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(Hypertension. 1997;29:115.)
© 1997 American Heart Association, Inc.
Research Articles (Issue 1, Part 1) |
Differential Human Renal Tubular Responses to Dopamine Type 1 Receptor Stimulation Are Determined by Blood Pressure Status
the Department of Pharmacology and Therapeutics, University College Cork (Ireland) (D.P.O'C.), and the Departments of Medicine and Pathology, University of Virginia Health Sciences Center, Charlottesville.
Correspondence to Dr Robert M. Carey, Box 395, University of Virginia Health Sciences Center, Charlottesville, VA 22908. E-mail rmc4c@virginia.edu.
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Abstract |
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We performed the present studies to determine whether a proximal renal tubular dopamine D1-like receptor defect exists in human essential hypertension. Twenty-four subjects were studied (13 normotensive and 11 hypertensive) in a randomized, double-blind, vehicle-controlled study using fenoldopam, a selective D1-like receptor agonist. Subjects were studied in sodium metabolic balance at 300 mEq/d, after which the salt sensitivity of their blood pressure was determined. Fenoldopam at peak doses of 0.1 to 0.2 µg/kg per minute decreased mean arterial pressure in hypertensive subjects but did not change mean pressure in normotensive subjects. Fenoldopam increased renal plasma flow to a greater extent in hypertensive than normotensive subjects. Fenoldopam increased both urinary and fractional sodium excretions in the hypertensive and normotensive groups. In normotensive but not hypertensive subjects, fenoldopam increased the fractional excretion of lithium and distal sodium delivery. In contrast, both distal fractional sodium reabsorption and sodium-potassium exchange fell significantly in hypertensive subjects. We conclude that human essential hypertension is associated with a reduction in the proximal tubular response to D1-like receptor stimulation compared with normotensive subjects. Hypertensive subjects appear to have a compensatory upregulation of renal vascular and distal tubular D1-like receptor function that offsets the proximal tubular defect, resulting in an enhanced natriuretic response to D1-like receptor stimulation.
Key Words: receptors, dopamine • blood pressure • kidney tubules, proximal • dopamine agonists
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Introduction |
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In essential hypertension, the kidney is considered a primary locus for the initiation and subsequent maintenance of the hypertensive process.1 2 Subgroups of hypertensive subjects have been described in whom distinct pathophysiological processes may underlie the onset of hypertension. The BP of some essential hypertensive individuals is influenced by alterations in salt intake. One such group is known as "non-modulators" because within this group, sodium intake fails to modify target tissue responsiveness to angiotensin II.3 Other findings often ascribed to salt-sensitive essential hypertensive individuals include suppressed PRA, low circulating aldosterone concentration, increased forearm vascular resistance, and decreased venous compliance.4
Dopamine has been shown to influence renal function through a direct interaction with dopamine receptor subtypes. Classically, the renal dopamine receptors have been divided into the D1-like and D2-like receptor subtypes.5 Dopamine and D1-like receptor agonists have been shown to increase urine flow rate and sodium excretion when infused systemically or intrarenally.6 7 The cellular mechanisms that direct these dopamine-mediated renal electrolyte fluxes have recently been clarified. In the kidney, dopamine is synthesized within proximal tubular cells7 and acts in a paracrine fashion8 to inhibit proximal tubular Na+-H+ antiport activity through an interaction with adenylyl cyclase.9 Dopamine also has been shown to inhibit basolateral membrane Na+,K+-ATPase activity, an effect mediated by protein kinase C.10 In view of these stimulatory actions of renal dopamine on sodium excretion, it has been suggested that some forms of human essential hypertension may result from a perturbation of the intrarenal dopaminergic system. Therefore, a decrease in renal dopamine production and failure in dopamine receptor–mediated inhibition of Na+,K+-ATPase have been suggested as possible causes.7
Spontaneously hypertensive and Dahl salt-sensitive hypertensive rats have salt-sensitive forms of hypertension.11 In addition, these rats have demonstrable abnormalities in the renal dopaminergic system.7 Thus, the natriuretic and antinatriuretic effects of D1-like receptor agonists and antagonists, respectively, are reduced in spontaneously hypertensive and Dahl salt-sensitive rats but not in normotensive controls (Wistar-Kyoto or Dahl salt-resistant strains).12 The decreased ability of D1-like receptor agonists to stimulate adenylyl cyclase activity results from an alteration in the proximal renal tubular D1-like receptor and/or a defective coupling mechanism between the D1-like receptor and its G protein.13
We undertook the present study to investigate the hypothesis that in human essential hypertension, a proximal renal tubular defect exists in which D1-like receptor stimulation fails to invoke a natriuretic response and that this defect is associated with salt sensitivity.
