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European Journal of Heart Failure 2004 6(5):593-599; doi:10.1016/j.ejheart.2003.11.020
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© 2004 European Society of Cardiology

The effect of dietary sodium restriction on neurohumoral activity and renal dopaminergic response in patients with heart failure

Margarida Alvelosa,*, António Ferreiraa,b, Paulo Bettencourta,b, Paula Serrãoc, Manuel Pestanad, Mário Cerqueira-Gomesa and Patrício Soares-da-Silvac

a Unit of Cardiovascular Research and Development Piso 9, Porto, Portugal
b Department of Medicine – Medicine B, Hospital S. João Porto, Portugal
c Institute of Pharmacology and Therapeutics, University of Porto Medical School Porto, Portugal
d Department of Medicine, Division of Nephrology, Hospital S. João Porto, Portugal

* Corresponding author. Present address: Margarida Isabel Ribeiro de Cavadas Pereira e Alvelos, Unidade de Investigação e Desenvolvimento Cardiovascular do Porto, Piso 9, Hospital de S. João, Alameda Hernâni Monteiro, 4200 Porto, Portugal. Tel.: +351-225096369; Fax: +351-225089788. E-mail address: malvelos{at}netcabo.pt


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: This work evaluates the effect of a low-sodium diet on clinical and neurohumoral parameters and on renal dopaminergic system activity in heart failure (HF) patients.

Methods: We included 24 patients with mild-to-moderate stable HF with left ventricle ejection fraction <40%. Twelve patients were studied before and after a 15-day low-sodium diet; 12 maintained their usual diet. Serum sodium and creatinine, plasma L-DOPA, dopamine, its metabolites, BNP and aldosterone, and 24-h urinary sodium, creatinine, L-DOPA, dopamine and metabolites were measured.

Results: The two groups were matched respecting to demographic and clinical parameters. Low-sodium diet caused significant reductions in weight, 24-h urinary volume and sodium and sodium fractional excretion. Renal delivery of L-DOPA and urinary excretion of L-DOPA significantly decreased while dopamine and metabolites were not affected. Urinary dopamine/L-DOPA and urinary dopamine/renal delivery of L-DOPA ratios increased, plasma L-DOPA decreased and plasma dopamine increased. Plasma aldosterone slightly rose, BNP decreased and noradrenaline and adrenaline increased. NYHA functional class was not affected by sodium restriction. Controls showed no differences.

Conclusions: These results suggest that sodium restriction leads to activation of antinatriuretic antidiuretic systems in HF patients. However, renal ability to synthesize dopamine is increased in this condition, probably as a counter-regulatory mechanism.

Key Words: Abbreviations • BNP, B-type natriuretic peptide • DOPAC, 3,4-dihydroxyphenylacetic acid • HF, heart failure • L-DOPA, L-3,4-dihydroxyphenylalanine

Received September 1, 2003; Revised November 11, 2003; Accepted November 19, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
The activation of the sympathetic and renin–angiotensin–aldosterone systems that occurs in heart failure (HF) leads to a reduction in renal blood flow and avid tubular reabsorption of sodium and water. The superimposed non-osmotic release of arginine–vasopressin increases this antidiuretic effect. The result of this neurohumoral activation is the formation of edema. The increase in left ventricular volume and pressure is a potent stimulator to the release and synthesis of natriuretic peptides, namely B-type natriuretic peptide (BNP). BNP exerts counter-regulatory natriuretic, diuretic and vasodilator actions [1–5]. In patients with mild-to-moderate compensated HF these two sets of systems are in a relative equilibrium; however, in patients with severe or decompensated HF the latter is clearly overwhelmed by the former [6,7].

The inability to excrete ingested sodium and the activation of neurohumoral mechanisms are well characterized features of congestive HF, and the influence of high sodium intake on hemodynamic, renal and hormonal parameters in patients with mild HF has been reported before [8,9]. Dietary sodium restriction is a mainstay in the management of patients with severe or decompensated HF [10]. In patients with severe volume overload, the effectiveness of diuretics is reduced, and dosages often need to be increased in the absence of sodium restriction [11]. Despite this consensus, to date no balanced study has been performed to assess the renal and neurohumoral interactions that occur when sodium intake is restricted. Thus, the role of sodium restriction in the therapeutic armamentarium of patients with mild-to-moderate compensated HF has not been established so far. In rats with chronic HF, salt restriction did not prevent the progression of cardiomegaly [12].

