- Email: [email protected]
Heart failure, aging, and renal synthesis of dopamine
Heart Failure, Aging, and Renal Synthesis of Dopamine Anto´nio Ferreira, MD, Paulo Bettencourt, MD, Manuel Pestana, MD, PhD, Flora Correia, BSc, Paula Serra˜o, BSc, Luı´s Martins, MD, PhD, Ma´rio Cerqueira-Gomes, MD, PhD, and Patrı´cio Soares-da-Silva, MD, PhD ● The present study evaluates renal dopaminergic activity in 23 patients with heart failure (HF), 10 age-matched controls, and 10 young subjects during normal-salt (NS) intake and after 8 days of low-salt (LS) intake (patients with HF and age-matched controls only). LS intake produced a marked reduction in urine volume in patients with HF but failed to affect urine volume in age-matched controls. Urinary sodium and fractional excretion of sodium were markedly reduced by LS intake in patients with HF and age-matched controls. Daily urinary excretion of L-3,4dihydroxyphenylalanine (L-dopa) and dopamine was lower in patients with HF than in age-matched controls. LS intake failed to alter L-dopa and dopamine urinary excretion in control subjects. In patients with HF, LS intake produced a significant decrease in urinary L-dopa excretion, but failed to alter the urinary excretion of dopamine. No significant differences were observed in urinary L-dopa, dopamine, and dopamine metabolite levels between aged controls and young healthy subjects. Urinary dopamine–L-dopa ratios in patients with HF on LS intake (24.5 ⴞ 7.1) were significantly greater than those with NS intake (11.6 ⴞ 1.3). Urinary dopamine–L-dopa ratios in old control subjects (LS, 9.7 ⴞ 1.3; NS, 9.3 ⴞ 1.1) did not differ from those in young healthy subjects (9.2 ⴞ 0.8). LS intake produced a marked increase in plasma aldosterone levels in both patients with HF (84.6 ⴞ 14.4 to 148.2 ⴞ 20.4 pg/mL; P ⴝ 0.0008) and controls (102.1 ⴞ 13.4 to 151.6 ⴞ 15.7 pg/mL; P < 0.04). Plasma norepinephrine levels were not significantly affected by LS intake in controls (5.1 ⴞ 1.62 to 6.3 ⴞ 1.6 pmol/mL; P ⴝ 0.22), but were significantly increased in patients with HF (5.8 ⴞ 0.8 to 7.1 ⴞ 0.9 pmol/mL; P ⴝ 0.04). In conclusion, patients with HF are endowed with an enhanced ability to take up (or decarboxylate) filtered L-dopa, which might counterbalance the reduced renal delivery of L-dopa, contributing to a relative preservation of dopamine synthesis. This may result as a compensatory mechanism, activated by stimuli leading to sodium reabsorption. Age seems to have no influence on renal dopamine production. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: L-3,4-Dihydroxyphenylalanine (L-dopa); dopamine; kidney; heart failure (HF).
T
HE PATHOPHYSIOLOGICAL course of heart failure (HF) is characterized by activation of several counterregulatory neurohumoral systems. Some of these systems have natriuretic and diuretic properties (natriuretic peptides), whereas others are antinatriuretic and antidiuretic (renin-angiotensin-aldosterone, sympathetic, and arginine-vasopressin systems).1-5 The balance between these systems modulates renal sodium handling. In overt HF, the former is clearly overwhelmed by the latter, resulting in renal vasoconstriction and marked sodium reab-
From the Unidade de Investigac¸a˜o e Desenvolvimento Cardiovascular do Porto; Servic¸o de Medicina 3 e Servic¸o de Nefrologia, Hospital S Joa˜o; and the Institute of Pharmacology and Therapeutics, Faculty of Medicine, Porto, Portugal. Received January 24, 2001; accepted in revised form April 27, 2001. Address reprint requests to Anto´nio Ferreira, MD, Servic¸o de Medicina 3–Piso 8, Hospital S Joa˜o, Al Hernani Monteiro, 4200 Porto, Portugal. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3803-0007$35.00/0 doi:10.1053/ajkd.2001.26834 502
sorption. However, in mild stable HF, there is some equilibrium between these two groups of counterregulatory systems.6,7 Dopamine exerts natriuretic and diuretic effects by activating D1-like receptors located at various regions in the nephron.8,9 By inhibiting main sodium transport mechanisms at the basolateral and apical membranes of the renal proximal tubules (Na⫹-K⫹ adenosine triphosphatase and Na⫹/H⫹ exchanger, respectively), dopamine increases urinary sodium excretion.10-12 The proximal tubules are endowed with high aromatic L-amino acid decarboxylase activity. Their epithelial cells are able to synthesize dopamine from circulating or filtered L-3,4-dihydroxyphenylalanine (L-dopa).12-17 The regulation of this nonneuronal renal dopaminergic system depends mainly on the availability of L-dopa, its decarboxylation to dopamine, and in-cell–outward amine transfer mechanisms.18 The kidney is endowed with high monoamine oxidase and cathecol-Omethyltransferase activities, resulting in extensive degradation of dopamine to 3,4-dihydroxyphenylacetic acid (DOPAC), the deaminated metabolite, and to homovallinic acid (HVA), the deaminated and O-methylated metabolite.18 The
American Journal of Kidney Diseases, Vol 38, No 3 (September), 2001: pp 502-509
HEART FAILURE, AGING, AND RENAL DOPAMINE
availability of dopamine to activate its specific receptors is determined by factors affecting the formation, mainly the amounts of L-dopa and sodium delivered to the kidney, and the degradation of the amine.19-21 The aging kidney undergoes structural changes that result in quantitative alterations in some renal functions, such as a decline in renal blood flow and glomerular filtration rate.22 Edema formation may be linked to abnormalities in the function of the renal dopaminergic system, such as a decreased ability to synthesize dopamine23,24 and deficient coupling of dopamine receptors to effector mechanisms.25-28 An increasing number of studies have shown that old animals may present particular deficiencies in the renal handling of L-dopa, its subsequent conversion to dopamine,29,30 and at the level of receptor number or coupling to G proteins.31-33 Compared with healthy subjects, patients with HF respond to dopamine infusion with greater increases in effective renal plasma flow, glomerular filtration rate, natriuresis, and diuresis.34 This could be caused by an increased hemodynamic effect of dopamine or a direct effect on the renal tubules. Conversely, it is expected that renal delivery of L-dopa should be reduced in patients with HF because of a decrease in cardiac output and renal blood flow. Dopamine synthesis, depending on the availability of its precursor, might also be affected. In this study, we evaluate the activity of the renal dopaminergic system in old patients with HF and compare it with that of age-matched healthy subjects and young healthy subjects. PATIENTS AND METHODS
Patients Twenty-three patients with HF and 20 healthy controls were enrolled onto the study. Patients had chronic HF (with no exacerbation or modification of therapy in the last 3 months) and left ventricle ejection fractions (EFs) less than 50%. Patients with HF with cardiac valve diseases, concomitant pulmonary diseases, hepatic or renal failure, or diabetes mellitus were excluded from the study. Controls were healthy subjects with normal echocardiographic evaluations. They were selected based on their age: 10 subjects aged younger than 30 years and 10 subjects aged older than 55 years. 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.