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Methods |
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Study Design
The protocol was approved by the Human Investigation Committee of the University of Virginia School of Medicine; written informed consent was obtained from the study subjects. The study was a randomized, double-blind, placebo-controlled crossover trial using the selective D1-like receptor agonist fenoldopam and was conducted over a period of 13 to 19 days at the General Clinical Research Center (GCRC) of the University of Virginia Health Sciences Center. To assess the renal effects of D1-like receptor stimulation in both normotensive (NT) and hypertensive (HT) subjects, 24 subjects were studied (13 NT and 11 HT). The HT subjects had mild to moderately severe essential hypertension, with screening supine diastolic BPs in the range of 95 to 114 mm Hg after a 3-week withdrawal from all hypertensive medications. Remediable causes of hypertension were excluded by appropriate screening tests. All subjects were deemed to be otherwise healthy as determined by screening procedures that included a full medical history and physical exam, standard 12-lead electrocardiogram, chest radiograph, and laboratory testing with complete blood count and differential count, fasting blood chemistry, and urinalysis with microscopy. All subjects were between the ages of 18 and 50 years and deviated no more than 20% from ideal body weight (according to the 1983 Metropolitan Life table).
The days of the study were numbered consecutively beginning with the screening day (day 1). The study included period I, when the subjects were studied at a dietary sodium intake of 300 mEq/d, and period II, at 10 mEq/d. After completion of the initial screening procedures, the subjects were placed on an isocaloric constant diet containing 300 mEq sodium and 60 mEq potassium per day for the first 5 days (days 1 through 5; preinfusion period I), during which time they were outpatients. All meals were prepared and consumed in the GCRC, and no other food was allowed. Daily monitoring was carried out of body weight, heart rate, and BP as measured with an automated BP device (Dinamap model 845 XT, Critikon Inc). Twenty-four–hour urine collections were analyzed from day 2 of the outpatient phase for sodium, potassium, and creatinine to confirm that the subjects were in metabolic balance. If subjects were not in balance on day 4, three additional days were allotted to bring them into balance. If the subjects still did not come into sodium metabolic balance at the end of this time, they were not entered into the study proper.
The subjects were admitted to the GCRC on the evening of day 5, at which time a history and physical examination were conducted, and further diagnostic screening laboratory tests and electrocardiogram were performed to update any changes in clinical status. No food was given after midnight on day 5, and the subjects remained supine until completion of the study at 4 PM on day 6. After completion of the day 6 study period, the subjects were allowed out of bed but remained as inpatients. They received the same diet as prescribed for preinfusion period I. Day 7 was an exact repeat of day 6. Upon randomization, subjects received fenoldopam or placebo on day 6 and the alternate regimen on day 7.