The epithelial cells of the renal proximal convoluted tubules are endowed with high L-aromatic aminoacid decarboxylase activity, being able to synthesize dopamine from filtered or circulating L-3,4-dihydroxyphenylalanine (L-DOPA) [13–18]. Dopamine of renal synthesis exerts paracrine natriuretic and diuretic effects by activating D1-like receptors located in all nephron segments, resulting in inhibition of the Na+–K+ ATPase and the Na+–H+ exchanger located in the basolateral and apical membranes, respectively [13,19–22]. Dopamine is rapidly metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC), the deaminated metabolite, and to homovanillic acid, the O-methylated and deaminated metabolite, by the action of monoamine oxidase and catechol-O-methyltransferase [23]. This non-neuronal renal dopaminergic system is highly active and its regulation depends on the amounts of L-DOPA delivered to the kidney, the uptake of L-DOPA by the epithelial cells, its decarboxylation into dopamine, the metabolization of newly formed dopamine and in outward amine transfer mechanisms [23]. The amount of sodium delivered to the kidney also affects the renal synthesis of dopamine and has been suggested to represent a major role in determining its availability [24–26]. Patients with HF have a reduced delivery of L-DOPA to the kidney as a consequence of a decreased renal blood flow. However, there is increasing evidence suggesting that the renal dopaminergic system may be considered as a natriuretic, diuretic counter-regulatory system activated in patients with HF by stimuli leading to sodium and water reabsorption [27–31].

The aim of the present study was to evaluate the effect of dietary sodium restriction on neurohumoral activation and renal dopaminergic system response in mild-to-moderate compensated HF.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1. Patients
This study enrolled 24 patients with mild-to-moderate chronic HF, with left ventricle ejection fraction lower than 40% and with no exacerbations or therapeutic changes in the previous 2 months. Patients with concomitant significant valve disease, renal or hepatic failure, diabetes mellitus or pulmonary diseases were excluded from the study. The patients were randomly assigned to two groups: 12 patients were submitted to a low-sodium diet (100 mmol Na+/day) during a 15-day period, while the remaining patients maintained their usual-salt diet (controls). The study was performed in accordance with the Declaration of Helsinki (1989) of the World Medical Association. The local ethics committee approved the study protocol, and participants gave informed consent.

2.2. Experimental procedures
Venous blood samples (for measurement of L-DOPA, dopamine, DOPAC, adrenaline, noradrenaline, aldosterone, BNP, sodium and creatinine) and 24-h urine collections (for L-DOPA, dopamine, DOPAC, homovanillic acid, noradrenaline, sodium and creatinine) were obtained at baseline and after the 15-day period on both low-salt and normal-salt diet groups. Venous blood samples were obtained from an antecubital vein after a 20-min rest in the supine position between 08.00 and 10.00 h after overnight fasting. Blood was immediately chilled in plastic tubes with heparin (for catecholamine measurement) and K3EDTA (for aldosterone and BNP), centrifuged (4.500 rpm for 15 min at 0 °C) and stored at –80 °C until it was assayed. Urine was collected in plastic containers with 15 ml of 6 M HCl to prevent spontaneous decomposition of monoamines and amine metabolites. Urine samples were stored in plastic tubes at –80 °C until assay. Quantification of catecholamines and its metabolites in urine (L-DOPA, dopamine, DOPAC, homovanillic acid and noradrenaline) and plasma samples (L-DOPA, dopamine, DOPAC, adrenaline and noradrenaline) was performed by high performance liquid chromatography with electrochemical detection, as previously described [32,33]. Dihydroxybenzylamine was used as an international standard, and the interassay coefficient of variation was less than 5%. Quantification of homovanillic acid was performed separately by high performance liquid chromatography with electrochemical detection, using 50-µl aliquots of filtered samples directly injected into the chromatograph. The lower limit of detection of L-DOPA, dopamine, DOPAC, homovanillic acid, adrenaline and noradrenaline ranged from 350 to 1.000 fmol. The plasma aldosterone assay was performed by radioimmunoassay using the Aldoctk-2 system (DiaSorin Srl, Saluggia, Italy) and plasma BNP was measured by immunoradiometric assay (Shianogi Co Ltd., Osaka, Japan). The interassay coefficient of variation was less than 8% and the lower limit of detection was 20 pg/ml for aldosterone and 2 pg/ml for BNP. The assay of sodium in urine and plasma samples was performed by indirect potentiometry using the autoanalyzer Beckman Synchron CX3 (Beckman Instruments, Brea, CA). The assay of creatinine in urine and plasma samples was performed using the kinetic technique with Jaffé reaction also using the autoanalyzer Beckman Synchron CX3, and creatinine clearance was calculated according to the formula [(UCr/PCr)xUVol]/1440, where UCr is urinary creatinine, PCr is plasma creatinine and UVol is urine volume. Fractional excretion of sodium was calculated using the equation [(UNaxPCr)/(PNaxUCr)]x100, where UNa is urinary sodium, PNa is plasma sodium, UCr is urinary creatinine and PCr is plasma creatinine.

