Clinical Science (1993) 81, 357-375 (Printed in Great Britain)
357
Editorial Review
Dopamine and the kidney: ten years on
M. R. LEE
Clinical Pharmacology Unit, Royal Infirmary, Edinburgh, U.K.
INTRODUCTION
Ten years ago the Editorial Board of Clinical
Science invited me to write an Editorial Review on
dopamine and the kidney. Th: result was published
in 1982 in Volume 62 [l]. It was my hope that it
would serve to stimulate other investigators to take
up this area of renal physiology and pharmacology
and to help to solve some of the problems left
unanswered at that time. Since 1982 much has
happened: there have been major successes, such as
the delineation of the renal and adrenal dopamine
receptors, and some relative failures, such as the
lack of development of clinically useful peripheral
dopamine agonists for use in hypertension and
congestive cardiac failure. Nevertheless, continuous
progress has been made and it is my task in this
Review to try to describe this general advance while
not omitting remaining areas of uncertainty.
The areas which I will undertake to describe are:
1. The renal receptors for dopamine.
2. The source of dopamine in the urine and its
formation in the kidney.
3. The actions of dopamine upon the kidney.
4. The interaction of renal dopamine with other
substances.
5. Dopamine formation in hypertensive and oedematous states.
6. The search for specific peripheral dopaminergic
agonists of therapeutic utility.
7. Final conclusions and unanswered questions.
1. RENAL RECEPTORS FOR DOPAMINE
The two key enzymes for the formation of dopamine (3,4-dihydroxyphenylethylamine) are tyrosine
hydroxylase (TH; tyrosine 3-mono-oxygenase, EC
1.14.16.2) and aromatic-L-amino-acid decarboxylase
(L-AAAD; EC 4.1.1.28). In dopaminergic neurons
there is no dopamine P-hydroxylase or phenylethanolamine N-methyltransferase [2]. As a result,
synthesis halts at dopamine and does not proceed to
noradrenaline or adrenaline. The enzyme L-AAAD
can also be found in neurons which synthesize 5hydroxytryptamine (5-HT, serotonin) [2]. This will
be referred to again in section 4 below in relation to
the possibility of 5-HT formation in the renal
tubules. Interestingly, immunochemical analyses of
brain cells have shown extensive neuronal systems
containing L-AAAD, but no TH or dopamine Phydroxylase [3]. These neurons would seem to
resemble the proximal tubule cells in the kidney,
which also appear only to contain L-AAAD [4] (see
below). When dopamine is released peripherally, it
acts on receptors distinguishable from classical LYand P-adrenoceptors. The first suspicion that this
was the case came from the results of Holtz et al.
[5], who showed that dopamine could produce a
fall in blood pressure, i.e. vasodilatation, in guinea
pigs and rabbits. When Goldberg [6] analysed this
effect more thoroughly, he found that the depressor
response could not be blocked by atropine, antihistamines or P-adrenoceptor antagonists. It is now
well accepted that there are specific dopamine receptors in many peripheral tissues, including certain
vascular beds, and, in particular, in the kidney [7].
Their distribution includes: presynaptically to inhibit noradrenaline release [8]; on the kidney tubules
and on the juxtaglomerular cells (see below); and in
the adrenal cortex [9]. Peripheral dopamine receptors have been subdivided into DA, and DA,
receptors [lo, 111. This has been achieved with the
help of specific agonists for DA, [fenoldopam (SKF
82526)l and DA2 (quinpirole) receptors and specific
antagonists (SCH 23390 for DA, and domperidone
for DA,; see Table 1). As a result, DA, receptors
have been demonstrated on renal, mesenteric,
coronary and cerebral arteries. They cause direct
vasodilatation blocked by SCH 23390, and also
cause diuresis and natriuresis. In contrast, DA,
Key words dopamine, hypertension, kidney, sodium.
Abbreviations: L-AAAD. aromatic-wnincr-acid decarboxylase; ANP, atrial natriuretic peptide; Ldopa, 3,Cdihydroxyphenylalanine;dopamine, 3,Cdihydroxyphenylethylamine;
DOPAC, dopacetic acid (3,Cdihydroxyphenylacetic acid); Gpp[NH]p, guanosine 5’+3,yimido]triphosphate; EHT, Mydroxytryptamine (serotonin); EHTP, Mydroxyi-tryptcrphm; PGE,, prostaglandin El; PRA, plasma renin activity; SHR spontaneously hypertensive rat; TH, tyrosine hydroxylse; WKY, Wistar-Kyoto rat.
Correspondence: Professor M. R. Lee, Clinical Pharmacology Unit, Royal Infirmary, buriston Place, Edinburgh EH3 9YW, U.K.
358
M. R. Lee
receptors are located in autonomic ganglia and
sympathetic nerve endings [l I]. They cause indirect
vasodilatation by inhibition of noradrenaline release
and also inhibit aldosterone production within the
adrenal gland.
DA, receptors seem to differ from DA, receptors
in their signal transduction mechanisms. DA, receptors have been found to activate adenylate cyclase
in the rat renal cortex [12]. This effect can be
mimicked by the DA, receptor agonist, fenoldopam,
and is blocked by SCH 23390, but not by the DA,
receptor antagonist ( -)-sulpiride. Fenoldopam can
also stimulate phospholipase C activity in rat renal
cortical membranes [131. When DA, receptors are
activated, there seems to be an inhibition of adenylate cyclase in rabbit renal and mesenteric arteries
and also in rat glomeruli. This effect is not antagonized by SCH 23390, but is largely prevented by
(-)-sulpiride, a DA, antagonist. The presence Gf
DA, receptors in the proximal tubule of the rat was
then confirmed by autoradiographic studies, using
3H-labelled SCH 23390 [ 141. Subsequently,
Takemoto and Katz [l5] have demonstrated DA,
binding sites throughout most segments of the
tubule. Felder et al. [I61 found DA, and DA,
receptors in both the apical and basolateral membranes of the proximal tubule. DA, activation
increased adenylate cyclase and phospholipase
activities but DA, activation had no effect.
A protein of molecular mass 32kDa has been
isolated from the caudate nucleus of the brain and
shown to be closely associated with D, receptors
[17]. It is a phosphoprotein and has been named
dopamine-regulated phosphoprotein (DARPP-32). It
is considered to be an intracellular third messenger
for dopamine. Recent work has shown immunoreactivity and RNA for this phosphoprotein in
specific areas of the renal tubule in several species.
Marked activity after radioactive labelling was
found in the medullary and cortical segments of the
thick ascending loop of Henle [lS]. This suggests
strongly that there are D , (DA,) receptors in the
ascending limb of the loop of Henle. The dopamine
D, (DA,) agonist, fenoldopam, causes a dosedependent inhibition of Na', K+-ATPase in the
thick ascending limb and this can be blocked by the
D, (DA,) antagonist, SCH 23390.
Much recent work has gone into the effect that
dopamine has on regulating Na', K+-ATPase
activity and the N a + / H + exchanger in the kidney.
Dopamine has been shown to regulate Na',
K+-ATPase activity in the proximal tubule and the
thick ascending limb of the loop of Henle [19]. As
will be described below, L-dopa (3,4-dihydroxyphenylalanine) is the principal precursor of dopamine formed locally in the kidney, and L-AAAD in
the proximal tubular cell is the enzyme that decarboxylates it to dopamine. When rat renal cortical
cells are studied in suspension, L-dopa at concentrations of 10-8mol/l and upwards inhibits
ouabain-sensitive oxygen consumption [20]. This
inhibition can be prevented by carbidopa, a peripheral dopa decarboxylase inhibitor which prevents
the conversion of L-dopa to dopamine. Other techniques have been used to confirm this inhibitory
action of dopamine on oxygen consumption, including 86Rb studies and K + flux monitored by a
sensitive potassium electrode [21].
Complementary studies have employed single
proximal tubular segments from the rat kidney.
When these segments were suspended in a
dopamine-containing medium, the rate of ATP
hydrolysis was decreased, with a dopamine concentration of lo-' mol/l giving maximal inhibition
[22]. Of great interest is the fact that dopamine
caused a change in the Michaelis constant for K + ,
suggesting that the catecholamine had caused a
conformational change in the N a + , K+-ATPase
molecule. The precursor, L-dopa, also caused inhibition in single proximal tubule segments and, as with
renal cortical cells, this inhibition could be blocked
by a dopa decarboxylase inhibitor (which would
prevent the generation of dopamine). It would
appear that, in the rat kidney, activation of both
DA, and DA, receptors is needed to inhibit Na',
K+-ATPase in proximal tubule segments [23].
When dopamine inhibits activity in this tissue, it
can be blocked both by the DA, antagonist, YM
09151, and the DA, antagonist, (+)-sulpiride. Similarly, both the DA, agonist, fenoldopam, and the
DA, agonist, LY-171555, are required to produce
significant inhibition of the enzyme; neither alone
will suffice. The interaction between DA, and DA,
receptors does not seem to be a unique property of
proximal tubular cells, as similar findings have been
reported for isolated neurons from the rat corpus
striatum [24]. Dopamine inhibition of Na',
K+-ATPase production in proximal tubules can be
inhibited both by pertussis toxin (suggesting G
protein involvement) [25] and by sphingosine, suggesting protein kinase involvement [26].