At 7 AM on study days 6 and 7 (infusion period I), three arm veins were cannulated for infusion of PAH, inulin, and vehicle in one arm; blood was sampled from a heparin lock in the opposite arm. The bladder was emptied and urine collected for 24-hour analysis. Body weight also was measured. A priming dose of sterile inulin (Taylor Pharmaceutical Co, 50 mg/kg) and PAH (Merck Sharpe & Dohme, 8 mg/kg) in 5% dextrose and water (D5W) was given intravenously. Thereafter, a continuous infusion of inulin and PAH was administered until completion of the study at a rate of 0.3 mL/min, each 100 mL of infusate containing 15 mL PAH at 0.2 g/mL, 20 mL inulin at 0.1 g/mL, and 65 mL D5W. An oral water load (20 mL/kg) was ingested over 30 minutes, and urine samples were collected every 30 minutes for the remainder of the study. After each urine collection, a volume of water equal to the volume of urine voided in the previous 30-minute period was ingested. Lithium carbonate (Eskalith, SmithKline Beecham; 600 mg) also was given orally at 7 AM. Subjects also received 100 mEq sodium and 20 mEq potassium in gelatin capsules at 7 AM and noon, at which time they would have received identical salt amounts in their meals during preinfusion period I. Supine BP and heart rate were recorded in duplicate with a Dinamap every 30 minutes until noon. The control measurement was defined as the mean of supine readings taken at 10, 10:30, and 11 AM (control measurements; 10 to 11 AM). Beginning at 10:15 AM, blood samples were obtained every 30 minutes (at the midpoint of each urine collection) until 3:45 PM.
At noon, an intravenous infusion of fenoldopam or placebo in D5W was begun. The initial dose was 0.001 µg/kg per minute. Thereafter, the infusion dose was increased every 30 minutes for 3 hours, such that the subjects received in succession 0.005, 0.01, 0.05, 0.1, and 0.2 µg/kg per minute until 3 PM. Supine BP and heart rate were measured in duplicate every 10 minutes during the experimental infusion period (11 AM to 2 PM), which was followed by a 2-hour postcontrol period (2 to 4 PM). The 30-minute urine samples were analyzed for PAH, inulin, sodium, potassium, lithium, and creatinine concentrations and osmolality. In addition, blood samples were analyzed for PRA, plasma aldosterone, and atrial natriuretic peptide concentrations at 10:45 and 11:45 AM and 12:45 and 3:45 PM.
After the postcontrol period on day 7, the ambulatory subjects were discharged from the GCRC. They were placed on a similar isocaloric diet containing 60 mEq potassium but only 10 mEq sodium per day. The subjects continued on this diet as outpatients for the next 5 days (days 8 through 12; period II). While on the prescribed diet, the subjects were monitored in a fashion identical to that for preinfusion period I. A similar extension was applied if the subjects did not come into sodium balance by day 12. On day 12, BP was measured for determination of salt sensitivity, and a blood sample was obtained at noon for determination of PRA, the subjects having been ambulatory for the previous 4 hours.
Analytic Methods
Serum and urinary sodium, potassium, creatinine, and lithium concentrations were determined with an autoanalyzer (Boehringer Mannheim Hitachi Analyser model 717). Urine and serum osmolalities were measured by means of freezing-point depression with an osmometer (model 302, Advanced Instruments Inc). Urine and plasma inulin and PAH concentrations were analyzed by the methods of Heyrovsky14 and Brun,15 respectively. PRA was resolved by radioimmunoassay according to the method of Sealey and Laragh.16 Plasma aldosterone levels were measured by a Coat-A-Count radioimmunoassay kit (Diagnostic Products Corp). Urinary cAMP concentrations were determined by automated radioimmunoassay as previously described.17
Renal Function Calculations
Clearances of sodium, potassium, lithium, inulin (=glomerular filtration rate [GFR]), PAH (=renal plasma flow [RPF]), free water, and osmolality were determined with standard calculations. Fractional excretion (FE) was deduced from the formula FEX=(ClearanceX/GFR)x100. Filtration fraction was calculated as (GFR/RPF)x100. Absolute and fractional proximal and distal tubular rates of water and sodium reabsorption were determined by lithium clearance measurements as previously described by Thomsen and Schou18 : Absolute Proximal Reabsorption=Cin-CLi, where Cin and CLi are inulin and lithium clearances, respectively; Fractional Proximal Reabsorption=[(Cin-CLi)/Cin]x100; and Distal Delivery of Sodium=CLixPNa, where PNa is plasma sodium concentration. Distal sodium delivery was also calculated from the formula (CH2O+CNa)xPNa, where CH2O and CNa are free water and sodium clearances, respectively.19 Fractional distal sodium reabsorption was calculated as [(CLi-CNa)/CLi]x100. Percent distal sodium reabsorption was also calculated as [CH2O/(CH2O+CNa)]x100.20 Distal sodium-potassium exchange was determined by the formula [UKV/(UNaV+UKV)]x100, where UKV and UNaV are potassium and sodium excretions, respectively. Fractional distal water reabsorption was calculated as [(CLi-UV)/CLi]x100, where UV is urine volume.