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Experimental Procedures Twenty-four–hour urine collections were performed while patients were on their usual diet with free intake of sodium (NS) and after (only for patients with HF and age-matched controls) 8 days of low-salt (LS) intake (sodium, 90 mmol/ d). Urine was collected in plastic containers with 15 mL of 6 mol/L of HCl to prevent spontaneous decomposition of monoamines and amine metabolites. Urine samples were stored in plastic tubes at –80°C until assay. Venous blood samples were obtained from an antecubital vein after 20 minutes of rest in the supine position between 8:00 and 10:00 AM after overnight fasting on both the NS and LS intakes. Blood was immediately chilled in plastic tubes with heparin (for catecholamine measurement) and K3EDTA (for aldosterone) and centrifuged (4,500 rpm for 15 minutes at 4°C) and stored at –80°C until assay. The assay of catecholamines and its metabolites in urine (L-dopa, dopamine, DOPAC, HVA, and norepinephrine) and plasma samples (L-dopa, dopamine, DOPAC, and norepinephrine) was performed by high-performance liquid chromatography with electrochemical detection, as previously described.35,36 Dihydroxybenzylamine was used as an internal standard, and the interassay coefficient of variation was less than 5%. Quantification of HVA was performed separately by high-performance liquid chromatography with electrochemical detection, using 50-L aliquots of filtered samples directly injected into the chromatograph. The lower limit of detection of L-dopa, dopamine, DOPAC, HVA, and norepinephrine ranged from 350 to 1,000 fmol. The aldosterone assay was performed by radioimmunoassay using the Aldoctk-2 system (Disorin Srl, Saluggia, Italy). The interassay coefficient of variation was less than 8%, and the lower limit of detection was 20 pg/mL. 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 cinetic technique with Jaffe´ reaction also using the autoanalyzer Beckman Synchron CX3. Fractional excretion of sodium (FENa) was calculated using the equation: [(UNa ⫻ PCr)/(PNa ⫻ UCr)] ⫻ 100 where UNa is urinary sodium, PNa is plasma sodium, UCr is urinary creatinine, and PCr is plasma creatinine. M-mode two-dimensional echocardiograms were performed in controls and patients with HF. One experienced cardiologist using the same echocardiography unit (Hewlett Packard 100CF; Hewlett Packard, Palo Alto, CA) performed all echocardiograms. No subject had to be excluded from the study because of inadequate echocardiogram quality or significant valve disease. Left ventricular systolic function was assessed by measurement of EF using the biplane disc summation method (Simpson rule) or the Bullet single and biplane ellipse method.
Statistical Analysis Mann-Whitney U test was used to evaluate differences in numerical variables between groups. Wilcoxon’s signedranks test was used to test for differences between measure-
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FERREIRA ET AL Table 1. Baseline Characteristics of Study Participants Young Controls Old Controls Patients With HF
Age (y) 25.8 ⫾ 0.5* 61.5 ⫾ 4.1 66.8 ⫾ 1.7 Male sex (%) 30 30 69.6* 1.74 ⫾ 0.05 1.69 ⫾ 0.05 1.72 ⫾ 0.04 BSA (m2) MAP (mm Hg) 87.7 ⫾ 2.8* 100.4 ⫾ 4.5 87.2 ⫾ 2.8* Abbreviations: BSA, body surface area; MAP, mean blood pressure. *P ⬍ 0.05 versus old controls.
ments performed before and after salt restriction. For comparisons of categorical variables, we used the likelihood ratio chi-square or Fisher’s exact test when appropriate. Data are expressed as mean ⫾ SEM. P less than 0.05 is considered statistically significant. Statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS Inc, Chicago, IL). To adjust for differences in glomerular filtration rate, urinary excretion of L-dopa, dopamine, and its metabolites was analyzed after adjustment for creatinine urinary excretion.
RESULTS
All patients with HF presented with left ventricular systolic dysfunction (EF, 28.9% ⫾ 1.9%) and were on therapy with lisinopril (18.5 ⫾ 1.7 mg/d) and furosemide (85.2 ⫾ 7.4 mg/d) without modifications in the therapeutic regimen during the last 3 months. No patient was administered -blockers, spironolactone, nonsteroidal antiinflammatory drugs, or other drugs known to affect sodium handling or renal dopamine production. Characteristics of the study population, which included age-matched controls and young healthy subjects, are listed in Table 1. As listed in Table 2, plasma levels of L-dopa, dopamine, DOPAC, norepinephrine, and aldosterone did not differ among patients with HF, Table 2.
age-matched controls, and young healthy subjects. As listed in Table 3, urine volume in patients with HF was significantly greater than that in age-matched and young controls. Urinary creatinine levels did not differ among patients with HF and corresponding control subjects. However, old controls had lower values of urinary creatinine than young controls. Urinary sodium levels also did not differ among the three groups, but young controls had a lower FENa than old controls and patients with HF. Young healthy subjects also had greater creatinine clearances than aged subjects and patients with HF, but no differences were found between old controls and patients with HF (Table 3). Daily urinary excretion of L-dopa in patients with HF was less than in corresponding controls (Fig 1); no significant differences were observed between old controls and young subjects (Fig 1). Urinary excretion of dopamine indexed to urinary creatinine in patients with HF was significantly less than that in age-matched (old) controls (Fig 1). Urinary dopamine levels in old subjects were similar to those observed in young subjects (Fig 1). Daily urinary excretion of dopamine metabolites (DOPAC and HVA) and norepinephrine was similar in the three groups of individuals (Table 4). As listed in Table 2, salt restriction did not affect plasma concentrations of L-dopa, dopamine, and DOPAC in patients with HF and age-matched controls. However, LS intake produced a statistically significant increment in plasma levels of norepinephrine in patients with HF; the slight increase in plasma norepinephrine levels in age-matched controls during LS intake
Plasma Levels of L-Dopa, Dopamine, DOPAC, Norepinephrine, and Aldosterone in Control Subjects and Patients With HF NS Intake Young Controls
L-Dopa (pmol/mL) Dopamine (pmol/mL) Norepinephrine (pmol/mL) DOPAC (pmol/mL) Aldosterone (pg/mL)
*P ⬍ 0.05 versus NS intake.