Dopamine has also been shown to modulate the
Na+/H exchanger in proximal tubular cells. Felder
and Jose [27] showed that DA, agonists decreased
the V,,,., but did not alter the K,, of the transporter. Furthermore, Gesek and Schoolwerth [28]
demonstrated that the inhibitory effect of dopamine
was much greater when the N a + / H + exchanger had
been stimulated either by angiotensin I1 or by aadrenoceptor agonists.
+
Recent work on the renal dopamine receptors
The classification that I have given above, grouping the renal dopamine receptors into DA, and
DA,, has been shown in the last five years to be too
simple [29]. In the brain several D, receptor subtypes have been cloned (D,,, D,, and D5) and each
one is coupled to the stimulation of adenylate
cyclase. The D, receptor has two isoforms: a shorter
form with 415 amino acid residues is now termed
the DZshor,receptor and a longer form with 444
Dopamine and the kidney: ten years on
amino acid residues is called the D,
receptor.
Both these receptors are coupled to the inhibition of
adenylate cyclase. The D3 and D, receptors are
closely related to, but different from, the D, receptor. Their status in relation to activation or inhibition of adenylate cyclase has not yet been
determined.
In the kidney the DA, receptors are approximately equivalent to the D, and D, receptors in
the brain. The DA, receptors are approximately
equivalent to the D, receptors in the brain. However, a new renal D, receptor has been described
which is not linked to adenylate cyclase. This
receptor has been located to the inner medulla and
has been named DA2k. Apparently, it acts by stimulating phospholipase A, production with a consequent increase in prostaglandin E, (PGE,) generation. So far, of the cloned dopamine receptors,
only the messenger RNA for D, has been found in
the kidney, but no doubt the signal for other
receptors will be found soon.
A word of caution should be given about this
proliferation of the renal dopamine receptors. What
is their function? Are any of them simply clearance
receptors, as has been demonstrated for atrial
natriuretic peptide (ANP)? In relation to the generation of PGE, there is no evidence in man that the
actions of dopamine are in any way mediated by the
prostaglandins, as indomethacin has no effect on the
natriuresis produced [see section 4(c) below]. In
other words, does the receptor DA2k have any
relevance
physiologically? These
important
questions will require to be resolved by future work.
When these relationships have been explored, it may
be possible to develop compounds which act specifically on a particular sub-group of the renal dopamine receptors.
2 SOURCE OF DOPAMINE IN THE URINE AND ITS
FORMATION IN THE KIDNEY
In my 1982 Review, I concluded that dopamine
must be formed locally in the mammalian kidney.
There were at that time three main hypotheses for
its formation: the intrarenal deconjugation theory;
the release from renal nerves; and the production
from L-dopa. I concluded that the main source of
renal dopamine must be circulating L-dopa. The
intervening years have reinforced this view and I
think it safe now to abandon the alternative
hypotheses (see Jeffrey et al. [30] and Soares-daSilva and Fernandes [31]). The tubular transport of
L-dopa has been characterized as an active process
with great structural specificity [32], and it might be
that uptake of L-dopa is one of the rate-limiting
processes in dopamine formation.
L-AAAD has been located to the renal cortex
when studied by histofluorescence techniques [33].
Biochemical studies have also suggested that most
of the dopamine formed originates in the proximal
359
convoluted tubules [34, 351. Hayashi et al. [4],
using microdissected nephron segments, have shown
that most of the L-AAAD is located in the proximal
tubules and that this activity is higher in proximal
convoluted tubules than in proximal straight
tubules. This finding has been confirmed for the
cytosolic fraction of rat renal cortical cells and rat
renal medullary cells. At most, it would appear that
the medulla forms about 6 8 % of renal dopamine.
Dietary sodium appears to be a major regulating
factor in the control of renal dopamine synthesis. In
normal circumstances there is a close relationship
between urinary sodium and urinary dopamine [36,
371. Sodium loading in man and the animal
increases excretion of dopamine [34, 37-39]. In
contrast, a low sodium diet results in decreased
urinary excretion of dopamine [4, 401. If urinary
dopamine is formed from the uptake and decarboxylation of circulating L-dopa, then inhibition of
L-AAAD should decrease urinary dopamine excretion. This has been reported several times [41, 421.
More recently, Goldstein et al. [43] showed, in
normal subjects who changed from a low sodium
(9mmol of Na'/day) diet to a high sodium
(249mmol of Na'/day) diet, that both urinary
L-dopa and urinary dopamine increased about twofold. Plasma L-dopa was unchanged by dietary salt
manipulation. They suggest therefore that salt loading resulted in an increased delivery of L-dopa to
sites of uptake by proximal tubular cells. An
increase in TH activity outwith the kidney, produced by increased sodium, could lead to increased
delivery of L-dopa to the kidney [44,451.
Other possibilities exist for the regulation of
dopamine synthesis in the kidney, apart from the
delivery of L-dopa to the tubule. Tubular transport
of some aromatic amino acids is sodium-dependent
[46] and this might be one mechanism for accelerated uptake. It is also possible that salt has intratubular effects on dopamine production. In addition,
there may be interactions between other modulators
of sodium excretion and dopamine production [31].
a-Human ANP has been reported to inhibit dopamine production in rat kidney slices loaded with Ldopa [31]. The inhibitory effect can be potentiated
by the cyclic GMP phosphodiesterase inhibitor,
zaprinast (M & B 22,948). Zaprinast added alone
also inhibited dopamine synthesis. These results
suggest that tubular accumulation of cyclic GMP
may restrict the uptake of L-dopa by the tubular
epithelial cells. When these workers carried out
similar experiments with the kidneys of salt-loaded
rats, dopamine production from L-dopa was not
inhibited by either a-human ANP or M & B 22,948,
suggesting that the inhibition they had observed
during the previous studies only occurs in conditions of 'normal' sodium transport.
Evidence is accumulating that cell electrolyte
homoeostasis does not simply affect L-dopa uptake
and conversion to dopamine, but also signal transduction. When the cell Na' concentration is
360
M. R. Lee
increased, the inhibition of Na', K+-ATPase by
L-dopa is increased. Similarly, in Sprague-Dawley
rats given a high sodium diet, urinary sodium
excretion increases and Na+, K+-ATPase activity
decreases in proximal tubular cells [47]. If the rats
are fed benserazide, an inhibitor of L-AAAD, both
actions are reversed, suggesting that dopamine is
contributing to the high sodium output. The effect
of L-AAAD inhibition on sodium output is transient
(as also observed by Ball and Lee in man [41]). It
may be that L-AAAD inhibition induces more synthesis of the decarboxylase enzyme to overcome the
initial blockade.
How specific a stimulus is sodium chloride for the
increased renal production of dopamine? Two studies from my own group have addressed this
problem. Harvey et al. [48] showed, in man, that
potassium chloride is not a stimulus to increased
dopamine production, whereas, in the rat, the chlorides of sodium, potassium and ammonium stimulated dopamine output in the urine [39]. The
potassium load in the rat was relatively greater
when compared with that given to man, which may
explain the discrepant results. The efficacy of ammonium chloride in the rat when compared with
sodium bicarbonate would suggest that the chloride
anion is of considerable importance to dopamine
production in the kidney. These studies are in many
ways the exact counterpart of those of Kotchen et
al. [49] on the control of renin release.
By contrast with crystalloids, Faucheux et al. [SO]
have shown that intravenous albumin in man
produces no increase in urine dopamine output.
This suggests that the renal sensing mechanism for
dopamine production can distinguish between different modalities of intravascular volume expansion.
Kuchel et al. [Sl] also showed that intravenous
administration of frusemide produces a sharp rise in
urinary dopamine formation, and this could be due
to a sharp rise in chloride concentration at the
macula densa. Could the increase in dopamine
contribute to the natriuretic effect of the loop
diuretic? This seems unlikely, as Jeffrey et al. [52] in
my laboratory showed that, in normal subjects,
when dopamine production was virtually completely
abolished by carbidopa, the natriuresis produced by
frusemide remained the same. In contrast, the administration of indomethacin significantly attenuated
the natriuresis produced by frusemide in the same
group of subjects, suggesting an important role for
the renal prostaglandins in the effect of the loop
diuretic.
Another controlling factor for dopamine production in the kidney has been described by Williams et
al. [53]. They studied normal subjects under metabolic balance conditions. The subjects were given
60g of protein to eat in the form of tuna fish. As a
result of the high protein diet, urinary dopamine
increased by SO%, whereas urinary noradrenaline
and urinary adrenaline did not increase at all,
suggesting that the increased production of dopa-
mine was located in the kidney. The increased
dopamine production and the associated natriuresis
was largely prevented by carbidopa. The same
group had previously shown, in the rat, that, if
dietary protein is restricted, then urinary dopamine
falls. The hypothesis they put forward is that tyrosine from the protein load is taken up by extrarenal
tissues and there converted to L-dopa. The L-dopa
circulates to the kidney, is taken up by the tubules
and then converted to dopamine. The site of extraneuronal conversion of tyrosine to L-dopa is at
present unknown, but from the parallel experiments
of Ben-Jonathan et al. [54] could be extra-adrenal
chromaffin tissue. This same tissue might also be
sensitive to the sodium ion and be the source of the
increased plasma L-dopa seen on sodium loading in
these particular experiments in the rat [SS].
