(Hypertension. 1997;30:1566-1571.)
© 1997 American Heart Association, Inc.
Articles |
Dopamine D3 Receptor in Peripheral Mononuclear Cells of Essential Hypertensives
From the Department of Cardiovascular and Respiratory Sciences (A.R., E.B.); University "La Sapienza" Rome, the Chair of Internal Medicine (P.M., M.S., F.V.); "San Vito" Hospital, University of Turin, Turin, the Section of Human Anatomy, Department of Pharmacological Sciences and Experimental Medicine (F.A.), University of Camerino, Camerino, Italy.
Correspondence to Francesco Amenta, MD, Sezione di Anatomia Umana, Dipartimento di Scienze Farmacologiche e Medicina Sperimentale, Via Scalzino, 5, 62032 Camerino, Italy. E-mail amenta{at}cambio.unicam.it
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Abstract |
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Abstract Dopamine D3 receptor was studied in peripheral mononuclear cells of high-normal, stage 1, stage 2, and stage 3 essential hypertensives using a radioligand binding assay technique with [3H]-7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT) as a radioligand. A group of de novo Parkinsonian patients was also examined as a reference group of impaired dopaminergic function. [3H]-7-OH-DPAT was bound specifically to human peripheral mononuclear cells in a manner consistent with the labeling of a dopamine D3 receptor. No changes in free dopamine, norepinephrine, epinephrine and aldosterone levels, renin activity, dissociation constant of [3H]-7-OH-DPAT binding, or the pharmacological profile of [3H]-7-OH-DPAT binding were found between normotensive control subjects and essential hypertensives or Parkinsonians. The density of peripheral mononuclear cell [3H]-7-OH-DPAT binding sites increased in essential hypertensives parallel to blood pressure value augmentation. A higher density of [3H]-7-OH-DPAT binding sites was found in Parkinsonians. In these patients, the density of [3H]-7-OH-DPAT binding sites was similar to that observed in high-normal subjects and in stage 1 essential hypertensives. The increased density of peripheral mononuclear cell dopamine D3 receptor in hypertension as well as in Parkinson's disease may represent an upregulation mechanism consequent to impaired dopaminergic function. In view of the difficulty in identifying markers of peripheral dopamine function, analysis of dopamine D3 receptor in peripheral mononuclear cells may help evaluate whether the dopaminergic system is involved in hypertension.
Key Words: dopamine • D3 receptors • mononuclear cells • radioligand binding assay • hypertension marker
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Dopamine exerts several cardiovascular and renal actions including increase of myocardial contractility and cardiac output without changes in heart rate, active and passive vasodilatation, diuresis, and natriuresis.1 2 3 4 Cardiovascular and renal actions of dopamine are mediated through the interaction with specific dopamine receptors belonging to the dopamine D1–like and dopamine D2–like superfamilies.1 2 3 4 5 6
Dopamine is involved in the control of blood pressure by acting on the central and peripheral nervous systems and on target organs such as the kidney and the adrenal gland.7 8 Dopamine as well as other catecholamines may have a role in the development of hypertension.9 10 Renal dopaminergic deficiency is related to the diminished ability to excrete salt in some forms of hypertension.11 Salt-sensitive hypertension is aggravated by sodium intake.11 12 Imbalance between noradrenergic antinatriuretic mechanisms and dopaminergic natriuretic mechanisms is probably involved in the pathophysiology of hypertension.11 12 13 Stimulation of postjunctional (D1-like) or prejunctional (D2-like) dopamine receptors may represent a therapeutic principle in the treatment of hypertension.14 15
One problem encountered in establishing the role of the peripheral dopaminergic system in hypertension is represented by low levels of free plasma dopamine, which are at the limits of detectability.12 Dopamine, although it is the largest constituent of plasma catecholamines, is conjugated primarily to sulfate or glucuronide, which are thought to represent two biologically inactive metabolites.16 17 The use of new techniques for detecting free plasma dopamine revealed decreased14 15 16 17 18 19 or unchanged20 free plasma dopamine levels in essential hypertensives. Sulfoconjugated plasma dopamine determination is also considered to be a possible marker of peripheral dopaminergic activity.12 18 19 20 21 22 The main problem in accepting dopamine sulfoconjugated as a marker of peripheral dopaminergic activity is that its biological role other than as a storage or reserve form of dopamine18 has not yet been established.