Criterion for Determination of Salt Sensitivity
The study design incorporated two different sodium intake periods: days 1 through 7, when the subjects were on a 300 mEq/d sodium diet, and days 8 through 13, when sodium intake was limited to 10 mEq/d. Salt-sensitive individuals were defined as those having an increase of 7 mm Hg or greater in baseline MAP in response to salt loading (ie, baseline MAP must be at least 7 mm Hg greater on day 6 than on day 13).4
Statistical Analysis
Results are reported as mean±SE. A value of P<.05 was considered significant. Paired t statistics were calculated for differences at specific time periods on the day of fenoldopam infusion compared with those on the placebo day (Table 3). One-way ANOVA was used for identification of changes over time during the fenoldopam and placebo infusions. ANOVA was used to demonstrate differences over time between the two groups of subjects. To analyze these separate effects, we grouped the data for six periods of the study as follows: control (10 to 11 AM), E1 (11:01 AM to noon; fenoldopam/placebo, 0.001 to 0.005 µg/kg per minute), E2 (12:01 to 1 PM; fenoldopam/placebo, 0.01 to 0.05 µg/kg per minute), E3 (1:01 to 2 PM; fenoldopam/placebo, 0.1 to 0.2 µg/kg per minute), postcontrol 1 (PC1, 2:01 to 3 PM), and postcontrol 2 (PC2, 3:01 to 4 PM). These latter tests were conducted on the derived net effect of fenoldopam defined as the difference of a variable from the preinfusion (control) value for a given fenoldopam dose subtracted from the same difference found on the placebo day. This method of analysis was used for data illustrated in Figs 3 through 10. Such analysis corrects for diurnal variation and differing baselines that could be found on the 2 consecutive study days. These two parameters can adversely influence the outcome of singular time point analysis.
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P<.0001.
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Baseline Data
A total of 13 NT and 11 HT subjects participated in the study. All HT subjects were found to be salt sensitive. The age (mean±SE) of the NT subjects was 31.6±2.1 years and the HT subjects, 42.8±2.6 years. In the NT group, 10 subjects were white and 3 black; in the HT group, 7 were white and 4 black. The NT subjects were all men, and the HT group included 5 men and 6 women. The differences in MAP with the subjects in metabolic balance at 300 versus 10 mEq sodium per day are shown in Fig 1. There was a significantly greater reduction in MAP in the HT than the NT group (P<.001) in response to dietary sodium depletion. The characteristics of the two subject groups at screening and during the study are presented in Table 1. Body weight did not differ significantly in the two study groups. As would be expected, the HT subjects had significantly higher systolic and diastolic BPs and heart rates in both supine and upright positions than the NT subjects. Within the two groups, no significant alterations in heart rate were observed during the different sodium diets (Table 2). In contrast, the NT and HT subjects had significantly higher systolic and diastolic BPs on high versus low sodium diets. The HT subjects were also characterized by a significantly lower 24-hour urinary potassium excretion on both high and low salt diets (Table 1). PRA with the subjects in the upright position on the low salt diet did not differ significantly between the two groups.
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) and group (mean±SE) (•) changes in MAP on switching from a diet containing 300 mEq/d sodium to one containing 10 mEq/d. With the criterion of a change in MAP 
7 mm Hg indicating salt sensitivity, the hypertensive subjects (HT) were salt sensitive (change in MAP=-21.6±3.1 mm Hg). NT indicates normotensive.