As has been pointed out earlier, dopamine produced in the kidney, principally from the proximal
tubules, could act as an intrarenal natriuretic hormone [l]. When dopamine synthesis is blocked, the
natriuresis produced by oral or intravenous salt
loading is attenuated [55a, 55bl. These studies can
be criticized, however, in that the drugs were administered systemically and the experiments were performed in anaesthetized animals.
In order to overcome the deficiencies present in
previous experiments, Siragy et al. [SSc] administered the DA, antagonist, SCH 23390, via the renal
artery in the conscious uninephrectomized dog. The
antagonist induced a dose-dependent decrease in
urine flow rate and sodium excretion without any
changes in renal plasma flow, glomerular filtration
rate, systemic arterial blood pressure, plasma aldosterone concentration or plasma renin activity
(PRA). Moreover, the effects could be reversed by
the specific DA, agonist, fenoldopam.
The role of renal DA, receptors in sodium excretion is not clear. Some compounds which are DA,
agonists, such as bromocriptine and quinpirole,
have been reported to increase renal blood flow
without having any effect on urine sodium excretion
[55d, 55e]. In order to try and clarify this problem,
Siragy et al. [SSf] infused the DA, antagonist YM
09151 into the renal artery of the conscious
uninephrectomized dog. This compound produced a
dose-related increase in renal plasma flow, glomerular filtration rate and filtration fraction, together
with a natriuresis and diuresis. The diuresis and
natriuresis could be explained completely in terms
of the observed changes in renal haemodynamics.
There were no changes in plasma aldosterone
concentration, PRA or systemic arterial blood pressure. All the effects could be blocked by simultaneous administration of a DA, agonist, quinpirole.
These results are puzzling and suggest that when
dopamine acts tonically on DA, receptors in the
kidney it is a vasoconstrictor and an antinatriuretic
(the opposite of what might have been assumed).
The question must be asked: can dopamine generated in the tubules gain access to the DA, receptors
Dopamine and the kidney: ten YCSKon
blocked by YM 09151 in these experiments, or,
indeed, are the effects on renal blood flow seen only
rarely under physiological circumstances?
However, it can be concluded, with reasonable
confidence, that the DA1 receptors, in particular, do
have a role in the normal physiological function of
the kidney.
To summarize, the main controlling factors for
renal dopamine production would appear to be the
sodium and/or chloride ions, dietary protein and the
intracellaular electrolytic and hormonal medium.
How these factors exert their control and where the
sensing mechanisms are located within or outwith
the kidney remain to be established. In physiological circumstances it is difficult to dissect out the
influence of dopamine from many other interacting
natriuretic and antinatriuretic factors.
3. ACTIONS OF DOPAMINE UPON THE KIDNEY
Infusion of dopamine results in a dose-dependent
increase in renal blood flow and a less marked rise
in glomerular filtration rate. There have been
numerous studies in animals. The dose required for
an increase in renal blood flow appears to be in the
range of 1-1Opg min-'kg-',
the upper limit
depending on the species used [59]. Glomerular
filtration rate is also increased in dogs with the
threshold at 0.5pg min-' kg-'. There have been few
similar studies in man. McDonald et al. [60] found
a mean increase in p-aminohippurate clearance (a
measure of renal blood flow) from 507 to 798ml/
min, using dopamine doses ranging from 2.6 to
7.1pg rnin-lkg-'. Inulin clearance (a measure of
glomerular filtration rate) rose from 109 to 126ml/
min. Ramdohr et al. [61] observed an increase in paminohippurate clearance from 782 ml/min to 1161
and 112lml/min for doses of 175 and 350pg/min,
respectively. Inulin clearance did not change significantly in this study. In a study on hypertensive
patients with unilateral renal disease, Breckenridge
et al. [62] found that renal blood flow increased
77% with a dose of 1pg min-lkg-' and 12% with
a dose of 2pg rnin-lkg-' when measured by an
indicator-dilution technique on the unaffected side.
A number of groups have studied the effect of
dopamine upon the intrarenal distribution of renal
blood flow. Most studies in the animals report an
increase in cortical blood flow. Some also report an
increase in medullary blood flow [63]. In man,
Hollenberg et al. [64], using a dose of 3pg
min-' kg-', described an increase in cortical renal
blood flow.
Attention has also been directed to the mechanisms whereby the effect on renal blood flow is
produced. That is, at which anatomical level is
vasodilatation seen? Hughes et al. [65] studied the
isolated preconstricted renal artery segment and
found that dopamine relaxed this vessel and that
this relaxation could be blocked by ( +)-sulpiride
and SCH 23390 (DA, antagonists). Edwards [66],
36I
working on isolated renal microvessels from rabbits,
studied their reactions to agonists and antagonists
by light microscopy. Dopamine caused a dosedependent relaxation of both noradrenaline-induced
and spontaneous tone in afferent and efferent glomerular arterioles. Relaxant activity was much less
marked in interlobular arteries. In a further study
he found that this relaxation seemed to be the result
of stimulation of DA1 receptors as the effects could
be mimicked by fenoldopam and SKF 87516, specific DA, agonists [67]. Contrasting results were
obtained by Steinhausen et al. [68] using a split
hydronephrotic rat kidney model. This enabled
them to see the kidney blood vessels directly. Dopamine was observed to produce a dose-dependent
dilatation of the arcuate and interlobular arteries
and also of the afferent glomerular arterioles. In
contrast to the results of Edwards [66], the response
of the efferent glomerular arteriole was less marked
than that of the pre-glomerular vessels, with an
observed increase in diameter of 27+10% for the
arcuate arteries as compared with 9 k2% for the
efferent arteriole. However, for technical reasons, it
should be noted that these workers found it impossible to observe the effects of catecholamine on the
very narrow region of the efferent arteriole near to
the glomerulus, and it may be that this area is a
high-resistance segment with a considerable effect
on intraglomerular haemodynamics. Measurements
of single-nephron filtration rates and the effect of
dopamine upon them will be required to resolve the
question of afferent/efferent balance. At least we can
now conclude with reasonable confidence that DA,
receptor stimulation is essential for the renal vasodilator effects of dopamine.
In an earlier section, I concluded that, in uitro,
dopamine had been shown to have effects both on
Na+, K +-ATPase-mediated transport as well as on
the Na+/H+ exchanger in the renal tubules. These
effects on sodium transport in uitro are reflected by
studies in uiuo in man and animals. In the first
description of the effects of dopamine in man by
McDonald et al. [60], they noted a natriuresis and
diuresis. With a dose range of 2.67.1 pg
min-lkg-', sodium output rose from 171 to
575pmol/min. Levinson et al. [69] also studied the
dose-response effect and found no response with
doses of 0.03 and 0.3 pg min-' kg-'. The first effect
was observed at a dose of 3 pg min-' kg-' and was
an increase in sodium output without a change in
urine volume.
The threshold for the natriuretic and diuretic
effects remains in dispute. Orme et al. [70] gave
long-term infusions of dopamine, ranging from 0.5
to 1.25pg min-' kg-', in hypertensive patients with
renal function impairment and produced a diuresis
and natriuresis on the first day only. It may be, of
course, that in the hypertensive patients the receptors for dopamine are 'up-regulated' and, as a
consequence, the threshold for dopamine is lowered
(see the section on essential hypertension below).
M. R. Lee
362
Baglin et al. [71] studied patients with chronic renal
failure, using a dopamine dose of 2,ug min-lkg-'
and observed a definite natriuresis, together with an
increase in potassium and calcium excretion.
It was also reported some years ago that intravenous dopamine produces a marked phosphaturia,
probably by an effect at the proximal tubular cell
[72]. Very recently, Berndt et al. [73] have looked
at the situation the other way round. They showed
that an increase in phosphate in the diet of rats kept
under metabolic balance conditions increased urinary dopamine output. Moreover, dopamine infusion
enhanced the phosphaturic effect of parathyroid
hormone infusion in rats. It would appear likely
from these preliminary findings in the rat that
phosphate is an additional controlling mechanism
for dopamine production which must be added to
those already established, for example, sodium
chloride and protein feeding.
4. INTERACTION OF RENAL DOPAMINE WITH
OTHER SUBSTANCES
The substances which I propose to discuss in this
Section are:
(a)
(b)
(c)
(d)
(e)
(f)
The renin-angiotensin system.
Vasopressin.
The renal prostaglandins.
ANP.
5-HT (serotonin).
Lithium.
(a) Renin-angiotensinsystem
This is an area where there has been much
confusion and where the doses of dopamine used
have often been so high as to be unphysiological.
The first consideration is that, at the doses
employed in the particular experiment, could dopamine have a P,-adrenoceptor effect or an a-adrenoceptor agonist effect, both of which could mediate
renin release? Further, dopamine by interacting with
the vascular DA, receptor could vasodilate the
afferent arteriole, stimulate the renal baroreceptor
and thus release renin, as do most vasodilators, for
example, hydralazine or minoxidil. This will be
referred to again when fenoldopam is discussed
under therapeutic possibilities (see section 6).