Peripheral mononuclear cells express dopamine receptors characterized using both a classic radioligand binding assay and molecular biology techniques.23 24 25 26 27 28 The present study was designed to assess whether dopamine D3 receptor expression is changed in peripheral blood mononuclear cells of patients with different degrees of essential hypertension. In view of the hypothesis of altered dopaminergic function in hypertension,11 12 13 a small group of de novo Parkinsonian patients was also investigated as a reference group of impaired dopaminergic function.
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Methods |
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Patients and Peripheral Blood Mononuclear Cells Preparation
Peripheral blood mononuclear cells were obtained from essential hypertensives of the outpatient clinic of our hypertension unit. The protocol was approved by the local ethical committee. In all patients, cardiac, renal, and hepatic diseases were excluded by physical examination, which included complete hematological and blood chemistry status, urine analysis, electrocardiogram, and chest X-ray. Hypertensive patients examined were classified according to the 1993 Joint National Committee Guidelines29 as high-normal subjects, stage 1 (mild), stage 2 (moderate), or stage 3 (severe) hypertensives. Classification was based on the average of at least two blood pressure recordings on two or more occasions. Selected patients had altered blood pressure levels over a 1-year follow-up period. Secondary hypertension was excluded by a full history and examination, which included renin activity, plasma aldosterone, and determination of urinary catecholamine levels. De novo Parkinsonian patients (n=8) and normotensive control subjects (n=16) selected from volunteers in the same age range of hypertensives or Parkinsonians (age, 46.3±5.4 years; sex, 10 males and 6 females) were also examined.
Groups of hypertensives included the following: (1) high-normal subjects (n=11; age, 38.9±6.5 years; sex, 9 males and 2 females), (2) stage 1 hypertensives (n=15; age, 46.3±10.5 years; sex, 12 males and 3 females), (3) stage 2 hypertensives (n=7; age, 47.8±8.6 years; sex, 5 males and 2 females), and (4) stage 3 hypertensives (n=5; age, 54.7±6.9 years; sex, 4 males and 1 female). Parkinsonian patients investigated included 8 subjects (age, 63.4±5.8 years; sex, 6 males and 2 females). Severe hypertensive patients were all newly diagnosed or resistant to pharmacological treatment. They were hospitalized and did not take antihypertensive drugs for at least 4 weeks and underwent diagnostic screening before starting antihypertensive treatment. Moderate hypertensives referring to our hypertension unit did not take medication for 4 weeks and were followed closely during this period.
Tests were carried out in the morning, and subjects were asked to abstain from beverages containing caffeine or alcohol for at least 12 hours, from smoking for 24 hours, and from eating for 8 hours before the test. Subjects did not receive any pharmacological treatment or were in washout for at least 4 weeks before admission to the study. Parkinsonian patients were never treated for Parkinson's disease and did not assume any drug with dopaminergic activity in the 6 months preceding the investigation. After a 30-minute period of rest, patients had blood pressure measured by a sphygmomanometer and heart rate measured at the radial pulse. A blood sample was then taken. Blood pressure was recorded at the beginning and before the end of the test. Values reported in the text are the mean of these two blood pressure measurements.
Subjects had a blood sample taken (40 mL) for routine laboratory tests, determination of plasma catecholamine and aldosterone levels, plasma renin activity, and peripheral blood mononuclear cells isolation. Plasma aldosterone levels and renin activity were measured in both the supine and the upright position. Blood was obtained from the antecubital vein and collected in plastic tubes containing heparin. The blood was diluted with an equal volume of 0.9% NaCl and carefully layered over 3 mL of Lymphoprep. Peripheral blood mononuclear cells were separated according to the procedures detailed elsewhere.27 28 Nonadherent cells were resuspended in a 0.9% NaCl solution to obtain a final concentration of 2.5 to 5x103 cells/L. Cell purity was >90% as determined by immunofluorescence staining with anti-CD14 (anti-human Leu M3) and CD3/CD19 (anti-human Leu 4/12). Labeled cells were then analyzed in a FACScan apparatus (Becton Dickinson).