M-mode and two-dimensional echocardiograms were performed in all patients using the same echocardiography unit (Hewlett Packard Sonos 5500, Hewlett Packard, Palo Alto, CA). Left ventricular systolic function was assessed by measurement of left ventricle ejection fraction using the biplane disc summation method (Simpson rule) or the Bullet single and biplane ellipse method.

2.3. Statistical analysis
Mann–Whitney U test was used to evaluate differences in numerical variables between the two groups. Wilcoxon's signed-ranks test was used to test for differences between measurements performed at baseline and after the 15-day diet period. For comparisons of categorical variables we used the likelihood ratio Chi-square or Fisher's exact test when appropriate. Data are expressed as mean±S.E.M. P<0.05 is considered statistically significant. Statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS Inc., Chicago, IL).


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
As shown in Table 1, the two groups of patients were well balanced relating to sex, age, body surface area, HF etiology, left ventricle ejection fraction, NYHA class, presence of atrial fibrillation, use and doses of angiotensin converting enzyme inhibitors, diuretics and β-blockers, and use of digoxin. Most of them were on angiotensin converting enzyme inhibitors and the remaining were on angiotensin II antagonists. No patient was on spironolactone, non-steroidal anti-inflammatory drugs or other drugs known to affect sodium handling or renal production of dopamine.


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  		Table 1 Baseline patients’ characteristics

 
At baseline, plasma levels of L-DOPA, dopamine, DOPAC, adrenaline, noradrenaline, aldosterone and BNP, and 24-h urinary excretion of L-DOPA, dopamine, DOPAC, homovanillic acid and noradrenaline did not differ between the two groups (Tables 2 and 3 and Figs. 1 and 2). Urine volume, urinary sodium, creatinine clearance and fractional excretion of sodium were also similar between the two groups (Table 4).


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  		Table 2 Plasma levels of dopamine, its precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), and metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in normal-salt and low-salt groups

 


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  		Table 3 Twenty-four-hour urinary excretion of dopamine metabolites and noradrenaline in normal-salt and low-salt groups

 


Figure 1
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  		Fig. 1 Plasma levels of noradrenaline, adrenaline, aldosterone and BNP at baseline (open columns) and after 15-day period (close columns) in normal-salt and low-salt groups. (*P< 0.05; {dagger}P=0.08).

 


Figure 2
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  		Fig. 2 Renal delivery of L-3,4-dihydroxyphenylalanine (L-DOPA), 24-h urinary excretion of L-DOPA and dopamine and urinary dopamine/L-DOPA ratio at baseline (open columns) and after 15-day period (close columns) in normal-salt and low-salt groups. (*P<0.05).

 


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  		Table 4 Twenty-four-hour urine volume, urinary creatinine, urinary sodium, creatinine clearance and fractional excretion of sodium in normal-salt and low-salt groups

 
The low-sodium diet markedly reduced body weight (from 68.53±5.45 to 67.31±5.30 kg, P<0.02), creatinine clearance, 24-h urine volume and urinary sodium, and fractional excretion of sodium (Table 4). The renal delivery of L-DOPA, which considers L-DOPA plasma levels and creatinine clearance, and the urinary excretion of L-DOPA were significantly reduced by low-sodium diet, while dopamine and its metabolites were not affected (Fig. 2 and Table 3). Urinary dopamine/L-DOPA ratio (Fig. 2) and urinary dopamine/renal delivery of L-DOPA ratio (from 0.50±0.03 to 0.64±0.07, P=0.03), two indexes of the renal dopamine synthesizing efficiency, were significantly increased by low-sodium diet. Plasma L-DOPA decreased while plasma dopamine increased in response to low-sodium diet. Plasma aldosterone slightly rose and BNP significantly decreased in response to low-sodium diet (Fig. 1). Plasma noradrenaline and adrenaline concentrations increased in response to low-sodium diet (Fig. 1). Urinary noradrenaline was not changed after low-sodium diet (Table 3). NYHA functional class was not affected by sodium restriction. There was a decrease in mean blood pressure, without clinical repercussions (from 97.6±7.7 to 85.1±4.6 mmHg, P<0.06) in response to low-sodium diet. Controls showed differences in neither body weight (from 72.81±3.53 to 71.85±3.32 kg, P=0.07) and mean blood pressure (from 114.4±9.2 to 108.1±3.9 mmHg, P=0.61) nor in any other parameters (Tables 2–4 and Figs. 1 and 2), including the urinary dopamine/renal delivery of L-DOPA ratio (from 0.64±0.05 to 0.69±0.06, P=0.64).