Carey et al. [74] found no changes in PRA in six
normal subjects given 2.5 mg of bromocriptine,
whereas Edwards et al. [75] found an increase in
PRA in normal subjects, using 7.5mg of bromocriptine. Ball et al. [76] found that plasma levels of
dopamine had to be 200 times normal in order to
produce renin release in the dog. Fenoldopam, a
specific DA, agonist, increases P R A in patients with
hypertension [77]. This might be due to peripheral
vasodilatation leading to stimulation of the sympathetic nervous system via the baroreceptors and
subsequent noradrenaline release, or by a direct
vasodilator effect within the kidney. In contrast to
fenoldopam [78, 791, gludopa (y-L-glutamyl-L-dopa),
which increases dopamine synthesis within the kidney, lowers PRA reproducibly (see section 6 below).
Presumably here, with gludopa, intrarenal dopamine
levels rise and the amine gains access to the juxtaglomerular cells via a different route, perhaps by the
increase in intratubular dopamine stimulating receptors on the macula densa which feed back to inhibit
renin release from the juxtaglomerular apparatus.
This could be an important mechanism for tubuloglomerular balance. If intrarenally generated dopamine can inhibit renin release from the juxtaglomerular apparatus, can angiotensin I1 inhibit
dopamine output? Recently, Eadington et al. [SO]
have demonstrated that infusion of angiotensin I1 in
subpressor doses in man reduces urinary dopamine
output. It would not seem from the present evidence
that the reduction in dopamine exerts an antinatriuretic effect, as the prior administration of carbidopa (an L-AAAD inhibitor) did not affect the
antinatriuretic effect of the peptide. Nevertheless,
this particular interaction between angiotensin/
dopamine and sodium handling deserves further
study.
(b) Vasopressin
Could the diuresis observed in some studies on
intravenous dopamine infusion in the animal and
man result from an interaction with vasopressin
(antidiuretic hormone)? The evidence at the moment
is conflicting. Lightman and Forsling [81] found
that vasopressin release from the pituitary was
inhibited by dopamine in man, but Rowe et al. [82]
could not confirm these observations. In contrast,
Ball et al. [76] found an increase in plasma vasopressin level after dopamine infusion in the dog.
However, the doses which they employed were very
high and emesis ensued, which is a known powerful
stimulus to vasopressin release. Reported studies
with DA, antagonists may serve to clarify the
situation. Metoclopramide, which crosses the bloodbrain barrier, stimulated vasopressin secretion in
man, whereas domperidone, which does not cross
the blood-brain barrier, did not [83]. These results
suggest that dopamire produced within the hypothalamus exerts a tonic inhibitory action on vasopressin synthesis (or release) and that the blockade
of this effect can result in increased plasma levels of
vasopressin.
Vasopressin may also interact with dopamine at
the level of the kidney. Muto et al. [84] showed that
dopamine inhibited the hydro-osmotic effect of
vasopressin in the cortical collecting tubule of the
rabbit kidney, whereas dopamine alone, at the same
dose level, failed to affect hydro-osmosis. Taken
together, these results suggest that dopamine may
inhibit vasopressin release from the brain in man
and may block the hydro-osmotic effect of vasopressin on the cortical collecting duct in the animal.
Dopamine and the kidney: ten
The evidence at the moment is fragmentary and
whether either (or both) of these actions has any
physiological importance remains to be established.
year^
on
363
other renal prostaglandins) under normal conditions
from the glomerulus, tubules, loop of Henle or
collecting ducts and, if so, whether this release has
any physiological or pathophysiological importance.
(c) Renal prostaglandins
This is also a very controversial area, as will
become apparent. The first study examined whether
interference with prostaglandin synthesis by inhibition of cyclo-oxygenase affects dopamine output in
the urine. Guellner et al. [85] found no effect of the
administration of indomethacin, a cyclo-oxygenase
inhibitor, on urinary dopamine output in women.
Using intravenous frusemide, a known stimulus of
both dopamine and prostaglandin production,
Jeffrey et al. [52] observed that the administration
of indomethacin did not attenuate the increase in
dopamine output seen after giving the loop diuretic
alone.
Can dopamine increase the renal production of
the prostaglandins and, if so, does this increased
production have any physiological importance?
Nadjer et al. [86] found that, when an infusion of
dopamine (1 pg min- kg- I ) produced an increase
in renal blood flow in normal man, this increase
could be prevented by indomethacin or ibuprofen
(cyclo-oxygenase inhibitors). Similarly, Yeyati et al.
[87] found that indomethacin (2 mg/kg) reversed the
effects of dopamine (6pg min-'kg-') in normal
subjects when measured in terms of renal vasodilatation and natriuresis. In contrast to these positive
findings, studies in my own laboratory, in normal
subjects given gludopa (a pro-drug for dopamine),
showed no consistent increase in either PGE, or
kallikrein in the urine and, when a dose of lOOmg
of indomethacin was given, there was no alteration
in the natriuresis produced [42].
Studies in uitro on glomeruli and tubules by
different groups have produced some very interesting results. Barnett et al. [88], working on isolated
rat glomeruli and cultured rat mesangial cells, found
that dopamine attenuated the reduction in glomerular and mesangial planar surface produced by
angiotensin 11. Indomethacin did not affect the
ability of dopamine to modify this effect of angiotensin 11. Moreover, when the rate of mesangial cell
production of PGE, was determined, dopamine was
found not to affect either the basal rate of production of the prostaglandin or the increased rate
resulting from the addition of angiotensin 11. Some
interesting work has emerged recently from studies
on cultures of inner medullary collecting duct cells
in the rat. Healy et al. [89] have shown that these
cells express a DA, receptor and, when they are
incubated with dopamine, there is increased production of PGE,. This stimulation of PGE, production
can be blocked by DA, antagonists, pertussis toxin
and phospholipase A, inhibitors. The increase in
PGE, seemed to require the presence of intracellular calcium. Further work will be required to
establish whether dopamine can generate PGEz (or
(d) ANP
There are remarkable similarities between the
effects of ANP and dopamine on the kidney. As a
result, investigators began to ask the question could
there be an interaction between them either in terms
of release of the hormones or at the receptor level
within the kidney?
In the rat, the diuretic and natriuretic effects of
ANP can either be attenuated or blocked by several
different dopamine antagonists [90-921. In a further
series of experiments in the rat, Lokhandwala et al.
[93] showed that when ANP was infused at a rate
of 1Opg h-' kg-' there was a significant natriuresis,
kaliuresis and diuresis. In a separate group of rats
given SCH 23390 (a DA, antagonist), the diuretic
and natriuretic effects were significantly reduced.
The effects of ANP on glomerular filtration rate,
blood pressure and heart rate were, however, maintained in the presence of the Schering compound.
Similarly, when carbidopa (an L-AAAD inhibitor)
was given to a group of rats, there was also a
reduction in the diuretic and natriuretic effects of
ANP. During the ANP infusion in these groups of
rats there was no change in the urinary excretion of
dopamine. The results with carbidopa suggest that
background levels of endogenous dopamine are
necessary for the expression of the full effects of
administered ANP. These findings are reminiscent of
those of Katoh et al. [94], who found that carbidopa attenuated the effect of ANP in volumeexpanded rats. The natriuretic response to ANP was
restored by small doses of dopamine, which did not
in themselves have a natriuretic action.
Recent work has suggested a mechanism for the
interaction of ANP with dopamine in the rat kidney. Soares-da-Silva and Fernandes [3 11, studying
rat renal cortical slices, showed that a-human ANP
(3.3 and 330 nmol/l) produced a marked inhibition
of the time-dependent accumulation of dopamine
and dopacetic acid (3,4-dihydroxyphenylaceticacid,
DOPAC) in the kidney. This inhibitory effect was
potentiated by zaprinast, a cyclic GMP phosphodiesterase inhibitor. Zaprinast alone decreased the
accumulation of both dopamine and DOPAC in the
slices. In contrast, in kidney homogenates, a-human
ANP was found not to affect the accumulation of
either dopamine or DOPAC, suggesting, first, that
intact cells are required for the inhibitory action
and, secondly, that a membrane-operated mechanism, coupled to the enzyme guanylate cyclase, is
involved in the control of L-dopa uptake into the
renal cells in this species. Here then we have a
paradoxical situation in the rat: dopamine is said to
be required for the full natriuretic effect of ANP to
364
M. R. Lee
be exerted and yet the atrial peptide is said to
inhibit L-dopa uptake (and dopamine formation) in
the renal cortical slice. This interaction in the rat is
obviously complex and further work will be
required to unravel it.
In man, the situation is also not clear. Initially
Wilkins et al. [95] suggested that carbidopa partially blocked the natriuretic effect of high dose ahuman ANP in normal subjects. However, work
from my own laboratory on (+)-sulpiride [96] and
by Allen et al. [97] on domperidone suggests that
neither DA, nor DA, activation is involved in the
renal natriuretic effect of ANP in man. Moreover, a
combined study between ourselves and the
Birmingham group could not reproduce the initial
results described with carbidopa blockade [98].