Radioligand Binding Assay
A 300-µL volume of a lymphocyte suspension containing
2.2x103 cells/L was incubated with increasing
concentrations (0.05 to 2 nmol/L) of [3H]
7-OH-DPAT for 30, 60, 90, and 120 minutes at 4°C, 23°C, and 37°C
according to a protocol detailed elsewhere.27 28
Nonspecific binding was defined by adding the incubation medium
containing the radioligand, a 1 µmol/L
concentration of (+)-butaclamol. The pharmacological profile of
[3H]-7-OH-DPAT binding to peripheral
mononuclear cells was assessed by incubating cells with a 0.5
nmol/L radioligand concentration in the presence of
increasing concentrations of compounds active on dopamine receptor
subtypes, serotonin (5-hydroxytryptamine,
5-HT) receptors, and adrenergic receptors.
At the end of incubation, cells were isolated onto Whatman GF-B glass fiber filters with a manifold apparatus. Filters were rapidly washed twice with ice-cold incubation buffer (1x 2 minutes) and transferred into scintillation vials, which were counted using a liquid scintillation counter at an efficiency of 40%.
In a series of preliminary experiments, the density of ß2-adrenoceptors was assessed in the different groups of patients investigated according to the protocol reported in an earlier paper from our group30 using [125I]cyanopindolol as a radioligand. In agreement with the most relevant studies reported in the literature,31 no significant differences were observed in the affinity or in the density of ß2-adrenoceptors among normotensive subjects, hypertensive patients, and Parkinsonians (data not shown).
Plasma Catecholamine, Aldosterone, and
Renin Activity
Plasma dopamine, norepinephrine, and
epinephrine levels were determined using reverse-phase,
ion-pair, high-pressure liquid chromatography coupled
with electrochemical detection.32 Plasma
aldosterone levels and renin activity were determined with
radioimmunoassay using kits purchased from Sorin Biomedical, with
coefficients of variation of 5% and 7%, respectively.
Data Analysis
Unless otherwise specified in the text, data are expressed as
mean±SE. Data from binding experiments were calculated using the
RADLIG program.33 In competition experiments, the
inhibition constant (Ki) was calculated from values
obtained in independent experiments performed in triplicate using 6 to
8 displacer concentrations.
Statistical differences in the density of [3H]-7-OH-DPAT binding by the different groups investigated, in plasma catecholamine and aldosterone levels and plasma renin activity were assessed by ANOVA. A post hoc Newman-Keuls test was used to assess the significance of differences between means.
A correlation coefficient was calculated between values of diastolic pressure and density of [3H]-7-OH-DPAT binding sites in the different groups of patients investigated using the parametric Bravais-Pearson test. Multiple regression analysis was then performed, with a significance level of P<.05.
Chemicals
[3H]-7-OH-DPAT (specific activity 160 Ci/mmol) was
purchased from Amersham. Lymphoprep was produced by Nycomed Pharma.
Anti-CD14 (anti-human Leu M3, cat. #7497) and CD3/CD19 (anti-human Leu
4/12, cat. #349211) antibodies were purchased from Becton Dickinson.
Bromocriptine and methysergide were obtained from Sandoz Pharma. Other
Chemicals were purchased from Research Biochemicals, Inc or
Sigma.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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[3H]-7-OH-DPAT was bound specifically to human peripheral mononuclear cells in the different groups investigated. The binding was time- (data not shown), temperature- (data not shown), and concentration-dependent (Fig 1
). Analysis of
[3H]-7-OH-DPAT binding to human peripheral
mononuclear cells revealed that it was bound to a single class of
high-affinity sites (Fig 2).
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) or plus 1 µmol/L (+)-butaclamol to
define nonspecific binding (
). Specific binding values (
)
were obtained by subtracting nonspecific from total binding. Points are
the mean±SE of triplicate determinations.
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), stage 1 essential hypertensives
(
), stage 2 essential hypertensives (
), and stage 3
essential hypertensives (x). The Bmax values of
[3H]-7-OH-DPAT specifically bound are expressed in fmol/L
per 103 cells per L and are shown on the abscissa. Points
are the means of triplicate determinations. Standard error was
<10%.
