05 was considered to be significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
After salt loading, MAP was reduced by -4 ± 4 mm Hg (range -13 to 0 mm Hg) in 19 sr subjects (16 males, 3 females) and increased by 6 ± 4 mm Hg (range 3–15 mm Hg) in nine ss subjects (five males, four females; Table 1Go). Sex distribution was not different between groups (Pearson {chi}2: P = 0.24). The sr and ss subjects were not different with respect to age (23.1 ± 1.9 and 25.4 ± 4.5 yr, respectively, NS) and body mass index (22.6 ± 2.8 and 21.6 ± 3.6 kg/m2, respectively, NS). The increase in body weight during the high-salt diet was not significant in either group (Table 1Go). Urinary sodium excretion was increased in each subject after salt loading and was not different between sr and ss subjects during either diet (Table 1Go). Twenty-four-hour urinary volume was increased in ss subjects after salt loading (2007 ± 791 vs. 1604 ± 752 ml, P < 0.05) but did not significantly change in sr subjects (1514 ± 467 vs. 1679 ± 557 ml, NS) and was not different between groups. Serum sodium and potassium concentrations during low- and high-salt diet were not different between sr and ss subjects (data not shown). Both groups demonstrated an appropriate suppression of plasma renin activity and plasma aldosterone after salt loading (Table 1Go). The HOMA indices did not significantly change in either group in response to sodium loading and were not different between groups (Table 1Go). Glomerular filtration rate and ERPF were not different between the groups and increased during the high-salt diet in both groups (Table 2Go). RVR was similar in sr and ss subjects during the low-salt diet, but after salt loading, a significant reduction of RVR was observed in sr subjects but not in ss subjects (Table 2Go). Consequently, the relative reduction in RVR was larger in sr than ss subjects (-10 ± 9% vs. -0.6 ± 8%, respectively, P = 0.01).


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  		TABLE 1. Blood pressure, sodium excretion, body weight, renin-aldosterone axis, and HOMA in sr and ss subjects

 

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  		TABLE 2. Renal hemodynamics in sr and ss subjects

 
Plasma cortisol decreased after salt loading in sr subjects, whereas no significant change was observed in ss subjects (Table 3Go). Plasma cortisol concentrations were not different between sr and ss subjects during either diet (Table 3Go). Neither the excretion of UFF and UFE nor the sum of urinary cortisol metabolites was different between the groups during the low-salt diet (Table 3Go). During the high-salt diet, a significant increase of UFF, UFE, and the sum of cortisol metabolites was observed in sr subjects. In contrast, UFE and the sum of cortisol metabolites were decreased in ss subjects (Table 3Go). Likewise, a difference in response to salt loading was observed in the sr and ss subjects with respect to the urinary excretion of ring A reduced metabolites. During the high-salt diet, the sr subjects demonstrated an increased excretion of THF [0.73 ± 0.26 vs. 0.59 ± 0.22 µg/min·m2 (2.0 ± 0.7 vs. 1.6 ± 0.6 nmol/min·m2), P < 0.05], allo-THF [0.73 ± 0.55 vs. 0.59 ± 0.33 µg/min·m2 (2.0 ± 1.5 vs. 1.6 ± 0.9 nmol/min·m2), P = 0.08], and THE [1.47 ± 0.70 vs. 1.14 ± 0.48 µg/min·m2 (4.0 ± 1.9 vs. 3.1 ± 1.3 nmol/min·m2), P < 0.05]. In ss subjects, however, the high-salt diet resulted in a decreased excretion of THF [0.44 ± 0.18 vs. 0.55 ± 0.18 µg/min·m2 (1.2 ± 0.5 vs. 1.5 ± 0.5 nmol/min·m2), P = 0.07] and allo-THF [0.40 ± 0.18 vs. 0.55 ± 0.26 µg/min·m2 (1.1 ± 0.5 vs. 1.5 ± 0.7 nmol/min·m2), P = 0.05], without a significant change in THE excretion [0.88 ± 0.51 vs. 1.17 ± 0.59 µg/min·m2 (2.4 ± 1.4 vs. 3.2 ± 1.6 nmol/min·m2), NS]. Accordingly, the relative changes in UFE, THF, allo-THF, THE and the sum of cortisol metabolites during the high-salt vs. the low-salt diet were also significantly different between sr and ss subjects (Fig. 1Go). The sr and ss subjects did not demonstrate significant differences in the urinary (THF+allo-THF)/THE) or UFF/UFE ratio during either diet (all P > 0.10, Table 3Go). Moreover, these 11ßHSD parameters remained unchanged after salt loading in both groups (all P > 0.10, Table 3Go).


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  		TABLE 3. Plasma cortisol at 0830 h and urinary excretion of sum of cortisol metabolites, free cortisol, free cortisone, and 11ßHSD parameters in sr and ss subjects

 


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  		FIG. 1. Individual percentage changes in urinary excretion of free cortisol, free cortisoneage and cortisol metabolites during high-salt, compared with low-salt, diet in sr ({circ}) and ss ({blacksquare}) subjects. {sum}metabolites, urinary sum of cortisol metabolites. Mean values presented by horizontal line. *, P < 0.05, {dagger}, P < 0.01.