53.2 ⫾ 3.2 44.5 ⫾ 4.2 5.6 ⫾ 0.8 54.2 ⫾ 6.9 95.4 ⫾ 5.2
Old Controls
49.1 ⫾ 5.4 42.3 ⫾ 8.2 5.1 ⫾ 1.6 60.3 ⫾ 16.6 102.1 ⫾ 13.4
LS Intake Patients With HF
41.7 ⫾ 2.5 38.2 ⫾ 2.8 5.8 ⫾ 0.8 60.0 ⫾ 7.2 84.6 ⫾ 14.4
Old Controls
Patients With HF
41.5 ⫾ 11.7 37.3 ⫾ 5.0 6.3 ⫾ 1.6 70.0 ⫾ 18.8 151.6 ⫾ 15.7*
39.2 ⫾ 2.8 38.6 ⫾ 3.3 7.1 ⫾ 0.9* 58.8 ⫾ 9.6 148.2 ⫾ 20.4*
HEART FAILURE, AGING, AND RENAL DOPAMINE Table 3.
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Urine Volume, Urinary Creatinine and Sodium Levels, Creatinine Clearance, and FENa in Control Subjects and Patients With HF NS Intake Young Controls
Urine volume (L/d) Urinary creatinine (g/d) Urinary sodium (mEq/d) Creatinine clearance (mL/min/1.73 m2) FENa (%)
LS Intake
Old Controls
Patients With HF
Old Controls
Patients With HF
1.55 ⫾ 0.21 1.22 ⫾ 0.20 1.52 ⫾ 0.10* 1.20 ⫾ 0.13 150.5 ⫾ 15.3 147.6 ⫾ 18.3 131.2 ⫾ 7.2* 97.1 ⫾ 14.4 0.58 ⫾ 0.06* 0.93 ⫾ 0.16
2.07 ⫾ 0.15*† 1.32 ⫾ 0.08 206.9 ⫾ 23.9 84.4 ⫾ 5.0† 1.24 ⫾ 0.13†
1.20 ⫾ 0.14 1.22 ⫾ 0.11 83.1 ⫾ 7.9‡ 91.7 ⫾ 10.3 0.52 ⫾ 0.09‡
1.74 ⫾ 0.12*‡ 1.09 ⫾ 0.08‡ 103.2 ⫾ 9.7‡ 71.4 ⫾ 5.9‡ 0.76 ⫾ 0.07*‡
*P ⬍ 0.05 versus old controls. †P ⬍ 0.05 versus young controls. ‡P ⬍ 0.05 versus NS intake.
did not reach statistical significance. LS intake also produced a marked increase in plasma aldosterone levels in patients with HF and agematched controls (Fig 2). LS intake resulted in a significant reduction in urine volume in patients with HF, but not in control subjects. Urinary creatinine levels and creatinine clearances were also reduced in response to salt restriction in patients with HF, but not in control subjects. Salt restriction also produced marked decreases in urinary sodium and FENa values in patients with HF and controls. During LS intake, only urine
Fig 1. Urinary sodium, Ldopa, dopamine, and dopamine (DA)–L-dopa ratios in patients with HF and controls during NS (■) and salt restriction (90 mmol/d; 䊐). *P < 0.05 versus old controls. §P < 0.05 versus NS intake.
volume and FENa in patients with HF were greater than in old control subjects (Table 3). Salt restriction failed to alter the 24-hour urinary excretion of L-dopa, dopamine, DOPAC, HVA, and norepinephrine in control subjects (Fig 1; Table 4). In patients with HF, LS intake produced a significant reduction in 24-hour L-dopa excretion, but failed to alter the urinary excretion of dopamine (Fig 1). However, urinary dopamine–L-dopa ratios (a measure of renal L-dopa utilization) in patients with HF on LS intake were markedly greater than on NS intake
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FERREIRA ET AL Table 4.
Urinary DOPAC, HVA, and Norepinephrine in Control Subjects and Patients With HF NS Intake Young Controls
Old Controls
LS Intake Patients With HF
Old Controls
Patients With HF
DOPAC (nmol/g creatinine) 4,658.4 ⫾ 635.9 5,578.5 ⫾ 708.8 6,176.2 ⫾ 980.9 6,466.8 ⫾ 943.2 4,845.4 ⫾ 609.8* HVA (nmol/g creatinine) 15,487.4 ⫾ 1,952.7 12,302.0 ⫾ 1,722.2 14,924.8 ⫾ 3,581.6 11,758.4 ⫾ 1,830.2 10,913.1 ⫾ 1,483.2* Norepinephrine (nmol/g creatinine) 208.9 ⫾ 18.4 279.0 ⫾ 73.0 313.9 ⫾ 91.0 188.0 ⫾ 41.1 249.9 ⫾ 33.6 *P ⬍ 0.05 versus NS intake.
and in both aged and young controls (Fig 1). In patients with HF, LS intake was accompanied by significant reductions in the urinary excretion of DOPAC and HVA, without changes in urinary norepinephrine levels (Table 4). Renal delivery of L-dopa, which considers L-dopa plasma levels and creatinine clearance (plasma L-dopa ⫻ creatinine clearance), in patients with HF on NS intake was significantly less than in control subjects on the same sodium regimen (Fig 3). This difference was further evidenced during LS intake (Fig 3). However, the percentage of decrease in renal delivery of L-dopa was similar in old controls (–22.5%) and patients with HF (–22.0%). Renal delivery of L-dopa in old controls during NS intake (4,572 ⫾ 784 pmol/min/1.73 m2) did not differ from that in young healthy subjects (6,930 ⫾ 544 pmol/ min/1.73 m2). DISCUSSION
The results of the present study indicate that patients with chronic stable HF have reduced urinary excretion of L-dopa and dopamine. This appears to result from reduced delivery of L-dopa to the kidneys. The ability of renal epithelial
tubular cells to take up or decarboxylate filtered L-dopa during NS intake was found to be identical in both groups. However, salt restriction resulted in a marked increase in renal L-dopa utilization in patients with HF. This increase in activity of the renal dopaminergic system is accompanied by an increase in activity of the sympathetic and renin-angiotensin-aldosterone systems, suggesting that the renal dopaminergic system may act in HF as a counterregulatory mechanism for stimuli leading to sodium reabsorption. Our results also suggest that in patients with HF, a moderate restriction in dietary salt produces a significant reduction in renal delivery of L-dopa without affecting L-dopa plasma levels. Salt restriction, by reducing the effective intravascular volume, leads to arterial underfilling. The subsequent decrease in activation of arterial mechanoreceptors leads to activation of several neurohumoral systems, namely, the sympathetic and renin-angiotensin-aldosterone systems, resulting in renal vasoconstriction and increased renal sodium reabsorption.1 Only patients with HF showed significant reductions in urine volume and renal function, evidenced by a significant
Fig 2. Plasma levels of norepinephrine and aldosterone in patients with HF and controls during NS (■) and salt restriction (90 mmol/d; 䊐). *P < 0.05 versus NS intake.