Looking at the question the other way about, does
dopamine infusion affect ANP synthesis or secretion? Two studies have addressed this issue, that of
Shenker et al. [99] and that of Tulassay et al. [loo].
Neither study showed any effect on ANP levels.
(e) SHT (serotonin)
It has become apparent in the last ten years that
5-HT can be formed in the kidney from 5-hydroxyL-tryptophan (5-HTP) by the action of tubular LAAAD [101-1031. Itskovitz et al. [lo41 then went
on to determine if 5-HTP could have effects on
renal function in rats. Slight reductions in the
clearance of p-aminohippurate and glomerular filtration rate were observed, but there were much
greater reductions in sodium and water excretion.
When L-dopa was added to 5-HTP, there was a
lessening of the antinatriuretic and antidiuretic
effect. These effects of L-dopa occurred without
change in the formation of 5-HT, suggesting a
functional reciprocal effect, rather than competition
for L-AAAD in the renal tubules. We have been
very interested in these observations by Itskovitz et
al. [lo41 and recently conducted a series of experiments in normal male subjects in which we infused
a
5-HTP and y-~-glutamyl-5-hydroxy-~-tryptophan,
potential pro-drug for the intrarenal formation of 5HT (see the section on gludopa below). Both tryptophan compounds proved to be antinatriuretic in
man and in the case of the glutamyl derivative there
is a virtual absence of systemic effects on pulse and
blood pressure [l05].
It remains to be established how the 5-HT and
dopaminergic systems interact under physiological
conditions. Can sodium loading or sodium deprivation affect the balance between 5-HT and dopamine
formation (or action) within the kidney? Preliminary
results suggest that 5-HT excretion in the urine
increases in sodium-depleted subjects [1061. The
possibility is also raised that there may be hypertensive states characterized by overproduction of 5HT in the kidney, which would benefit by blockade
of specific tryptaminergic receptors.
(f) Lithium
Thomsen [1071 suggested that lithium could be
used as a method for the measurement of proximal
tubular handling of sodium. We intended to use this
technique to analyse the effects of gludopa on the
kidney. We therefore administered 750 mg of lithium
carbonate to normal subjects in the evening before
gludopa infusion on the next day. To our surprise,
gludopa, under these conditions, failed to produce a
natriuresis and we soon confirmed that the effect
was due to lithium at a serum concentration of
0.29 f0.09 nmol/l [1083. Moreover, lithium at this
dose was natriuretic. The effect of lithium that we
observed could be due to an effect either on Na',
K+-ATPase or on the phosphatidylinositol cycle.
The blocking action of lithium does not appear to
be restricted to dopamine. We have obtained similar
results with ANP [lo91 and angiotensin I1 [Ill].
A note of controversy was raised by Girbes et al.
[llO] who investigated the renal effects of fenoldopam with and without previous lithium administration. They used a dose of 300mg of lithium
carbonate, generating serum lithium concentrations
of 0.12+0.025mmol/l at the start of the infusion.
They found that lithium at these levels did not
attenuate the effect of fenoldopam on natriuresis or
renal blood flow. There are two possible explanations for the divergent results. The first is that other
receptors may be involved with gludopa (DA, and
adrenergic) compared with fenoldopam (principally
DA,) or, second, that the dose of lithium is critical.
The latter explanation seems the more likely in view
of some recent observations from our group [lll].
Using two different doses of lithium carbonate,
750mg and 250mg, it was found that the antinatriuretic effect of angiotensin I1 was attenuated only
by the higher dose of lithium. The responses after
250mg of lithium did not differ from those observed
after placebo. We can conclude that 250-300mg of
lithium carbonate probably does not interfere with
the action of dopamine (or dopaminergic agents) on
the kidney. Nevertheless, the lithium clearance
method should not be used uncritically and suitable
control periods (or control days) should be incorporated into the protocols. These controls will be
needed to exclude the blocking effects on various
hormones and also the potential intrinsic effect of
lithium on natriuresis and PRA. With these provisos, it may still be possible to obtain useful results
with the lithium clearance method.
5. DOPAMINE FORMATION IN HYPERTENSIVE
AND OEDEMATOUS STATES
The following disease states will be considered:
I. Hypertension.
11. Congestive cardiac failure.
111. Diabetes mellitus.
Dopamine and the kidney: ten p~on
I. Renal dopamine in experimental and clinical
hypertension
(a) Rat models of essential hypertension. The Dahl
rat. The pioneer work of Dahl led to the development of the Dahl R (resistant to salt) and the
Dahl S (sensitive to salt) strains. Yoshimura et al.
[112] studied the Dahl rat and its response to
sodium loading when compared with Wistar rats.
The Dahl S rats excreted less dopamine in the urine
on a normal (0.8% NaCl) diet and this was accompanied by a reduced urinary output of cyclic AMP.
De Feo et al. [113] have reported a decreased renal
content of dopamine in Dahl S rats on a high
sodium diet, and Racz et al. [114] have found a
decreased urinary output of dopamine in the Dahl S
rat. Of course, the situation in the Dahl S rat may
be complex, as Racz et al. [114] have also reported
that a high salt diet enhances sympathoadrenomedullary discharge in this rat and this could also
contribute to the genesis and maintenance of raised
arterial blood pressure in this strain.
The spontaneously hypertensive rat (SHR).
Abnormalities in the renal dopaminergic system
have been reported in this rat from an early age,
when compared with its control strain, the WistarKyoto rat (WKY). Renal dopamine levels are higher
in the SHR than the WKY after 4 weeks of age,
but, at this time, the SHR shows a tendency to
retain sodium [llS]. This has been interpreted by
Yoshimura and Takahashi [116] as a compensatory
mechanism, whereby dopamine may act to decrease
blood pressure and increase sodium excretion. In
support of this theory, the same workers found that
inhibition of dopamine synthesis by carbidopa in
the SHR decreased sodium excretion and accelerated the development of high blood pressure. Recent
work has thrown some light on the nature of the
renal defect in the SHR. Kinoshita et al. [117]
reported a defect in these rats in the DA, receptor
G protein coupling to adenylate cyclase in the
proximal convoluted tubule of the kidney. This
defect was found at 3 weeks of age before hypertension was apparent. In support of this observation, it has also been noted that the natriuretic
effect of DA, agonists is reduced in the SHR [118].
The DA, agonist, bromocriptine, also delays the
onset of hypertension in the SHR, suggesting that a
defect in this part of the dopaminergic system may
also be involved [ll6]. Kaneko et al. [I191 studied
the effects of pramipexole, a mixed dopamine DA,
and DA, agonist, on the blood pressure and sodium
excretion of the SHR. The natriuretic effect of
pramipexole was less in the SHR than in the WKY
when mean arterial blood pressure was in the same
range. Since the natriuretic effect of DA, agonists is
mediated in part by increasing renal tubular cyclic
AMP, it is possible that the sodium retention noted
in the young SHR is due to decreased
DA,-stimulated adenylate cyclase activity in the
proximal tubule [27]. This seems to occur in spite
365
of an increased renal dopamine concentration and
possibly an increased number of DA, receptors.
The contribution of DA2 receptors to sodium
transport in the SHR remains difficult to evaluate.
In the dog, the DA, blocker, domperidone, did not
block the natriuretic effects of dopamine [120].
However, a number of DA2 effects could result in a
natriuresis, and a depression of renin output and
also of aldosterone secretion [l2l]. Further, there
would also be an inhibition of noradrenaline release
by an effect at the presynaptic receptors. Downregulation of the DA, receptors in the SHR might
have an additional effect in raising blood pressure.
Felder and Van Campen [122] studied the proximal tubular receptors for dopamine in the SHR. In
this strain, the guanine nucleotide guanosine 5’-[B,yimidoltriphosphate ( G p p p H l p ) failed to reduce
the affinity of fenoldopam for 3H-labelled SKF
38393 binding to renal tubular DA, receptors.
Sodium ions reduced the affinity of fenoldopam for
SKF 38393 binding in the proximal tubular cells of
the SHR, but to a lesser extent than the WKY.
They concluded that the SHR has a defective DA,
receptor, or stimulatory G protein-receptor coupling, which interferes with the ability of
Gpp[NH]p to act on the DA receptor/G protein
complex.
These results in hypertensive strains of rats are
extremely interesting, but they must be interpreted
with caution for two reasons. First, it has been
shown recently that inbred strains of rat are not
genetically homogenous when obtained from different breeding centres. Secondly, these strains are not,
of necessity, a paradigm for essential hypertension
in man. As will be described below, it would appear
that, in several different studies in hypertensive
patients, the natriuretic effect of dopamine (and
dopamine-like drugs) is increased, suggesting that
the renal dopamine receptors are ‘up-regulated’, not
‘down-regulated‘ as would be inferred from the
studies in the SHR.
(b) Essential hypertension in man. For many years
the major proposal which dominated theories on
the nature of hypertension was that it was an excess
of a factor (or factors) which produced vasoconstriction and/or sodium retention in the kidney.