 
In the combined subjects, the absolute blood pressure change after salt loading was negatively correlated with the percentage change in the sum of cortisol metabolites (rs = -0.38, P < 0.05) and positively with the percentage change in RVR (rs = 0.40, P < 0.05). Multiple regression analysis confirmed that salt sensitivity, categorized as sr and ss, was negatively associated with the percentage change in sum of cortisol metabolites (P = 0.008), independently from gender (P = 0.09). Likewise, the absolute blood pressure change after salt loading was also negatively associated with the percentage change in sum of cortisol metabolites (P = 0.02) but not with gender (P = 0.60). Thus, the differences in urinary cortisol metabolite excretion in response to salt loading between the sr and ss groups were not confounded by the chosen cut-off point to define salt sensitivity. Moreover, there was no significant contribution of gender to the observed differences in cortisol metabolite excretion between groups. Further analysis revealed negative bivariate correlations between the sum of cortisol metabolites during high-salt diet and the percentage changes in plasma 0830 h cortisol (rs = -0.42, P < 0.05) and RVR (rs = -0.37, P = 0.05) in the combined subjects. In addition, the absolute change in sum of cortisol metabolites after salt loading correlated negatively with the percentage change in plasma 0830 h cortisol (rs = -0.45, P < 0.05). There was also a negative correlation between the percentage changes in sum of cortisol metabolites and RVR after salt loading (rs = -0.37, P = 0.05). Multiple regression analysis indeed disclosed independent negative relationships (multiple R = 0.53) of the sum of cortisol metabolites after salt loading with the percentage changes in plasma 0830 h cortisol (P = 0.03) and RVR (P = 0.04). There was no significant correlation between the percentage changes in plasma 0830 h cortisol and absolute blood pressure changes after salt loading (rs = 0.12, P > 0.50). Finally, as shown in Fig. 2Go, the percentage change in HOMA after salt loading correlated positively with the percentage change in plasma cortisol (rs = 0.60, P = 0.001) and negatively with the percentage change in sum of cortisol metabolites (rs = -0.48, P < 0.01).



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  		FIG. 2. A, Positive correlation between percentage changes in HOMA index and plasma cortisol at 0830 h after salt loading (rs = 0.60, P = 0.001). B, Negative correlation between percentage changes in HOMA index and urinary sum of cortisol metabolites ({sum}metabolites) after salt loading (rs = -0.48, P < 0.01).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study clearly demonstrates changes in cortisol metabolism in response to dietary sodium in normotensive subjects. Interestingly, the sum of urinary cortisol metabolites, which can be considered as an estimate of cortisol elimination, was on average increased in sr, but decreased in ss subjects after salt loading. Likewise, the excretion of UFF, UFE, and each of the individual cortisol metabolites (THF, allo-THF, and THE) was higher after salt loading in sr subjects but was unaltered or lower in ss subjects. Of note, these changes in cortisol metabolite excretion after salt loading were accompanied by a decrease in plasma cortisol concentration, particularly in sr individuals. Taken together, it can be envisaged from these data that salt loading induces an increase in cortisol elimination and hence a decrease in circulating cortisol in sr subjects, whereas these effects of salt loading on cortisol metabolism are blunted in ss individuals. The in vivo parameters of 11ßHSD activity, i.e. the ratio of urinary (THF+allo-THF)/THE and UFF/UFE, were not different between sr and ss subjects, and there was no effect of sodium intake on these parameters. Thus, the present study does not support the notion that the 11ßHSD setpoint is a major determinant of salt sensitivity in normotensive subjects. In the whole group, individual changes in insulin sensitivity were found to be correlated with alterations in plasma cortisol levels as well as in cortisol elimination after salt loading, suggesting that sodium loading may affect insulin sensitivity through effects on cortisol metabolism.

Because UFF excretion represents only about 1% of the total cortisol secretion rate and is known to be influenced by urinary flow, it is preferable to measure urinary cortisol metabolite excretion, both to assess the overall 11ßHSD setpoint and estimate cortisol elimination and production (8, 27, 28). Recently Ferrari et al. (9) also studied the relationship between cortisol metabolism and salt sensitivity in a group of 20 healthy volunteers, but the effect of sodium intake on the sum of urinary cortisol metabolite excretion as such was not reported. They also did not observe an effect of sodium intake on the 11ßHSD setpoint. In contrast to our study, the (THF+allo-THF)/THE ratio at baseline was significantly higher in ss than in sr subjects (9). The reasons for this discrepancy with respect to the 11ßHSD setpoint remain unclear but could be related to differences in the prescribed sodium intake and the population studied.