The effect of sodium restriction was further investigated by comparing the differences in the variations of study variables produced by low- and normal-salt diets. As shown in Table 5, the variations in urinary sodium, fractional excretion of sodium, plasma BNP and urinary dopamine/L-DOPA ratios in low-salt diet were significantly greater than in normal-salt diet. The amplitude of the variation in plasma L-DOPA and dopamine and in urinary L-DOPA in low-salt diet showed a trend to be greater than in normal-salt diet. No other differences with statistical significance were found (Table 5).


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  		Table 5 Variations ({Delta}) in study variables and the statistical significance for the differences between normal- and low-salt diets

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
Sodium retention and volume overload are fundamental hallmarks of the HF syndrome, and most of the symptoms and physical signs that occur in this condition largely result from the inability to excrete sodium and water [6,7]. However, in this work we studied euvolemic patients, most of them under diuretic therapy. They responded to low-salt diet with volume depletion and consequent activation of sympathetic and renin–angiotensin–aldosterone systems, and decrease in BNP production. Therefore, it seems that in stable euvolemic HF patients under diuretic therapy, salt restriction can worsen neurohumoral steady state.

Recently, it has been shown that patients with chronic stable HF, when compared to healthy controls, have a reduced urinary excretion of L-DOPA and dopamine that appears to result from reduced delivery of L-DOPA to the kidneys. [29] In this study, both normal- and low-salt groups presented an identical ability of renal epithelial tubular cells to take up and/or decarboxylate filtered L-DOPA during normal-salt intake. However, in conditions of salt restriction, HF patients showed a marked increase in renal L-DOPA utilization, with an increased ability to synthesize dopamine. This indicates that patients with HF are endowed with the ability to increase the activity of their renal dopaminergic system in response to stimuli leading to volume depletion and sodium retention. In the present study, low-salt diet was accompanied by significant decreases in body weight, blood pressure and creatinine clearance. This indicates that body fluid volume was decreased. As a consequence, BNP also decreased and the sympathetic and renin–angiotensin–aldosterone systems were activated. The activation of these vasoconstrictor, antinatriuretic and antidiuretic systems may have induced a reduction in renal blood flow. The result of these hemodynamic and neurohumoral alterations was an increase in renal sodium and water reabsorption (as indicated by a decrease in urine volume and in urinary sodium and fractional excretion of sodium). This may also explain the reduction in the renal delivery of L-DOPA and consequently the decrease in 24-h urinary excretion of L-DOPA. Another interesting observation is that low-salt diet was accompanied by a reduction in L-DOPA plasma levels, which may have contributed to the reduction of the renal delivery of L-DOPA. This decrease in plasma levels of L-DOPA may be explained by a reduction in L-DOPA absorption from the gut [34]. However, plasma levels of dopamine increased in response to low-sodium diet, which could be interpreted as the activation of a vasodilator and natriuretic counter-regulatory system, as previously proposed by Dzau [27]. Urinary dopamine remained unaltered despite the reduction of urinary excretion of its precursor, L-DOPA. Urinary dopamine/L-DOPA ratios and urinary dopamine/renal delivery of L-DOPA ratios were increased, indicating that sodium restriction was accompanied by an increase in the renal dopamine synthesizing efficiency. An increase in the uptake and/or decarboxylation of filtered L-DOPA may explain the improved ability to synthesize dopamine. Renal dopamine metabolism was not affected by low-salt diet (as indicated by the similarity in the urinary excretion of DOPAC and homovanillic acid). Renal noradrenergic tonus was not affected by sodium restriction. Taken together, these results suggest that sodium restriction, leading to a deleterious activation of antinatriuretic and antidiuretic systems, is accompanied by activation of the renal dopaminergic system, with an increased ability to synthesize dopamine, probably as a counter-regulatory mechanism.

We studied a well-balanced population on controlled low-sodium intake, finding no significant differences between the two groups, with respect to demographic characteristics, medications, renal function and levels of neurohumoral activation. Several conditions other than cardiac dysfunction may affect renal dopamine production. Because the renal tubules are the main source of renal dopamine, renal parenchymal diseases, namely chronic renal failure, are associated with decreased urinary excretion of dopamine [35–37]. For this reason, patients with other diseases known to affect renal dopamine production were excluded from this study. However, acute modifications on some medications, namely furosemide, are also known to influence renal dopamine production and sodium handling [38–40]. However, only patients with chronic stable HF without modifications in the therapeutic regimen or clinical status in the last 2 months were selected for inclusion in the study. Thus, it is likely that the increased renal ability to synthesize dopamine, despite the reduced availability of L-DOPA, might be the mechanism for the preservation of the amine synthesis in patients with mild-to-moderate compensated HF under sodium restriction.

In conclusion, salt restriction in patients with mild-to-moderate stable HF under diuretic therapy may induce volume depletion and neurohumoral activation. However, increases in the renal rate of L-DOPA utilization during sodium restriction may relate to activation of counter-regulatory mechanism.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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