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Cardiovascular Responses to D1-Like Receptor Stimulation
Table 3 lists all absolute values for cardiovascular and renal responses to fenoldopam or placebo infusion during the preinfusion (control) and peak infusion (E3) periods. Fig 2 shows heart rate responses to the increasing fenoldopam infusion for the NT and HT groups and depicts both placebo and test days. To illustrate best the effects of the D1-like receptor agonist on cardiovascular parameters, Fig 3 depicts the net effect of fenoldopam in the two subject groups that takes account of the diurnal changes measured on the vehicle control day (derived as previously outlined). Fenoldopam infusion resulted in a progressive tachycardia in both groups. The increase in heart rate was most marked during the E3 period (HT, +11.84±2.04 beats per minute, P=.0002; NT, +8.92±1.63, P=.0001). All other graphs are presented in this manner.
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In addition to tachycardia, a significant decrease in MAP was recorded in the HT group during the peak of the fenoldopam infusion (-9.70±3.97 mm Hg, P=.03, Fig 4) in contrast to the NT group (-1.67±1.79 mm Hg, P=NS). A decrease in diastolic BP in the HT subjects was the major determinant of this mean BP change, as can be seen in Table 3.
Renal Responses to D1-Like Receptor Stimulation
Fenoldopam infusion resulted in a significant and progressive natriuresis in the NT and HT groups (Fig 5 and Table 3). The increase in sodium excretion was significant by the first infusion period in the HT group, with further increments in the second and third infusion periods, the net effect being greater for all periods in the HT group (E3: NT, +0.169±0.060 mEq/min, P=.02; HT, +0.439±0.060, P<.001). On cessation of the fenoldopam infusion, sodium excretion decreased immediately (Fig 5). As shown in Fig 6, fractional sodium excretion was significantly elevated in both the second and third infusion periods in both groups (E3: NT, +1.64±0.42%, P=.002; HT, +2.10±0.60%, P=.006). In addition to the natriuretic response, there was a concomitant diuresis in the HT subjects but not in the NT subjects (Fig 7), the increase in urine volume being significant in both the E2 and E3 infusion periods. Free water clearance was unaffected by fenoldopam infusion, but osmolar clearance increased significantly in the HT subjects in both the second (P=.0015) and third (P=.0006) infusion periods. Urinary excretion and fractional excretion of potassium were unaltered by the fenoldopam infusion (Table 3). Fractional lithium excretion (Fig 8) was increased in NT subjects in both the second and third infusion periods but not in the HT subjects (E2: NT, +9.55±2.64%, P=.004; HT, +7.22±6.34%, P=NS; E3: NT, +13.62±2.76%, P=.0005; HT, +2.78±6.16%, P=NS).
Fractional distal sodium reabsorption was significantly and progressively reduced in the HT subjects from the second infusion period (Fig 9 and Table 3). No significant alterations were noted in the NT group in any of the fenoldopam infusion periods (E3: NT, -1.1±1.35%, P=NS; HT, -5.97±1.34%, P=.001). Fractional distal water reabsorption did not change significantly in either of the study groups during the infusion periods. In contrast, distal Na-K exchange fell dramatically in the HT subjects through the second and third infusion periods (Fig 10). The NT subjects exhibited a similar though less significant reduction (E3: HT, -6.24±0.76%, P=.0001; NT, -3.52±1.13%, P=.009).
Clearance of inulin did not change in either of the study groups during the fenoldopam infusion. Renal plasma flow, as estimated by PAH clearance, increased in the third infusion period in the HT but not NT subjects (HT, +286±121 mL/min, P=.04). Filtration fraction decreased accordingly in the third infusion period in the HT but not NT subjects (HT, -3.19±1.30%, P=.04; NT, -5.04±3.47%, P=NS).
Hormonal Responses to D1-Like Receptor Stimulation
Circulating levels of PRA and aldosterone as well as urinary cAMP measured in the second infusion period did not change significantly in both subject groups.