Table 1 summarizes dissociation constant
(Kd) and maximum density of binding sites
(Bmax) values in the different groups investigated. As
shown, Kd values were similar in healthy control subjects,
hypertensives, and Parkinsonians (Table 1). Bmax values
were significantly increased both in hypertensive and in Parkinsonian
patients in comparison with healthy control subjects (Fig 2
and Table 1). The increase was of a similar extent in high-normal subjects and
stage 1 hypertensives (Fig 2 and Table 1). A further augmentation of
the density of dopamine D3 receptor was found in stage 2
and stage 3 hypertensives (Fig 2 and Table 1). No differences in the
density of dopamine D3 receptor were seen between stage 2
and stage 3 essential hypertensives (Fig 2 and Table 1). In
Parkinsonian patients, which were normotensive, the density of
[3H]-7-OH-DPAT binding sites was higher in comparison
with healthy control subjects (Fig 2 and Table 1); it was similar to
that found in high-normal subjects or stage 1 essential hypertensives
(Fig 2 and Table 1). Regression analysis revealed a significant
liner correlation (R=.999) between diastolic
pressure values and density of mononuclear cells
[3H]-7-OH-DPAT binding sites (data not shown). No such a
correlation was observed in Parkinsonians (data not shown).
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Data on the pharmacological profile of [3H]-7-OH-DPAT
binding to human peripheral mononuclear cells of healthy
control subjects and stage 3 hypertensives are summarized in Table 2. As shown, Ki values were
not significantly different from healthy control and stage 3 essential
hypertensive patients. Peripheral mononuclear cells
obtained from high-normal subjects, other groups of essential
hypertensives (stages 1 and 2), or Parkinsonian patients displayed a
pharmacological profile similar to that of healthy control subjects or
of stage 3 hypertensives (data not shown). The pharmacological profile
of [3H]-7-OH-DPAT binding to human peripheral
mononuclear cells was consistent with the labeling of a
dopamine D3 receptor. In fact, compounds displaying a
dopamine D2–like receptor activity or both a dopamine
D1–like and a dopamine D2–like receptor
activity as well as the preferential dopamine D3 receptor
agonists 7-OH-DPAT and quinpirole were the most potent competitors of
[3H]-7-OH-DPAT binding to human peripheral
mononuclear cells (Table 2). Compounds active on dopamine
D1–like receptors, dopamine D4 receptor, 5-HT
receptors, or adrenergic receptors were less effective displacers of
[3H]-7-OH-DPAT binding or were without effect (Table 2).
Competition curves of [3H]-7-OH-DPAT binding by dopamine
were similar in the absence or presence of guanosine triphosphate (Fig 3 and Table 2).
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Data on plasma catecholamine (free dopamine,
norepinephrine, and epinephrine) levels are
summarized in Table 3. As shown, no
significant differences were noticeable in plasma
catecholamine levels among healthy control subjects and
hypertensive or Parkinsonian patients (Table 3). Similar results were
obtained for plasma aldosterone levels and renin activity,
which were not different in the various groups investigated (data not
shown).
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Discussion |
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Several lines of evidence indicate the involvement of central and peripheral dopaminergic mechanisms in the pathogenesis of hypertension.9 10 11 34 Central and peripheral dopamine receptors were divided into the D1-like and the D2-like receptor superfamilies on the basis of pharmacological and biochemical evidence.5 6 35 The application of molecular biology techniques to dopamine receptor research has shown that the dopamine D1–like receptor superfamily includes two receptor subtypes, the D1 (D1a in the rat) and D5 (D1b in the rat) receptors.5 6 35 Dopamine D2–like receptors include the D2, D3, and D4 receptors.5 6 35
Human peripheral mononuclear cells express primarily dopamine D3 and D5 receptor subtypes, which were characterized mainly by radioligand binding assay and molecular biology techniques.24 26 27 28 Dopamine D3 receptor is a guanine-insensitive dopamine receptor subtype which, in the brain, probably mediates the antipsychotic effects of neuroleptics.36 Data of radioligand binding experiments performed in this study suggest that, in our experimental conditions, we have labeled a dopamine D3 receptor.