HEART FAILURE, AGING, AND RENAL DOPAMINE
Fig 3. Renal delivery of L-dopa in patients with HF and controls during NS (■) and salt restriction (90 mmol/d; 䊐). *P < 0.05 versus old controls. §P < 0.05 versus NS intake.
decrease in creatinine clearance. This was accompanied by marked increases in plasma aldosterone and norepinephrine levels, indicating intense neurohumoral activation, which might explain the marked reduction in the delivery of L-dopa to the kidneys. However, the excretion of dopamine adjusted to urinary creatinine remained unaltered. In this respect, it is interesting to observe that urinary sodium and FENa responded to salt restriction with significant reductions in patients with HF and healthy subjects. Urinary sodium levels were identical in the two groups on LS intake, but FENa was significantly greater in patients with HF than controls. Simultaneously, the renal utilization (uptake or decarboxylation) of L-dopa responded to sodium restriction in patients with HF with a further increase, suggesting that in HF, stimuli leading to sodium reabsorption may be accompanied by increased activation of the renal dopaminergic system. This increase in the ability to utilize L-dopa suggests that therapeutic supplementation with L-dopa may result in enhanced formation of dopamine, contributing to improve sodium handling in HF. Oral supplementation with L-dopa was found to produce a striking increase in urinary dopamine and urinary sodium levels in patients with HF.37 Enhanced renal L-dopa availability, together with the increased ability to take up or decarboxylate L-dopa, would explain the remarkable increase in renal dopamine formation observed in that study. HF is accompanied by sympathetic activation that is particularly intense in patients with an
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acute exacerbation or severe HF. The HF population studied here had moderate HF and was stable. Thus, their sympathetic activation would not be expected to be very high. Their baseline plasma norepinephrine levels were only slightly greater than those of age-matched controls, and no significant differences were found in urinary norepinephrine levels. This indicates that their renal sympathetic activity was not significantly increased. Patients with HF were administered angiotensin-converting enzyme inhibitors and furosemide. However, only patients with chronic stable HF without modifications in the therapeutic regimen or clinical status in the last 3 months were selected for inclusion on the study. These criteria aimed to avoid the influence of acute modifications in the diuretic regimen on renal dopamine production and sodium handling. Intravenous loop diuretics acutely increase urinary dopamine excretion by increasing tubular chloride concentration,38 but there is no evidence that chronic stable administration of diuretics influences renal dopamine production. FENa in patients with HF was greater than in the other groups, probably because patients with HF were administered furosemide. However, despite the proven effect of acutely administrated diuretics on renal sodium handling and FENa, the use of diuretics does not interfere with FENa as long as drug dose and dietary sodium intake are relatively constant,39 as is the case in the present study. Several conditions other than cardiac dysfunction may affect renal dopamine production. Because renal tubules are the main source of renal dopamine, renal parenchymal diseases, ie, chronic renal failure, are associated with decreased urinary excretion of dopamine.40-42 For this reason, patients with other diseases known to affect renal dopamine production were excluded from this study. However, these results must be interpreted with caution and further investigations are needed, ie, studying patients with HF of different degrees of severity. Other investigators have shown that dopamine fails to produce natriuresis during volume depletion.43 However, L-dopa supplementation was shown to significantly increase renal dopamine production and natriuresis in patients with HF.37 Conversely, patients with postinfarction asymptomatic left ventricular dysfunction
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FERREIRA ET AL
were shown to have more intense activation of the renal dopaminergic system than postinfarction patients without ventricular dysfunction.44 This was accompanied by a simultaneous increase in cardiac natriuretic peptide production, suggesting that the increased efficiency to synthesize dopamine may have preserved urinary sodium excretion in these patients. Data on the influence of age on renal dopamine production are conflicting. Several studies showed that age might be associated with deficiencies in the renal handling of L-dopa and its subsequent conversion to dopamine,29-33,35,36 whereas others have supported no alterations in aging.45-47 In the present study, the finding that renal dopaminergic tonus was identical in old and young subjects, evidenced by similar urinary excretion of dopamine and its metabolites (DOPAC and HVA) and identical utilization of L-dopa, indicates that age is not an important factor in determining renal dopamine synthesis in patients with HF. This apparent discrepancy between animal and human studies may be an example of species difference. In conclusion, patients with HF are endowed with the ability to increase the activity of the renal dopaminergic system in response to stimuli leading to volume depletion and sodium retention that does not appear to be related with age. However, their overall renal dopamine production is reduced compared with healthy subjects. This appears to result from reduced delivery of L-dopa to the kidney. The increased ability to take up or decarboxylate filtered L-dopa is a guarantee that its supplementation may result in enhanced formation of dopamine with subsequent natriuresis and diuresis. REFERENCES 1. Schrier RW: Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy. N Engl J Med 319:10651072, 1998 2. Schrier RW: Body fluid volume regulation in health and disease: A unifying hypothesis. Ann Intern Med 113:155159, 1990 3. Gilmore JP: Contribution of baroreceptors to the control of renal function. Circ Res 14:301-317, 1964 4. Schrier RW, Berl T: Mechanism of effect of alpha adrenergic stimulation with norepinephrine on renal water excretion. J Clin Invest 52:502-511, 1973 5. Schrier RW, Bert T, Anderson RJ: Osmotic and nonos-
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24. Soares-da-Silva P, Pestana M, Vieira-Coelho MA, Fernandes MH, Albino-Teixeira A: Assessment of renal dopaminergic system activity in the nitric oxide-deprived hypertensive rat model. Br J Pharmacol 14:1403-1413, 1995 25. Kansra V, Chen CJ, Lokhandwala MF: Dopamine fails to stimulate protein kinase C activity in renal proximal tubules of spontaneously hypertensive rats. Clin Exp Hypertens 17:837-845, 1995 26. Chen C, Beach RE, Lokhandwala MF: Dopamine fails to inhibit renal tubular sodium pump in hypertensive rats. Hypertension 21:364-372, 1993 27. Hussain T, Lokhandwala MF: Renal dopamine DA1 receptor coupling with Gs␣ and Gq/11␣ proteins in spontaneously hypertensive rats. Am J Physiol 41:F339-F346, 1997 28. Kinoshita S, Sidhu A, Felder RA: Defective dopamine-1 receptor adenylate cyclase coupling in the proximal convoluted tubule from the spontaneously hypertensive rat. J Clin Invest 84:1849-1856, 1989 29. Armando I, Nowicki S, Aguirre J, Barontini M: A decreased tubular uptake of dopa results in defective renal dopamine production in aged rats. Am J Physiol 268:F1087F1092, 1995 30. Soares-da-Silva P, Fernandes MH: A study on the renal synthesis of dopamine in aged rats. Acta Physiol Scand 143:287-293, 1991 31. Galbusera M, Garattini S, Remuzzi G, Mennini T: Catecholamine receptor binding in rat kidney: Effect of ageing. Kidney Int 33:1073-1077, 1988 32. Ricci A: The renal dopaminergic system in ageing. J Auton Pharmacol 10:S19-S24, 1990 (suppl 1) 33. Kansra V, Hussain T, Lokhandwala MF: Alterations in dopamine DA1 receptor and G proteins in renal proximal tubules of old rats. Am J Physiol 42:F53-F59, 1997 34. Ramdohr B, Schuren KP, Biamino G, Schroder R: Effect of dopamine on hemodynamics and renal function in patients with severe congestive heart failure. Klin Wochenschr 51:549-556, 1973 ´ PC, Fer35. Pestana M, Vieira-Coelho MA, Pinto-do-O nandes MH, Soares-da-Silva P: Assessment of renal dopaminergic system activity during cyclosporine A administration in the rat. Br J Pharmacol 115:1349-1358, 1995 36. Vieira-Coelho MA, Hussain T, Kansra VV, Serra˜o P, Guimara˜es JT, Pestana M, Soares-da-Silva P, Lokhandwala MF: Aging, high salt intake and renal dopaminergic activity in Fisher 344 rats. Hypertension 34:666-672, 1999 37. Grossman E, Shenkar A, Peleg E, Thaler M, Gold-