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Discussion |
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On the basis of studies of animal models of hypertension, we hypothesized that a proximal tubular defect in D1-like receptor responsiveness would be demonstrable in human essential hypertension. We tested this hypothesis by comparing renal tubular responses to the specific D1-like receptor agonist fenoldopam in NT and HT subjects. We used both fractional lithium excretion and measurements of free water and sodium clearances as markers of proximal tubular function. Fractional lithium excretion has been shown to estimate accurately end-proximal fluid delivery in salt-replete states.18 21 22 23 24 Fractional lithium excretion is remarkably constant from day to day in a given individual25 and serves as a valid and accurate measure of proximal tubular fluid transport. Free water and sodium clearance measurements also have been used successfully to estimate proximal and distal tubular functions.19
Fenoldopam infusion resulted in a significant natriuresis in both groups of subjects. However, the natriuresis was both detectable at a lower fenoldopam infusion dose and significantly greater at the highest dose in HT compared with NT subjects. In addition, fenoldopam infusion resulted in a significant diuresis in HT subjects. The increase in sodium excretion noted in both groups was largely the result of tubule-mediated processes, as evidenced by the marked increase in fractional sodium excretion. However, fractional lithium excretion and distal sodium delivery (based on free water and sodium clearances) increased only in NT subjects. In contrast, fractional distal sodium reabsorption (measured by both lithium and nonlithium methods) was markedly reduced in HT subjects during fenoldopam infusion, and this reduction was absent in NT subjects. This reduction in the rate of fractional distal sodium reabsorption in HT subjects during fenoldopam infusion also was confirmed by the calculation of distal Na+-K+ exchange rates: There was a significantly greater fall in the HT than the NT group. Natriuresis is usually accompanied by an enhanced rate of potassium excretion. No such increase was noted in our HT subjects, further strengthening the interpretation that activation of distal tubular D1-like receptors is involved in the natriuretic response to fenoldopam in essential hypertension.
In addition to these renal tubular responses to fenoldopam infusion, differences also were noted in systemic and renal hemodynamic responses between the study groups. Fenoldopam significantly decreased diastolic BP in both the NT and HT groups, the reduction being more pronounced in the HT subjects, with a consequent fall in MAP. The decrease in BP was accompanied by a significant increase in heart rate in both groups. Renal blood flow, as estimated by PAH clearance, increased significantly only in the HT subjects during fenoldopam infusion.
On the basis of the results described in the present study, it is reasonable to conclude that HT subjects have more pronounced renal natriuretic and diuretic responses to D1-like receptor stimulation than NT subjects. However, the renal mechanisms inducing the natriuresis with fenoldopam infusion differed distinctively between the two groups of subjects studied. In HT subjects, the enhanced sodium excretion resulted predominantly from a reduction in distal tubular sodium reabsorption, with a possible contribution from augmented renal blood flow. In the NT subjects, the natriuresis resulted from decreased proximal tubular sodium reabsorption.
D1-like receptors have been demonstrated in the medullary thick ascending limb7 26 and cortical collecting duct.27 Although lithium clearance methods do not allow us to differentiate among the responses of the various distal nephron segments, for the purposes of the present study, we defined "distal tubule" as the medullary thick ascending limb and/or cortical collecting duct. Dopamine and fenoldopam decrease Na+,K+-ATPase activity in these tubule segments.7 26 27
As demonstrated by Gill et al,28 29 subjects with salt-sensitive essential hypertension fail to increase urinary dopamine in response to increased salt intake because of deficient renal DOPA uptake and/or decarboxylation to dopamine. This defect also could account for a reduction in proximal tubular sodium reabsorption in salt-sensitive essential hypertension but would not explain the decreased proximal tubular response to fenoldopam described in the present report. However, if one assumes that the defect described by Gill et al is present in addition to proximal tubular unresponsiveness to fenoldopam in salt-sensitive essential hypertension, then an important sequela, first outlined by Lee,30 becomes apparent: D1-like receptors at other renal sites may be upregulated. The present study provides indirect evidence that such upregulation may occur, in that the natriuretic response was more marked in the HT than the NT group for all fenoldopam infusion rates studied. This augmented output resulted from a heightened level of distal tubular activity, which is consistent with, but does not prove, upregulation of distal tubular D1-like receptors. In addition, there may be upregulation of renal vascular D1-like activity, as evidenced by the augmented renal vasodilatation in the HT compared with the NT subjects.