The effects of salt loading on urinary cortisol metabolite excretion could be due to a direct effect of dietary sodium intake on either adrenal cortisol secretion or cortisol elimination. A primary increase in cortisol elimination will indirectly enhance adrenal cortisol secretion through an intact feedback response of the hypothalamus-pituitary-adrenal axis. Notably, we found that the sodium induced increase in urinary cortisol metabolite excretion in sr subjects was accompanied by a decrease in plasma morning cortisol concentration, which strongly suggests a direct effect of dietary sodium loading on cortisol elimination. Such a sodium-induced decrease in circulating cortisol in sr subjects is in keeping with a previous report (29). In agreement with a primary enhancing effect of sodium loading on cortisol elimination, the changes in plasma cortisol were negatively correlated with the changes in urinary cortisol metabolite excretion in the whole group. In ss subjects, the change in plasma cortisol was not significant, whereas urinary cortisol metabolite excretion tended to decrease. In this respect, the aforementioned inverse relationship between the sum of cortisol metabolites and the percentage change in plasma cortisol is of relevance. It suggests that the reciprocal relationship between changes in urinary cortisol metabolite excretion and plasma cortisol can be regarded as a continuum rather than as a qualitatively different response to salt loading in ss subjects.

The pathophysiological mechanisms underlying these sodium-dependent alterations in cortisol elimination are uncertain. It has been previously shown that the hepatic vascular resistance is higher in ss than in sr hypertensive individuals during a high-salt diet (15). Hepatic vascular resistance was not determined in our study, but we did demonstrate a difference in renal vascular response in relation to salt sensitivity. RVR after salt loading was decreased in sr subjects but not in ss subjects. Furthermore, we observed a positive relationship between salt sensitivity and the relative changes in RVR. These findings are in line with our previous study demonstrating an elevated RVR after salt loading in patients with salt-sensitive hypertension (14). The current results as well as other data support the notion that salt sensitivity is associated with a tendency toward vasoconstriction in response to salt loading (13). We, indeed, found an independent negative relationship between the relative changes in RVR and the sum of urinary cortisol metabolites in response to salt loading. Thus, it can be hypothesized that the pathophysiological link between the blood pressure response to salt loading and alterations in cortisol elimination is at least in part attributable to vascular effects, resulting not only in sodium-dependent hemodynamic changes in kidney but also in liver. According to this proposition, sr subjects would respond to sodium loading with an increase in hepatic flow, resulting in an enhanced hepatic cortisol elimination. In ss subjects, hepatic flow would be expected to remain unchanged or even decreased after salt loading, abrogating a rise in hepatic cortisol elimination.

Salt loading has been variably reported to ameliorate, worsen, or exert no effect on insulin sensitivity (3, 10, 11, 12). In the present study, insulin sensitivity was determined by the HOMA index, which is highly correlated to total body glucose disposal as determined by the euglycemic hyperinsulinemic clamp technique (30). Although the HOMA index did not significantly change in the sr and ss groups, we did find an inverse relationship between the percentage changes in sum of cortisol metabolites and in HOMA index after salt loading. Furthermore, the percentage change in plasma cortisol was positively correlated with the percentage change in HOMA index. Taken together, these findings suggest that individual changes in insulin sensitivity after salt loading can result in part from changes in plasma cortisol levels, consequent to alterations in cortisol elimination. That subtle increases in circulating cortisol can indeed deteriorate insulin sensitivity is corroborated by a recent documentation of increased insulin resistance in subjects with subclinical Cushing’s syndrome (31). Theoretically, changes in plasma cortisol could also contribute to sodium-induced effects on blood pressure (32). No significant correlation between changes in plasma cortisol levels and blood pressure response was, however, found in the present study. This suggests that alterations in circulating cortisol are unlikely to represent a major determinant of salt sensitivity.

It should be noted that the duration of our study was limited. Although it is common practice to study salt sensitivity after short-term changes in sodium intake, it remains unknown whether the observed hormonal and hemodynamic changes will be sustained during long-term variations in sodium intake.

In conclusion, urinary cortisol metabolite excretion after salt loading is increased in sr subjects and tends to decrease in ss normotensive subjects. This phenomenon probably is due to alterations in cortisol elimination, which might be secondary to sodium-dependent changes in hepatic flow. Although variations in cortisol metabolism do not seem to be a determinant of salt sensitivity per se, changes in circulating cortisol might contribute to sodium-induced alterations in insulin sensitivity. Our data do not support the possibility that the 11ßHSD setpoint is a major determinant of salt sensitivity.


   Acknowledgments
 
We especially thank Rob Lohr, Hilda van der Molen, Jan van der Molen, and Marchien Velvis for performing the gas chromatographic analyses.


   Footnotes
 
This work was supported by grants (97-27 and 01-13) from the J. K. de Cock Foundation, Groningen, The Netherlands.

Abbreviations: allo-THF, Allo-tetrahydrocortisol; ERPF, effective renal plasma flow; HOMA, homeostatic model assessment; 11ßHSD, 11ß-hydroxysteroid dehydrogenase; MAP, mean arterial blood pressure; RVR, renal vascular resistance; sr, salt-resistant; ss, salt-sensitive; THE, tetrahydrocortisone; THF, tetrahydrocortisol; UFE, urinary free cortisone; UFF, urinary free cortisol.

Received October 18, 2002.

Accepted May 23, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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