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stein DS: Renal effects of L-dopa in heart failure. J Cardiovasc Pharmacol 33:922-928, 1999 38. MacDonald TM, Craig K, Watson ML: Frusemide, ACE inhibition, renal dopamine and prostaglandins: Acute interactions in normal man. Br J Clin Pharmacol 28:683694, 1989 39. Rose BD: Measuring and application of urine chemistries, in Day W, Navrozov M (eds): Clinical Physiology of Acid-Base and Electrolyte Disorders. Singapore, McGrawHill, 1989, pp 353-360 40. Casson IF, Lee MR, Brownjohn AM, Parsons FM, Davison AM, Will EJ, Clayden AD: Failure of renal dopamine response to salt loading in chronic renal disease. BMJ 286:503-506, 1983 41. Itskovitz HD, Wynn NC: Renal functional status and patterns of catecholamine excretion. J Clin Hypertens 1:223227, 1985 42. Pestana M, Jardim H, Serra˜o P, Soares-da-Silva P, Guerra L: Reduced urinary excretion of dopamine and metabolites in chronic renal parenchymal disease. Kidney Blood Press Res 21:59-65, 1998 43. Agnoli GC, Cacciari M, Garutti C, Ikonomu E, Lenzi P, Marchetti G: Effects of extracellular fluid volume changes on renal response to low-dose dopamine infusion in normal women. Clin Physiol 7:465-479, 1987 44. Ferreira A, Bettencourt P, Pestana M, Oliveira N, Serra˜o P, Maciel MJ, Cerqueira-Gomes M, Soares-da-Silva P: Renal synthesis of dopamine in asymptomatic postinfarction left ventricular systolic dysfunction. Clin Sci 99:195-200, 2000 45. Lehmann M, Spori U, Keul J: [Excretion of free dopamine, noradrenaline and adrenaline in 190 males in relation to age and blood pressure]. Klin Wochenchr 63:264271, 1985 46. Nicolau GY, Haus E, Lakatua D, Sackett-Lundeen L, Bogdan C, Plinga L, Petrescu E, Ungareanu E, Robu E: Differences in the circadian rhythm parameters of urinary free epinephrine, norepinephrine and dopamine between children and elderly subjects. Endocrinologie 23:189-199, 1985 47. Komori T, Habuchi Y, Inoue H, Sakai T, Suzuki K, Ohtsuka K, Tanaka H, Fujita N, Yoshimura M: [Application of urinary free dopamine as a marker of renal function, and comparison with other renal marker]. Rinsho Byori 45:679684, 1997
T
HE PATHOPHYSIOLOGICAL course of heart failure (HF) is characterized by activation of several counterregulatory neurohumoral systems. Some of these systems have natriuretic and diuretic properties (natriuretic peptides), whereas others are antinatriuretic and antidiuretic (renin-angiotensin-aldosterone, sympathetic, and arginine-vasopressin systems).1-5 The balance between these systems modulates renal sodium handling. In overt HF, the former is clearly overwhelmed by the latter, resulting in renal vasoconstriction and marked sodium reab-
From the Unidade de Investigac¸a˜o e Desenvolvimento Cardiovascular do Porto; Servic¸o de Medicina 3 e Servic¸o de Nefrologia, Hospital S Joa˜o; and the Institute of Pharmacology and Therapeutics, Faculty of Medicine, Porto, Portugal. Received January 24, 2001; accepted in revised form April 27, 2001. Address reprint requests to Anto´nio Ferreira, MD, Servic¸o de Medicina 3–Piso 8, Hospital S Joa˜o, Al Hernani Monteiro, 4200 Porto, Portugal. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3803-0007$35.00/0 doi:10.1053/ajkd.2001.26834 502
sorption. However, in mild stable HF, there is some equilibrium between these two groups of counterregulatory systems.6,7 Dopamine exerts natriuretic and diuretic effects by activating D1-like receptors located at various regions in the nephron.8,9 By inhibiting main sodium transport mechanisms at the basolateral and apical membranes of the renal proximal tubules (Na⫹-K⫹ adenosine triphosphatase and Na⫹/H⫹ exchanger, respectively), dopamine increases urinary sodium excretion.10-12 The proximal tubules are endowed with high aromatic L-amino acid decarboxylase activity. Their epithelial cells are able to synthesize dopamine from circulating or filtered L-3,4-dihydroxyphenylalanine (L-dopa).12-17 The regulation of this nonneuronal renal dopaminergic system depends mainly on the availability of L-dopa, its decarboxylation to dopamine, and in-cell–outward amine transfer mechanisms.18 The kidney is endowed with high monoamine oxidase and cathecol-Omethyltransferase activities, resulting in extensive degradation of dopamine to 3,4-dihydroxyphenylacetic acid (DOPAC), the deaminated metabolite, and to homovallinic acid (HVA), the deaminated and O-methylated metabolite.18 The
American Journal of Kidney Diseases, Vol 38, No 3 (September), 2001: pp 502-509
HEART FAILURE, AGING, AND RENAL DOPAMINE
availability of dopamine to activate its specific receptors is determined by factors affecting the formation, mainly the amounts of L-dopa and sodium delivered to the kidney, and the degradation of the amine.19-21 The aging kidney undergoes structural changes that result in quantitative alterations in some renal functions, such as a decline in renal blood flow and glomerular filtration rate.22 Edema formation may be linked to abnormalities in the function of the renal dopaminergic system, such as a decreased ability to synthesize dopamine23,24 and deficient coupling of dopamine receptors to effector mechanisms.25-28 An increasing number of studies have shown that old animals may present particular deficiencies in the renal handling of L-dopa, its subsequent conversion to dopamine,29,30 and at the level of receptor number or coupling to G proteins.31-33 Compared with healthy subjects, patients with HF respond to dopamine infusion with greater increases in effective renal plasma flow, glomerular filtration rate, natriuresis, and diuresis.34 This could be caused by an increased hemodynamic effect of dopamine or a direct effect on the renal tubules. Conversely, it is expected that renal delivery of L-dopa should be reduced in patients with HF because of a decrease in cardiac output and renal blood flow. Dopamine synthesis, depending on the availability of its precursor, might also be affected. In this study, we evaluate the activity of the renal dopaminergic system in old patients with HF and compare it with that of age-matched healthy subjects and young healthy subjects. PATIENTS AND METHODS
Patients Twenty-three patients with HF and 20 healthy controls were enrolled onto the study. Patients had chronic HF (with no exacerbation or modification of therapy in the last 3 months) and left ventricle ejection fractions (EFs) less than 50%. Patients with HF with cardiac valve diseases, concomitant pulmonary diseases, hepatic or renal failure, or diabetes mellitus were excluded from the study. Controls were healthy subjects with normal echocardiographic evaluations. They were selected based on their age: 10 subjects aged younger than 30 years and 10 subjects aged older than 55 years. 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.