The present study has some limitations. It was designed as a double-blind, randomized, crossover study with all 24 subjects undergoing the investigational protocol before the codes were broken and data analyzed. Thus, criteria for salt sensitivity were applied after completion of the fenoldopam studies. At that time, it became apparent that all 11 HT subjects studied met the established criteria for salt sensitivity, and we were not allowed to enter additional HT subjects by the fenoldopam supplier. For this reason, there was no salt-resistant HT control group, and thus, we are unable to conclude that the renal D1-like dopaminergic defect is confined to salt-sensitive HT subjects. Studies including a salt-resistant HT group should be conducted in the future. However, our study clearly identifies a proximal tubular defect in subjects with salt-sensitive essential hypertension compared with NT subjects.
Another potential limitation of the present study is the use of lithium clearance measurements for assessment of segmental renal tubular sodium handling. The use of lithium clearance has been criticized because lithium has been shown to increase sodium excretion and abolish natriuresis produced by pharmacological amounts of the dopamine prodrug gludopa.31 However, subsequent studies have shown that oral lithium had no influence on sodium excretion or renal hemodynamics during administration of fenoldopam or dopamine in normal subjects.32 33 Furthermore, Olsen et al34 have demonstrated that dopamine infusion increased endogenous and exogenous values of lithium clearance and fractional excretion to the same extent. These studies validate lithium clearance as appropriate for the measurement of proximal tubular function in response to dopamine.32 33 34 In addition, in the present study we used two different measurement methods, lithium clearance and free water and sodium clearances, to quantify proximal and distal sodium reabsorption in vitro. The parallel changes using sodium and free water clearances confirmed the measurements based on lithium clearance.
The impetus for performing the present study was the demonstration of a proximal tubular defect in D1-like receptor responsiveness in the spontaneously hypertensive and Dahl salt-sensitive hypertensive rat models. In both of these models, D1-like receptor agonists (eg, dopamine or fenoldopam) fail to invoke a natriuretic response,7 35 36 suggesting that the dopaminergic proximal tubular defect may be important in the pathogenesis of the hypertension. The present study, demonstrating greater than normal natriuretic responses to fenoldopam in salt-sensitive essential hypertensive subjects, does not support a pathophysiological role of the dopaminergic defect in humans. The reasons for the differences between salt-sensitive hypertension in the rat models and humans are unclear at present. Further studies of the possibility of distal tubular D1-like receptor upregulation in response to decreased renal dopamine production, as described by Gill et al,28 29 would be of interest.
In summary, we have shown that salt-sensitive essential hypertensive subjects have more pronounced renal natriuretic and diuretic responses to the infusion of the D1-like receptor agonist fenoldopam than NT subjects. The renal mechanisms inducing the natriuresis were shown to be different between HT and NT subjects, such that in HT subjects, the enhanced sodium excretion was engendered by a reduction in distal tubular sodium reabsorption, with a possible contribution from augmented renal blood flow. In NT subjects, the natriuresis resulted from an augmented delivery of sodium from proximal to distal nephron sites.
These results suggest that a proximal tubular D1-like receptor defect is present in human essential hypertension. Whether this defect is similar biochemically and/or pharmacologically to the proximal tubular D1-like receptor defect found in spontaneously hypertensive and Dahl salt-sensitive hypertensive rats requires further study. In contrast to these salt-sensitive animal models, however, the present study demonstrates that in human subjects, there is a distal tubular D1-like receptor–mediated compensation for the proximal tubular dopaminergic defect.
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Acknowledgments |
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We acknowledge the National Institutes of Health (NIH) International Fogarty Center, from which Dr O'Connell received an International Fogarty Fellowship. Data management and analysis were made possible by support from NIH grant M01-RR-800847 to the University of Virginia GCRC.
Received July 29, 1996; first decision August 14, 1996; accepted August 14, 1996.
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References |
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