Obvious candidates for the factors involved, such as
noradrenaline and angiotensin 11, soon presented
themselves. The countervailing argument that hypertension could be due to a lack of a vasodilator
substance (or substances) received little attention. In
a landmark article, Warren and O’Connor [I231
suggested that hypertension in the Afro-American
was more likely to be due to lack of a systemic
vasodilator effect and they suggested the renal
kallikrein-kinin system as a possible candidate for
the defective vasodilator system. As I shall describe
in this section, another powerful candidate for the
defective vasodilator function is the renal dopaminergic system.
Several early reports described a reduction in
366
M. R. Lee
urinary dopamine excretion in patients with essential hypertension [124, 1253. At that time dopamine
was widely regarded simply as a precursor of noradrenaline and the observations were passed over,
although Januszewicz et al. [125] remark clearly in
their discussion that “the greater part of dopamine
excreted in the urine is produced in the kidneys”!
These early studies were of a cross-sectional nature.
When it became apparent that sodium loading of
normal subjects under metabolic balance conditions
increased urinary dopamine [126], it was very
important to salt load hypertensive subjects to
establish whether their urinary dopamine output
responded appropriately. By comparison with the
normal subjects, the patients with essential hypertension showed not a blunted rise, as we had
expected, but a paradoxical fall in urinary dopamine
output. This fall was highly significant statistically
[1271. The hypertensive patients tended to develop
a more positive sodium balance and to gain more
weight than did normal subjects. Blood pressure
rose little over the 5 day period of salt loading. A
similar inability to mobilize dopamine in the kidney
was seen in patients with essential hypertension who
were given intravenous frusemide [ 1281 which
usually increases urinary dopamine output (see
section 2 above).
In a study of 61 hypertensive patients, Kuchel et
al. [1291 found higher conjugated dopamine levels
in the plasma, but lower conjugated noradrenaline
levels. In the urine there was a lower excretion of
free dopamine, but a greater excretion of free noradrenaline. These authors also suggested that certain
hypertensive patients had surges of dopamine into
the plasma, the clinical effects of which mimicked
pheochromocytoma. This condition they named
pseudopheochromocytoma. They suggest that the
surges of dopamine may hinder the biodisposal of
free noradrenaline and adrenaline, thus having an
indirect effect on adrenergic tone. An important
Japanese study separated hypertensive patients into
salt-sensitive and salt-resistant subjects [ 1303. The
salt-resistant subjects showed a mean rise in blood
pressure of 0.5mmHg on salt loading and a prompt
increase in urinary dopamine, whereas the saltsensitive subjects showed a mean rise in blood
pressure of 10.5mmHg on salt loading and no
increase in urinary dopamine.
The question can now be put: is the failure to
mobilize dopamine in the kidney a cause of hypertension or a consequence of the hypertensive process? Two studies by Japanese ,groups have
addressed this question. Saito et al. [131] studied
the first-degree normotensive relatives of patients
with hypertension and found that the relatives had
lost the normal regression between urinary sodium
and urinary dopamine. This suggests that the
abnormality of renal dopamine production in the
hypertensive patient is inherited, not acquired.
Further supporting evidence comes from the work
of Imura and Shimamoto [132]. The Sapporo
group had already shown that urinary dopamine
excretion was lower in hypertensive patients than in
normotensive subjects, particularly in those hypertensive patients in the low renin group [133, 1341.
In this study [132] they took young healthy normotensive subjects with a family history of hypertension [FH(+)] and without a family history
[FH( -)I. In the FH( +) individuals, there was a
significant decrease in free dopamine in the urine.
There seemed to be a normal delivery of L-dopa to
the renal tubules, but a defective uptake or conversion to dopamine in the FH( +) individuals. The age
of the normotensive FH( ) individuals was between
20 and 30 years, and this suggests that the dopamine fault is inherited. One can conclude from these
studies that there is a sub-group of Japanese hypertensive patients (with low PRA) who have an
inherited fault in renal dopamine production and
this may also be associated with salt sensitivity of
their blood pressure.
Does this problem exist in other ethnic groups?
The evidence is gathering, but is not, so far, conclusive. In the last five years we have studied the
sodium/dopamine relationship in the urine of
normotensive groups of Caucasians, Ghanaians,
Zimbabweans, Iranians and Thais. Caucasians have
a strong positive correlation between urinary
sodium and urinary dopamine and they share this
positive relationship with Zimbabweans and Thais.
In contrast, Ghanaians and Iranians do not show
this positive regression [135]. Moreover, if normotensive Ghanaians are loaded with salt by mouth,
they fail to increase urinary dopamine [1361. These
results suggest that the groups of Ghanaians and
Iranians, which we studied, have lost (or indeed
never acquired) the linkage in the kidney between
salt and dopamine. Of course, we do not know the
dietary history of these groups, in relation to salt
and L-dopa, but these preliminary findings suggest
that certain ethnic groups may be susceptible to salt
loading because they fail to generate more dopamine in the kidney.
Blacks from the West Coast of Africa formed the
basis for the American Black of today, as a result of
the infamous slave trade. It is also known that
hypertension in American blacks is characterized by
a higher incidence of salt sensitivity [137] and this
is associated with failure to excrete sodium loads as
efficiently as Caucasians. Sowers et al. [ 1381 studied
a group of American Blacks, both hypertensive and
normotensive. Urinary dopamine excretion was decreased in these hypertensive Black subjects, as
compared with the normotensive Black subjects (on
both high and low salt intakes). There was a small
increase in dopamine in both groups when salt
intake was increased. The results of the study by
Sowers et al. [138] on the normotensive Blacks are
in accord with those from our studies on the
normotensive Ghanaians. The diminished urinary
dopamine response to dietary salt in normotensive
Blacks may reflect the greater prevalence of salt
+
Dopamine and the kidney: ten years on
sensitivity in normal Blacks. Gill et al. [139]
observed no increase in urinary dopamine in saltsensitive hypertensive subjects with normal PRA, in
contrast to the increase produced in normotensive
subjects when changed from a low to a high salt
diet. The racial background of the subjects in the
study of Gill et al. [139] is not stated. Sowers et al.
[138] also observed an increased plasma ANP level
on dietary salt loading in the hypertensive group
when compared with the normotensive group, suggesting that in these subjects the natriuretic peptide
is attempting to compensate for the defective dopaminergic response in the kidney. From this important study it would thus appear that the American
Black, both normotensive and hypertensive, may
have the ‘dopamine fault’ in the kidney and in this
way resembles the Japanese (both hypertensive and
first-degree relatives), the Caucasian (hypertensive),
the Ghanaian (normotensive) and the Iranian
(normotensive). Studies on Ghanaian and Iranian
hypertensives, both salt-sensitive and salt-resistant,
would be very interesting in this respect.
If the putative renal dopaminergic fault exists in
the kidneys of some hypertensive patients, then
failure to generate dopamine on salt loading might
be accompanied by an increased number of dopamine receptors in the kidney or an increased affinity
for dopamine in a normal population of receptors,
that is ‘up-regulation’. Several studies have now
appeared which would support this concept.
Kikuchi et al. [140] studied the haemodynamic and
natriuretic effects of intravenous dopamine in
patients with essential hypertension and found a
greater increase in urine volume, sodium output and
fractional excretion of sodium when compared with
normotensive subjects. Andrejak and Hary [1411
confirmed these observations with a dose level of
dopamine of 2pg min-’kg-’.
Both p-aminohippurate and inulin clearances showed a greater
increase in the hypertensive patients, as also did
sodium excretion. This dose of dopamine also lowered systolic and diastolic blood pressures significantly in the hypertensive patient, but had no effect
on these haemodynamic parameters in the normotensive subject. In two separate studies in our
laboratory with the renal dopaminergic pro-drug,
gludopa, we have found a similar increased natriuresis in hypertensive patients [142, 1431. All these
studies suggest then that the renal dopamine receptors are ‘up-regulated’ in essential hypertension and
further support the hypothesis that the intrarenal
generation of dopamine is somehow defective. These
studies are also in direct contrast to those in the
SHR described in a previous section, where the
dopamine receptors are ‘down-regulated’. This ‘upregulation’ of the receptors also holds out the
possibility that specific selective dopamine agonists
might be developed which would have a marked
therapeutic effect in essential hypertension (see
below).
Several caveats must be entered here. It cannot be
367
assumed that all ‘salt-sensitive’hypertensive patients
will have the dopamine fault. There may well be
defects (or deficiencies) in other natriuretic systems,
for example, ANP, renal kallikrein or the renal
prostaglandins. The nature of the fault or faults may
also vary from one ethnic group to another. It will
be important to establish the prevalence of the
dopamine fault in different groups and whether it is
inherited or acquired as a result of secondary renal
damage. A mandatory condition in such studies will
be to establish that the hypertensive groups under
investigation are age- and sex-matched with normal
control subjects. Evidence is accumulating from
animal studies that the dopamine system may
become blunted with age. The number of DA, renal
receptors is at least 50% lower in aged rats [144].
Also, Amenta et al. [145] have shown that the
stimulatory effect of dopamine on cyclic AMP production is 40% lower in renal arteries from aged
rabbits. Taken together with maintained or
enhanced a-adrenergic activity in older individuals,
this could mean that the balance in the kidney
between dopamine and noradrenaline, the so-called
‘natriuretic index’, shifts towards sodium retention
in the elderly [146].