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Experimental Procedures Twenty-four–hour urine collections were performed while patients were on their usual diet with free intake of sodium (NS) and after (only for patients with HF and age-matched controls) 8 days of low-salt (LS) intake (sodium, 90 mmol/ d). Urine was collected in plastic containers with 15 mL of 6 mol/L of HCl to prevent spontaneous decomposition of monoamines and amine metabolites. Urine samples were stored in plastic tubes at –80°C until assay. Venous blood samples were obtained from an antecubital vein after 20 minutes of rest in the supine position between 8:00 and 10:00 AM after overnight fasting on both the NS and LS intakes. Blood was immediately chilled in plastic tubes with heparin (for catecholamine measurement) and K3EDTA (for aldosterone) and centrifuged (4,500 rpm for 15 minutes at 4°C) and stored at –80°C until assay. The assay of catecholamines and its metabolites in urine (L-dopa, dopamine, DOPAC, HVA, and norepinephrine) and plasma samples (L-dopa, dopamine, DOPAC, and norepinephrine) was performed by high-performance liquid chromatography with electrochemical detection, as previously described.35,36 Dihydroxybenzylamine was used as an internal standard, and the interassay coefficient of variation was less than 5%. Quantification of HVA was performed separately by high-performance liquid chromatography with electrochemical detection, using 50-L aliquots of filtered samples directly injected into the chromatograph. The lower limit of detection of L-dopa, dopamine, DOPAC, HVA, and norepinephrine ranged from 350 to 1,000 fmol. The aldosterone assay was performed by radioimmunoassay using the Aldoctk-2 system (Disorin Srl, Saluggia, Italy). The interassay coefficient of variation was less than 8%, and the lower limit of detection was 20 pg/mL. 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 cinetic technique with Jaffe´ reaction also using the autoanalyzer Beckman Synchron CX3. Fractional excretion of sodium (FENa) was calculated using the equation: [(UNa ⫻ PCr)/(PNa ⫻ UCr)] ⫻ 100 where UNa is urinary sodium, PNa is plasma sodium, UCr is urinary creatinine, and PCr is plasma creatinine. M-mode two-dimensional echocardiograms were performed in controls and patients with HF. One experienced cardiologist using the same echocardiography unit (Hewlett Packard 100CF; Hewlett Packard, Palo Alto, CA) performed all echocardiograms. No subject had to be excluded from the study because of inadequate echocardiogram quality or significant valve disease. Left ventricular systolic function was assessed by measurement of EF using the biplane disc summation method (Simpson rule) or the Bullet single and biplane ellipse method.
Statistical Analysis Mann-Whitney U test was used to evaluate differences in numerical variables between groups. Wilcoxon’s signedranks test was used to test for differences between measure-
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FERREIRA ET AL Table 1. Baseline Characteristics of Study Participants Young Controls Old Controls Patients With HF
Age (y) 25.8 ⫾ 0.5* 61.5 ⫾ 4.1 66.8 ⫾ 1.7 Male sex (%) 30 30 69.6* 1.74 ⫾ 0.05 1.69 ⫾ 0.05 1.72 ⫾ 0.04 BSA (m2) MAP (mm Hg) 87.7 ⫾ 2.8* 100.4 ⫾ 4.5 87.2 ⫾ 2.8* Abbreviations: BSA, body surface area; MAP, mean blood pressure. *P ⬍ 0.05 versus old controls.
ments performed before and after salt restriction. For comparisons of categorical variables, we used the likelihood ratio chi-square or Fisher’s exact test when appropriate. Data are expressed as mean ⫾ SEM. P less than 0.05 is considered statistically significant. Statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS Inc, Chicago, IL). To adjust for differences in glomerular filtration rate, urinary excretion of L-dopa, dopamine, and its metabolites was analyzed after adjustment for creatinine urinary excretion.
RESULTS
All patients with HF presented with left ventricular systolic dysfunction (EF, 28.9% ⫾ 1.9%) and were on therapy with lisinopril (18.5 ⫾ 1.7 mg/d) and furosemide (85.2 ⫾ 7.4 mg/d) without modifications in the therapeutic regimen during the last 3 months. No patient was administered -blockers, spironolactone, nonsteroidal antiinflammatory drugs, or other drugs known to affect sodium handling or renal dopamine production. Characteristics of the study population, which included age-matched controls and young healthy subjects, are listed in Table 1. As listed in Table 2, plasma levels of L-dopa, dopamine, DOPAC, norepinephrine, and aldosterone did not differ among patients with HF, Table 2.