Studies on the influence of hypertension on both central and peripheral dopamine receptors were performed primarily using spontaneously hypertensive rats. In the central nervous system, a decrease, an increase, or no changes in the density of dopamine receptors were reported.23 37 38 39 40 Other investigations found altered coupling of dopamine D2 receptors without changes in their density9 or upregulation of either D1-like or D2-like receptors in the brain of prehypertensive and hypertensive rats.41 At the periphery, renal D1-like receptors were the dopamine receptor population investigated to a greater extent. A reduced ability of dopamine D1–like receptor agonists to stimulate adenylate cyclase because of defective coupling between the receptor and the G-protein–adenylate cyclase complex, not accompanied by changes in receptor density, was reported.41 42 43 Defective coupling between dopamine D1-like receptors and phospholipase C was also found in the kidney of spontaneously hypertensive rats.44 Studies on renal dopamine D2–like receptors did not find changes in the genetic expression of dopamine D3 receptor between normotensive Wistar-Kyoto and spontaneously hypertensive rats.45
Human studies on the influence of hypertension on dopaminergic system are difficult to interpret because of the low levels of plasma free dopamine and the uncertainly about the significance of plasma dopamine sulfoconjugated.12 18 19 20 21 22 Despite the difficulty in identifying a peripheral marker of peripheral dopaminergic function in hypertensives, the majority of investigations suggested the occurrence of impaired dopaminergic function in essential hypertension, which was probably related to local tissue dopamine depletion.11 12 17 18 19 20 21 22 A decreased ability of the dopamine D1–like agonist fenoldopam to inhibit renal proximal tubular reabsorption in patients with salt-sensitive essential hypertension was also reported.46 However, no changes in dopamine D5 receptor expression were found in peripheral mononuclear cells of essential hypertensives.47
In the present study, no signs of impaired peripheral dopaminergic function were observed. In fact, plasma catecholamine levels, plasma aldosterone, and renin activity were in the normal range. The only change observed was an increased dopamine D3 receptor expression in peripheral mononuclear cells of essential hypertensives. This phenomenon is related, in some way, to blood pressure changes, because the number of peripheral mononuclear cells [3H]-7-OH-DPAT binding sites increased with augmentation of blood pressure levels and a significant linear correlation was found between diastolic pressure values and density of [3H]-7-OH-DPAT binding sites. To establish whether increased density of [3H]-7-OH-DPAT binding sites was related to an impairment of dopaminergic function in hypertensives, a group of de novo normotensive Parkinsonian patients was investigated. Parkinson's disease is a neurological disorder characterized by progressive loss of brain dopaminergic neurons, which represents the best known disease-induced model of impaired dopaminergic function.48 Hence, the group of de novo normotensive Parkinsonian patients investigated served as a reference group of impaired dopaminergic function. In mononuclear circulating cells of Parkinsonians, an increased density of dopamine D3 receptor of similar extent to that found in high-normal and stage 1 essential hypertensives was observed. This suggests that the occurrence in essential hypertensives of an impaired dopaminergic function is characterized by increased dopamine D3 receptor density in peripheral mononuclear cells, similar to that found in Parkinsonian patients. The increased density of dopamine D3 receptor in peripheral mononuclear cells of both essential hypertensives and Parkinsonians probably represents an upregulation phenomenon related to decreased dopaminergic function. The increased density of peripheral mononuclear cells' dopamine D3 receptor in stage 2 and stage 3 essential hypertensives in comparison with less severe hypertensives suggests the occurrence of a progressive impairment of dopaminergic function with worsening of hypertension.
The increase of peripheral mononuclear circulating cells' dopamine D3 receptor in essential hypertensives and Parkinsonians was not accompanied by changes in the pharmacological profile of radioligand binding. This suggests that modifications of receptor density probably do not depend by variations in the genetic expression of dopamine D3 receptor. In view of the difficulty to identify peripheral markers of dopamine function, our findings suggest that analysis of the density of the dopamine D3 receptor subtype in circulating mononuclear cells may contribute to understanding the involvement of the peripheral dopaminergic system in hypertension.
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Acknowledgments |
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The present study was supported in part by grants from the Italian National Research Council (C.N.R.) and from "La Sapienza" University.
Received February 20, 1997; first decision March 25, 1997; accepted June 25, 1997.
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