(c) Primary aldosteronism. Acute administration
of mineralocorticoid appears to suppress dopamine
production temporarily [147]. The situation appears
to be different in chronic overproduction of aldosterone by an adrenal adenoma (Conn’s syndrome).
Here Kuchel et al. [148] have reported that both
free and conjugated dopamine levels in the urine are
high, probably in an attempt to compensate for the
sodium retention produced by aldosterone. Moreover, after surgical excision of the adenoma, removing the source of overproduction of aldosterone,
these workers noted that urinary dopamine fell
towards normal.
(d) Hypertensive disease of pregnancy. Studies on
urinary dopamine in hypertensive pregnancy have
shown two patterns [149]. In those women with
significant proteinuria (greater than 0.5 g/l of urine),
urinary dopamine increased to levels greater than in
normotensive pregnancy, suggesting that the kidney
was attempting to compensate for excessive sodium
retention and an expanded extracellular fluid
volume. In contrast, in the non-proteinuric hypertension of pregnancy, there seemed to be a relative
failure to generate dopamine. Renal dopamine may
be one of the vasodilator systems of normal pregnancy. Perkins et al. [l50] had previously shown
that there is about a 30% increase in urinary
dopamine in normal pregnancy and that this
increase can be detected as early as the 16th week of
pregnancy. By the sixth week postpartum, levels of
dopamine have fallen back to normal non-pregnant
values. Further work is now required on the role of
dopamine in normal and hypertensive pregnancies
and its relationship to other hormonal systems, such
as the renal prostaglandins.
(e) Renal dopamine and chronic renal failure.
368
M. R.
Casson et al. [151] studied eight patients with
chronic glomerulonephritis who were in stable chronic renal failure, comparing them with five agematched normal subjects. The studies were carried
out under metabolic balance conditions, first on a
low sodium diet, and then with added sodium
chloride. Urinary dopamine excretion was much
lower in the patients than in the control subjects
and did not rise significantly in the patients on salt
loading when compared with the normal response
seen in the control subjects. Itskovitz and Gilberg
[152] found that, with increasing degrees of renal
failure, free dopamine in the urine diminished and
had virtually disappeared when plasma creatinine
concentration was greater than 530 pmol/l. If endogenous dopamine production is decreased in chronic
renal failure, as our results and those of Itskovitz
and Gilberg [152] would suggest, then perhaps the
renal response to dopamine (or dopaminergic drugs)
would be increased ('up-regulation'). Alternatively, if
the DA, and DA, receptors in the renal blood
vessels and tubules are destroyed, by the pathological process causing the renal disease, then the
response to exogenous dopamine could be blunted.
Wee et al. [153] reported the effects on renal
function of intravenous dopamine infusion (2 pg
min-' kg-') in a large group of patients with renal
disease (1 3 1 subjects). The increase in renal plasma
flow and glomerular filtration rate observed was
related to baseline glomerular filtration rate. Below
a glomerular filtration rate of 50mlmin-' 1.73m-,,
dopamine failed to affect the glomerular filtration
rate and effective renal plasma flow. Similarly,
Tulassay et al. [154], with a dose of dopamine of
2pg rnin-lkg-', found only a small increase in
effective renal plasma flow (14%) and no increase in
glomerular filtration rate in paediatric patients with
advanced renal failure (mean glomerular filtration
rate 17mlmin-' 1.73mP2). My own view is that
the failure or relative failure of vascular and tubular
responses to dopamine in chronic renal failure is
more likely to be due to loss of receptors, together
with sclerosis of blood vessels, and that the remaining 'intact nephrons' are working under full natriuretic pressure. More extended studies will be
required to resolve this dilemma.
II. Congestive cardiac failure
Dopamine infusion in patients with congestive
cardiac failure results in marked increases in effective renal plasma flow and glomerular filtration rate
with a pronounced natriuresis. Ramdohr et al. [l55]
observed a mean increase of 70% in p-aminohippurate clearance and of 36% in inulin clearance,
whereas the same dose of dopamine given to normal
subjects resulted only in a 48% rise in p-aminohippurate clearance and no significant change in
inulin clearance. Similar findings have been reported
by other groups. The increased response could be
due to an increased haemodynamic effect of dopa-
Lee
mine or to an increased effect on the tubule. There
have been no studies, as far as I am aware, on
endogenous renal dopamine formation in congestive
cardiac failure in man. Is production decreased, as
might be expected, in response to the reduced renal
blood flow and/or increased noradrenergic discharge
to the kidney? Dopamine agonists used in cardiac
failure, such as ibopamine and dopexamine (see
below), cause a natriuresis and a diuresis in patients
with congestive cardiac failure. This will be discussed further in section 6 on possible therapeutic
strategies.
111. Diabetes mellitus
Diabetic patients have an impaired ability to
excrete sodium after intravenous salt loading [1561'
and it has been suggested that increased tubular
sodium reabsorption is one of the first functional
changes to occur. Stenvinkel et al. [157] studied
intrarenal dopamine formation after intravenous
sodium chloride infusion in Type I (insulindependent) diabetes. In the control subjects, sodium
chloride infusion resulted in a prompt increase in
urinary sodium excretion which was paralleled by a
corresponding increase in urinary dopamine output.
In contrast, in the diabetic patients, the increase in
sodium excretion was markedly delayed and no
significant increase in urinary dopamine output was
observed. The ratio between urinary excretion of
sodium and urinary output of dopamine was
comparable in the diabetic patients and in the
control subjects, both in the basal state and after
sodium chloride infusion. We have obtained similar
results in Type I diabetes in the basal state in our
laboratory [l58]. In the study of Stenvinkel et al.
[157], circulating insulin levels were higher in the
diabetic patients than in the control subjects, suggesting perhaps that insulin can suppress the mobilization of dopamine in the kidney. Many studies
have shown that insulin is antinatriuretic, for example, that of De Fronzo et al. [159], although the
site for its action remains controversial. If defective
renal dopamine mobilization is confirmed in Type I
diabetes by other studies, it may be possible to
prevent the low-renin hypertensive state, which
often develops over the course of many years in
these individuals, by the judicious administration of
small doses of renally selective dopamine agonists.
6. SEARCH FOR SPECIFIC PERIPHERAL
DOPAMlNERGlC AGO NISTS OF THERAPEUTIC
UTILITY
In the light of the background knowledge of the
renal dopaminergic system that has been generated
over the last 25 years, and the postulated abnormalities in essential hypertension and congestive
cardiac failure, a search has been undertaken for
Dopamine and the kidney: ten years on
369
Table 1. Dopaminc agonists, antagonists and pro-drugs
DAi
DA*
Non-selective
Agonists
Fenoldopam (SKF 82526)
SKF 87516
FPL 630124R
Quinpirole (LY 171555)
Bromocriptine
Gludopa (y+glutarnykdopa)*
Docarpamine (TA 870)*
Epinine
lbopaminet
SIM 2055t
Dopexamine
Antagonists
SCH 23390
Domperidone
(-)-Sulpiride
YM 09151
Metoclopramide
Sulpiride (racemic)
Haloperidol
Cis-Thiothixene
Trifluoperazine
*Prodrug for dopamine.
tProdrug for epinine.
agents which would specifically activate the peripheral dopaminergic system. So far this search has
met with only moderate success. Space precludes
more than a general account of these agents. For a
more detailed treatment, the reader is referred to the
review by Girbes [160]. It should also be noted that
some of the agents, for example, fenoldopam and
gludopa, have given valuable insights into the physiology and pharmacology of dopamine in the kidney and peripheral vascular system. Generally, the
compounds can be divided into two groups: (1)
direct agonists, for example, fenoldopam, dopexamine and FPL 63012AR; (2) pro-drugs for dopamine or epinine, such as gludopa, docarpamine,
ibopamine, SIM 2055, (see Table 1).
Direct agonists
(a) Fenoldopam (SKF 82526). This compound is a
substituted benzazepine which stimulates DA,
receptors selectively [161]. It has also been suggested that the compound has some a-adrenolytic
activity [162]. In normal man, administration of
fenoldopam by mouth induces a fall in blood pressure, systemic vasodilatation and renal vasodilatation, together with a diuresis and a natriuresis [77,
1631. In patients with hypertension, a marked fall in
blood pressure is observed [164-1661. White and
Halley [1671 compared the effects of intravenous
fenoldopam and intravenous sodium nitroprusside
in patients with severe hypertension. The authors
concluded that fenoldopam lowered blood pressure
in a manner similar to nitroprusside. However, in
contrast to the nitrovasodilator, fenoldopam had
additional desirable renal effects, including increased
urinary flow and sodium excretion. Problems with
fenoldopam at the present time include tolerance to
the acute hypotensive effect [1663, relatively poor
bioavailability by mouth (35%) [168] and an acute
rise in PRA which may also limit the hypotensive
effect. The rise in PRA may be partially due to
reflex sympathetic activation and partly due to a
direct stimulation of renin release from the juxtaglomerular cells [77]. In spite of these difficulties,
fenoldopam may act as a useful template for the
development of pro-drugs based on the substituted
benzazepines.