age-matched controls, and young healthy subjects. As listed in Table 3, urine volume in patients with HF was significantly greater than that in age-matched and young controls. Urinary creatinine levels did not differ among patients with HF and corresponding control subjects. However, old controls had lower values of urinary creatinine than young controls. Urinary sodium levels also did not differ among the three groups, but young controls had a lower FENa than old controls and patients with HF. Young healthy subjects also had greater creatinine clearances than aged subjects and patients with HF, but no differences were found between old controls and patients with HF (Table 3). Daily urinary excretion of L-dopa in patients with HF was less than in corresponding controls (Fig 1); no significant differences were observed between old controls and young subjects (Fig 1). Urinary excretion of dopamine indexed to urinary creatinine in patients with HF was significantly less than that in age-matched (old) controls (Fig 1). Urinary dopamine levels in old subjects were similar to those observed in young subjects (Fig 1). Daily urinary excretion of dopamine metabolites (DOPAC and HVA) and norepinephrine was similar in the three groups of individuals (Table 4). As listed in Table 2, salt restriction did not affect plasma concentrations of L-dopa, dopamine, and DOPAC in patients with HF and age-matched controls. However, LS intake produced a statistically significant increment in plasma levels of norepinephrine in patients with HF; the slight increase in plasma norepinephrine levels in age-matched controls during LS intake
Plasma Levels of L-Dopa, Dopamine, DOPAC, Norepinephrine, and Aldosterone in Control Subjects and Patients With HF NS Intake Young Controls
L-Dopa (pmol/mL) Dopamine (pmol/mL) Norepinephrine (pmol/mL) DOPAC (pmol/mL) Aldosterone (pg/mL)
*P ⬍ 0.05 versus NS intake.
53.2 ⫾ 3.2 44.5 ⫾ 4.2 5.6 ⫾ 0.8 54.2 ⫾ 6.9 95.4 ⫾ 5.2
Old Controls
49.1 ⫾ 5.4 42.3 ⫾ 8.2 5.1 ⫾ 1.6 60.3 ⫾ 16.6 102.1 ⫾ 13.4
LS Intake Patients With HF
41.7 ⫾ 2.5 38.2 ⫾ 2.8 5.8 ⫾ 0.8 60.0 ⫾ 7.2 84.6 ⫾ 14.4
Old Controls
Patients With HF
41.5 ⫾ 11.7 37.3 ⫾ 5.0 6.3 ⫾ 1.6 70.0 ⫾ 18.8 151.6 ⫾ 15.7*
39.2 ⫾ 2.8 38.6 ⫾ 3.3 7.1 ⫾ 0.9* 58.8 ⫾ 9.6 148.2 ⫾ 20.4*
HEART FAILURE, AGING, AND RENAL DOPAMINE Table 3.
505
Urine Volume, Urinary Creatinine and Sodium Levels, Creatinine Clearance, and FENa in Control Subjects and Patients With HF NS Intake Young Controls
Urine volume (L/d) Urinary creatinine (g/d) Urinary sodium (mEq/d) Creatinine clearance (mL/min/1.73 m2) FENa (%)
LS Intake
Old Controls
Patients With HF
Old Controls
Patients With HF
1.55 ⫾ 0.21 1.22 ⫾ 0.20 1.52 ⫾ 0.10* 1.20 ⫾ 0.13 150.5 ⫾ 15.3 147.6 ⫾ 18.3 131.2 ⫾ 7.2* 97.1 ⫾ 14.4 0.58 ⫾ 0.06* 0.93 ⫾ 0.16
2.07 ⫾ 0.15*† 1.32 ⫾ 0.08 206.9 ⫾ 23.9 84.4 ⫾ 5.0† 1.24 ⫾ 0.13†
1.20 ⫾ 0.14 1.22 ⫾ 0.11 83.1 ⫾ 7.9‡ 91.7 ⫾ 10.3 0.52 ⫾ 0.09‡
1.74 ⫾ 0.12*‡ 1.09 ⫾ 0.08‡ 103.2 ⫾ 9.7‡ 71.4 ⫾ 5.9‡ 0.76 ⫾ 0.07*‡
*P ⬍ 0.05 versus old controls. †P ⬍ 0.05 versus young controls. ‡P ⬍ 0.05 versus NS intake.
did not reach statistical significance. LS intake also produced a marked increase in plasma aldosterone levels in patients with HF and agematched controls (Fig 2). LS intake resulted in a significant reduction in urine volume in patients with HF, but not in control subjects. Urinary creatinine levels and creatinine clearances were also reduced in response to salt restriction in patients with HF, but not in control subjects. Salt restriction also produced marked decreases in urinary sodium and FENa values in patients with HF and controls. During LS intake, only urine
Fig 1. Urinary sodium, Ldopa, dopamine, and dopamine (DA)–L-dopa ratios in patients with HF and controls during NS (■) and salt restriction (90 mmol/d; 䊐). *P < 0.05 versus old controls. §P < 0.05 versus NS intake.
volume and FENa in patients with HF were greater than in old control subjects (Table 3). Salt restriction failed to alter the 24-hour urinary excretion of L-dopa, dopamine, DOPAC, HVA, and norepinephrine in control subjects (Fig 1; Table 4). In patients with HF, LS intake produced a significant reduction in 24-hour L-dopa excretion, but failed to alter the urinary excretion of dopamine (Fig 1). However, urinary dopamine–L-dopa ratios (a measure of renal L-dopa utilization) in patients with HF on LS intake were markedly greater than on NS intake
506
FERREIRA ET AL Table 4.
Urinary DOPAC, HVA, and Norepinephrine in Control Subjects and Patients With HF NS Intake Young Controls
Old Controls
LS Intake Patients With HF
Old Controls
Patients With HF
DOPAC (nmol/g creatinine) 4,658.4 ⫾ 635.9 5,578.5 ⫾ 708.8 6,176.2 ⫾ 980.9 6,466.8 ⫾ 943.2 4,845.4 ⫾ 609.8* HVA (nmol/g creatinine) 15,487.4 ⫾ 1,952.7 12,302.0 ⫾ 1,722.2 14,924.8 ⫾ 3,581.6 11,758.4 ⫾ 1,830.2 10,913.1 ⫾ 1,483.2* Norepinephrine (nmol/g creatinine) 208.9 ⫾ 18.4 279.0 ⫾ 73.0 313.9 ⫾ 91.0 188.0 ⫾ 41.1 249.9 ⫾ 33.6 *P ⬍ 0.05 versus NS intake.
and in both aged and young controls (Fig 1). In patients with HF, LS intake was accompanied by significant reductions in the urinary excretion of DOPAC and HVA, without changes in urinary norepinephrine levels (Table 4). Renal delivery of L-dopa, which considers L-dopa plasma levels and creatinine clearance (plasma L-dopa ⫻ creatinine clearance), in patients with HF on NS intake was significantly less than in control subjects on the same sodium regimen (Fig 3). This difference was further evidenced during LS intake (Fig 3). However, the percentage of decrease in renal delivery of L-dopa was similar in old controls (–22.5%) and patients with HF (–22.0%). Renal delivery of L-dopa in old controls during NS intake (4,572 ⫾ 784 pmol/min/1.73 m2) did not differ from that in young healthy subjects (6,930 ⫾ 544 pmol/ min/1.73 m2). DISCUSSION
The results of the present study indicate that patients with chronic stable HF have reduced urinary excretion of L-dopa and dopamine. This appears to result from reduced delivery of L-dopa to the kidneys. The ability of renal epithelial
tubular cells to take up or decarboxylate filtered L-dopa during NS intake was found to be identical in both groups. However, salt restriction resulted in a marked increase in renal L-dopa utilization in patients with HF. This increase in activity of the renal dopaminergic system is accompanied by an increase in activity of the sympathetic and renin-angiotensin-aldosterone systems, suggesting that the renal dopaminergic system may act in HF as a counterregulatory mechanism for stimuli leading to sodium reabsorption. Our results also suggest that in patients with HF, a moderate restriction in dietary salt produces a significant reduction in renal delivery of L-dopa without affecting L-dopa plasma levels. Salt restriction, by reducing the effective intravascular volume, leads to arterial underfilling. The subsequent decrease in activation of arterial mechanoreceptors leads to activation of several neurohumoral systems, namely, the sympathetic and renin-angiotensin-aldosterone systems, resulting in renal vasoconstriction and increased renal sodium reabsorption.1 Only patients with HF showed significant reductions in urine volume and renal function, evidenced by a significant
Fig 2. Plasma levels of norepinephrine and aldosterone in patients with HF and controls during NS (■) and salt restriction (90 mmol/d; 䊐). *P < 0.05 versus NS intake.
HEART FAILURE, AGING, AND RENAL DOPAMINE
Fig 3. Renal delivery of L-dopa in patients with HF and controls during NS (■) and salt restriction (90 mmol/d; 䊐). *P < 0.05 versus old controls. §P < 0.05 versus NS intake.
decrease in creatinine clearance. This was accompanied by marked increases in plasma aldosterone and norepinephrine levels, indicating intense neurohumoral activation, which might explain the marked reduction in the delivery of L-dopa to the kidneys. However, the excretion of dopamine adjusted to urinary creatinine remained unaltered. In this respect, it is interesting to observe that urinary sodium and FENa responded to salt restriction with significant reductions in patients with HF and healthy subjects. Urinary sodium levels were identical in the two groups on LS intake, but FENa was significantly greater in patients with HF than controls. Simultaneously, the renal utilization (uptake or decarboxylation) of L-dopa responded to sodium restriction in patients with HF with a further increase, suggesting that in HF, stimuli leading to sodium reabsorption may be accompanied by increased activation of the renal dopaminergic system. This increase in the ability to utilize L-dopa suggests that therapeutic supplementation with L-dopa may result in enhanced formation of dopamine, contributing to improve sodium handling in HF. Oral supplementation with L-dopa was found to produce a striking increase in urinary dopamine and urinary sodium levels in patients with HF.37 Enhanced renal L-dopa availability, together with the increased ability to take up or decarboxylate L-dopa, would explain the remarkable increase in renal dopamine formation observed in that study. HF is accompanied by sympathetic activation that is particularly intense in patients with an
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acute exacerbation or severe HF. The HF population studied here had moderate HF and was stable. Thus, their sympathetic activation would not be expected to be very high. Their baseline plasma norepinephrine levels were only slightly greater than those of age-matched controls, and no significant differences were found in urinary norepinephrine levels. This indicates that their renal sympathetic activity was not significantly increased. Patients with HF were administered angiotensin-converting enzyme inhibitors and furosemide. However, only patients with chronic stable HF without modifications in the therapeutic regimen or clinical status in the last 3 months were selected for inclusion on the study. These criteria aimed to avoid the influence of acute modifications in the diuretic regimen on renal dopamine production and sodium handling. Intravenous loop diuretics acutely increase urinary dopamine excretion by increasing tubular chloride concentration,38 but there is no evidence that chronic stable administration of diuretics influences renal dopamine production. FENa in patients with HF was greater than in the other groups, probably because patients with HF were administered furosemide. However, despite the proven effect of acutely administrated diuretics on renal sodium handling and FENa, the use of diuretics does not interfere with FENa as long as drug dose and dietary sodium intake are relatively constant,39 as is the case in the present study. Several conditions other than cardiac dysfunction may affect renal dopamine production. Because renal tubules are the main source of renal dopamine, renal parenchymal diseases, ie, chronic renal failure, are associated with decreased urinary excretion of dopamine.40-42 For this reason, patients with other diseases known to affect renal dopamine production were excluded from this study. However, these results must be interpreted with caution and further investigations are needed, ie, studying patients with HF of different degrees of severity. Other investigators have shown that dopamine fails to produce natriuresis during volume depletion.43 However, L-dopa supplementation was shown to significantly increase renal dopamine production and natriuresis in patients with HF.37 Conversely, patients with postinfarction asymptomatic left ventricular dysfunction
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FERREIRA ET AL
were shown to have more intense activation of the renal dopaminergic system than postinfarction patients without ventricular dysfunction.44 This was accompanied by a simultaneous increase in cardiac natriuretic peptide production, suggesting that the increased efficiency to synthesize dopamine may have preserved urinary sodium excretion in these patients. Data on the influence of age on renal dopamine production are conflicting. Several studies showed that age might be associated with deficiencies in the renal handling of L-dopa and its subsequent conversion to dopamine,29-33,35,36 whereas others have supported no alterations in aging.45-47 In the present study, the finding that renal dopaminergic tonus was identical in old and young subjects, evidenced by similar urinary excretion of dopamine and its metabolites (DOPAC and HVA) and identical utilization of L-dopa, indicates that age is not an important factor in determining renal dopamine synthesis in patients with HF. This apparent discrepancy between animal and human studies may be an example of species difference. In conclusion, patients with HF are endowed with the ability to increase the activity of the renal dopaminergic system in response to stimuli leading to volume depletion and sodium retention that does not appear to be related with age. However, their overall renal dopamine production is reduced compared with healthy subjects. This appears to result from reduced delivery of L-dopa to the kidney. The increased ability to take up or decarboxylate filtered L-dopa is a guarantee that its supplementation may result in enhanced formation of dopamine with subsequent natriuresis and diuresis. REFERENCES 1. Schrier RW: Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy. N Engl J Med 319:10651072, 1998 2. Schrier RW: Body fluid volume regulation in health and disease: A unifying hypothesis. Ann Intern Med 113:155159, 1990 3. Gilmore JP: Contribution of baroreceptors to the control of renal function. Circ Res 14:301-317, 1964 4. Schrier RW, Berl T: Mechanism of effect of alpha adrenergic stimulation with norepinephrine on renal water excretion. J Clin Invest 52:502-511, 1973 5. Schrier RW, Bert T, Anderson RJ: Osmotic and nonos-
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