(b) Dopexamine (Dopacard, Fisons Pharmaceuticals). This recently marketed compound shows
structural resemblances both to salbutamol and to
dopamine [169]. Its vasodilator effects are a consequence of potent b,-adrenoceptor stimulation with
additional renal vasodilatation due to selective DA,
receptor stimulation. It also exhibits positive inotropic activity by blocking neuronal reuptake of
noradrenaline (Uptake-1) and by stimulation of
myocardial P2-adrenoceptors. Dopexamine has
insignificant direct b,-adrenoceptor agonist activity
and no a-adrenoceptor agonist activity [1701.
The renal effects of dopexamine have been examined in several studies. Magrini et al. [171] measured renovascular parameters in patients with mild
to moderate hypertension who were undergoing
diagnostic renal vein catheterization. Dopexamine
was given at two dose levels, 1 and 3pg
min-' kg-', and this resulted in significant doserelated increases in mean renal blood flow, together
with a decrease in renal vascular resistance. There
was no systemic vasodilatation at these dose levels.
Renal blood flow increased relatively more than
cardiac output, consistent with a selective DA,
receptor-mediated renal vasodilator effect. Leier et
al. [172] also reported favourable renal responses in
a study on 12 patients with low output congestive
cardiac failure. Significant increases in renal blood
flow were observed at doses of dopexamine between
0.25 and 1 pg min-lkg-'. These dose levels also
resulted in an increase in urine volume and sodium
excretion. Mousdale et al. [173] compared the renal
effects of dopexamine, dobutamine and dopamine in
normal subjects. Renal plasma flow increased significantly at all doses of dopamine and at the two
highest doses of dopexamine, but was unaffected by
dobutamine. Dopexamine appeared to have about
370
M. R.
one-third of the activity of dopamine when comparing their action at the renal vascular receptors.
Dopexamine improves haemodynamic parameters in
patients with chronic heart failure [174] and also in
patients undergoing coronary bypass surgery [1751.
An increase in cardiac output and stroke volume
index is found, together with a fall in systemic
vascular resistance. Dopexamine therefore appears
to be a useful therapeutic agent, albeit with restricted clinical indications.
(c) FPL 63012AR. The group at Fisons Pharmaceuticals decided to try and modify the structure of
dopexamine further by introducing extra substituents into the dopamine nucleus. From this work
emerged the compound FPL 63012AR, which has
proved to be a powerful DA, receptor agonist in
the dog kidney, ten times as potent as dopamine
[176]. Unlike dopamine, FPL 63012AR has no
activity at DA, receptors or at al-, u,-, /Il- or
P,-adrenoceptors. It also inhibits noradrenaline
Uptake 1 into brain synaptosomes. Intravenous
infusion of the compound into anaesthetized and
conscious dogs reduced systemic vascular resistance
and increased renal blood flow to the kidney. These
effects were accompanied by hypotension and tachycardia. It will be very interesting to see how this
compound compares with fenoldopam and dopexamine if and when it undergoes clinical trial.
Dopaminergic prodrugs
(a) Ibopamine. Ibopamine is a pro-drug for epinine, being the di-isobutyryl ester of N-methyldopamine (epinine). When administered by mouth it
is de-esterified by esterases in the gut and liver to
yield epinine. The released epinine has been shown
to stimulate a- and /J-adrenoceptors and DA, and
DA, receptors [177]. The effect on renal function
has been variable. Harvey et al. [178], in my
laboratory, found no effect on sodium handling or
creatinine clearance, but others have found a definite effect [179, 1803. The most promising clinical
findings have been in congestive cardiac failure.
Ibopamine increases cardiac index by up to 33%
and reduces systemic and pulmonary vascular resistance [181, 1823. In patients with congestive cardiac
failure, the increased plasma noradrenaline levels
commonly observed, which are an index of the
severity of the condition, are reduced by ibopamine
[l83, 1841. This may be the result of inhibition of
noradrenaline overflow by the effects of the compound on DA, receptors or a,-adrenoceptors, or
could simply be due to the better clinical state of
patients who receive the drug. There seems to be
little hypotensive effect of the compound. Adverse
effects have been few, but include dyspepsia and
palpitations. This substance is now widely used in
Europe for congestive cardiac failure, but it is not
yet licensed in the U.K.
(b) SIM 2055. This substance is another pro-drug
for epinine; its chemical structure is epinine 4-ortho-
Lee
phosphate. Phosphatases in the gut, liver and kidney will liberate the active principle, epinine, either
into the blood if given orally, or into the kidney if
given intravenously. In anaesthetized dogs,
Casagrande et al. [185] showed that this compound
induced a dose-dependent renal vasodilatation without any change in systemic haemodynamic parameters. It is too early yet to say whether this prodrug will have a useful effect in hypertension or
congestive cardiac failure.
(c) (y-L-glutamyl-L-dopa). This substance has been
used extensively in our laboratory as a pro-drug for
renal dopamine [1861. It is sequentially converted
to renal dopamine by y-glutamyltransferase and LAAAD. It has a moderate natriuretic effect in man
and is hypotensive if given for more than 3-4 h. The
most interesting feature of the compound is that, in
spite of the natriuresis produced, renin levels are
lowered, suggesting that when dopamine is generated intrarenally it inhibits secretion from the juxtaglomerular cells (contrast the action of fenoldopam
on renin release described above). In hypertensive
patients, there is an increased natriuresis [142] and
a greater effect on blood pressure [143]. Gludopa is
most unlikely to become an effective therapeutic
agent as its bioavailability is very poor, only 1-2.5%
[187]. Nevertheless, it has given many useful
insights, both physiological and pharmacological.
The y-glutamyl concept for renal localization of
agonist may yet prove useful in therapeutic terms
[188], as will be illustrated with TA 870 (see below).
(a) Docarpamine (TA 870). In this compound
there are reflections both of ibopamine and gludopa
in that the catechol 3- and 4-hydroxyl groups are
protected by esterification and the amino group of
the side chain is acylated with N-acetylmethionine.
The N-acetylmethionine group will be removed by
y-glutamyltransferase in the kidney and elsewhere
(compare y-L-glutamyl-L-dopa) and the ester groups
by esterases (compare ibopamine). Ozawa et al.
[189] studied the renal effects of 600mg of docarpamine in normal subjects and in groups of patients
with stable chronic renal failure of varying severity.
Renal plasma flow increased in all groups as did
urinary sodium output, but glomerular filtration
increased only in the normal subjects. A single dose
of docarpamine (1200 mg) in patients with congestive cardiac failure (New York Heart Association
Class 111 and IV) produced a significant decrease in
left ventricular end systolic volume, but no change
in end diastolic volume (as measured by M mode
echocardiography [1901). Although these preliminary results are encouraging, it is too early yet to
say whether this compound will prove useful
therapeutically.
7. FINAL CONCLUSIONS AND UNANSWERED
QUEST10NS
In the ten year period since my first Review was
written, a great deal of progress has been made. It
Dopamine and t h e kidney: t e n years o n
has become firmly established that dopamine produced in the kidney acts as an intrarenal natriuretic
hormone. There seem to be subsets of patients with
hypertension where a definite dopamine ‘fault’ has
been identified. There have, however, been
disappointments. Progress on the development of
peripheral dopamine agonists has been slow, limited
by the development of tolerance to their effects and
poor bioavailability.
There are still many important unanswered
questions:
1. How is the production of dopamine in the
kidney controlled? Is it by the delivery of Ldopa, or the rate of uptake of L-dopa, or the
rate of conversion of L-dopa in the tubular
cell?
2. Where is the sodium-sensing structure or
mechanism which controls dopamine production? How do protein and phosphate loading
exert their effects?
3. Does 5-HT production exert a counterregulating effect on dopamine production (or
action) in the proximal tubular cells?
4. How common is the dopamine ‘fault’ in different groups of hypertensive patients? Is it inherited or acquired?
5. What happens to dopaminergic mechanisms in
the ageing kidney? Does a failure (or relative
failure) contribute to the rise in blood pressure
with age in Western Society?
6. Can effective oral dopaminergic agonists be
developed for essential hypertension? Will the
effect of ibopamine on congestive cardiac
failure be confirmed when more clinical trials
are done?
At all events, we can now see clearly that dopamine, once regarded, in the periphery, as simply a
precursor for noradrenaline and adrenaline, is an
important regulator in its own right, both of the
kidney and the peripheral vascular system. In 1977,
S. G. Ball and I [41] asked the question ‘How can
it be that there is so much dopamine in human
urine, greatly out of proportion to noradrenaline
and adrenaline?. This question can now be answered very clearly and with confidence. Dopamine
has joined renin and the prostaglandins as one of
the central players in the regulation of renal
function.
ACKNOWLEDGMENTS
This Review is dedicated to the memory of
Professor L. I. Goldberg [191]. His work first interested me in the peripheral actions of dopamine. I
also thank my co-workers over the years, first, in
Leeds, and, since 1984, in Edinburgh. Finally, I
thank Ms Elspeth Shields, my Administrative
Secretary, for her indefatigable efforts with the
manuscript.
37 I
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