| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Institute for Cardiovascular Studies, College of Pharmacy,
University of Houston (Texas).
Dopamine receptors are located at various regions within the kidney of
both experimental animals and humans, including the renal vasculature,
sympathetic nerve terminals innervating different sites,
juxtaglomerular cells, and renal
tubules.10 13 17 18 19 The
D1-like receptors are present on the smooth
muscle of renal arteries and juxtaglomerular
apparatus and on the renal
tubules.13 19 20 The
D2-like receptors are expressed in the intimal
layer of the renal vasculature, glomeruli, sympathetic nerve terminals,
and the renal tubules.13 19 21 The tubular
D1-like dopamine receptor density is higher in
humans than in rats.13 Another feature of the
tubular dopamine receptors is higher density of
D1-like receptors in the proximal tubules than in
the distal parts of the nephron,13 as well as in
the renal vasculature.13 Also,
D1-like and D2-like
receptors are located on both basolateral and brush border membranes of
the proximal tubules.11
A positive correlation has been reported between sodium intake/urinary
excretion and renal dopamine production/urinary excretion in
both experimental animals and humans.27 28
Several studies have shown the role of dopamine in the regulation of
sodium excretion during acute volume expansion and during acute
increase in sodium intake.29 30 31 For example, we
have shown that almost 60% of the natriuresis seen during acute volume
expansion (5% of body weight) is accompanied by an increase in urinary
dopamine excretion and could be antagonized by SCH
2339030 and attenuated by carbidopa, an
inhibitor of dopa decarboxylase which converts
L-dopa into dopamine.31 The increased
sodium excretion seen in animals placed on a high sodium diet is
accompanied by an increase in urinary dopamine
excretion.32 33 These results suggest that
endogenously formed kidney dopamine plays a pivotal role in
maintaining body sodium homeostasis during increases in sodium
intake.
The source of dopamine that activates tubular dopamine
receptors is believed to be nonneuronal. The tubular cells contain
dopa-decarboxylase in abundance.34 The substrate
L-dopa is filtered freely from glomerulus and is actively
transported into the tubular cells where L-dopa is
converted to dopamine by decarboxylation
process.35 36 Once dopamine is synthesized, it is
transported out of the cells where it can interact with dopamine
receptors.
The process from the activation of D1-like
dopamine receptors to the inhibition of Na,K-ATPase and Na,H-exchanger
activity involves multiple cellular signaling pathways that despite a
great deal of work appear to be complex and are yet to be completely
understood. Initially, a positive correlation between dopamine infusion
and urinary cAMP excretion implicated adenylyl cyclase as one of the
second messengers in the action of dopamine.47
Later, in the brush border vesicle preparations, the inhibition of
Na,H-exchanger by dopamine was shown to be linked to cAMP-dependent as
well as cAMP-independent mechanisms.37 38 48 In
mTAL and CCD, accumulation of cAMP and activation of PKA by dopamine
also leads to the inhibition of Na,K-ATPase
activity.41 In addition, dopamine-related
phosphoprotein-32 (DARPP-32), present in high amounts in mTAL, has
also been implicated in dopamine-mediated inhibition of Na,K-ATPase
activity in mTAL.49 In the proximal tubules, most
investigators believe that the cAMP pathway is not the mechanism that
mediates the inhibition of Na,K-ATPase activity by dopamine. However,
one study43 has suggested the role of dopamine
stimulation of cAMP in the inhibition of Na,K-ATPase activity in the
proximal tubules. The inhibition of Na,K-ATPase activity through the
mechanism of PKA activation has been shown to result from the agonist
occupancy of D1A receptors expressed in
fibroblast LTK- cells. In the proximal tubules,
the role of PLC in the inhibition of Na,K-ATPase activity by dopamine
is well documented and supported by several
studies.39 50 51 52 The animals placed on a high
sodium diet showed an increase in urinary dopamine excretion, increase
in PLC activity,32 and decrease in Na,K-ATPase
activity.33 In vitro, an analogue of
diacylglycerol (1-oleoyl-2-acetyl-racglycerol) and a direct
activator of PKC mimic the inhibitory effects
of dopamine on Na,K-ATPase activity, and U73122, a PLC
inhibitor, abolishes the effect of
dopamine.39 These studies suggest the involvement
of PLC and PKC in the D1-like receptor signaling
system that leads to the inhibition of Na,K-ATPase activity. Dopamine
and D1-like receptor agonists stimulate PLC
activity in kidney cortex that has been shown to be independent of the
adenylyl cyclase pathway.50 52 We have reported
the direct stimulation of PKC activity by dopamine and the
D1-like receptor agonist
fenoldopam.53 Thus, the activation of
D1-like receptors causes the stimulation of PLC
with resulting generation of inositol triphosphate and diacylglycerol.
Diacylglycerol stimulates PKC, which in turn induces inhibition of
Na,K-ATPase activity.54 Interestingly,
The role of the PLA2 pathway has also been
reported in the cellular signaling systems involved in dopamine-induced
inhibition of Na,K-ATPase activity in the proximal tubules, which is
distinct compared with other segments of the
nephron.41 61 According to the scheme proposed by
Satoh et al41 in the PLC/PKC-dependent mechanisms
of dopamine action (via D1-like receptors), PKC
leads to the activation of PLA2, which in turn
releases arachidonic acid from membrane lipids.
Arachidonic acid is further metabolized by cytochrome
P450 producing various metabolites. Recently, it was reported that one
of the metabolites of arachidonic acid, 20-HETE,
inhibits Na,K-ATPase activity via a PKC-dependent
pathway.62 In mTAL and CCD, the
PLA2 pathway interacts with PKA to inhibit
Na,K-ATPase activity.41 Although there is ample
evidence for the role of a PLA2 pathway in
dopamine receptor signaling, the link between the receptor and
PLA2 is not known. The
Figure
Although dopamine receptor–mediated regulation of sodium-transporting
enzymes is present throughout the nephron length, dopamine
receptors located at the proximal tubules and CCD (compared with other
segments of the nephron) seem to play an important role in the
natriuretic response to exogenously administered dopamine
and to dopamine produced endogenously during high salt
intake.33 It is likely that the proximal portion
of the nephron is of greater importance because it is the site of major
fluid and salt reabsorption, and it is at this site that dopamine
receptor–mediated signaling is selectively defective and unable to
regulate Na,K-ATPase and Na,H-exchanger activity in various forms of
hypertension in humans and animal models, as discussed below.
Physiological and biochemical interactions between
angiotensin II and dopamine receptors have been reported in
the kidney.63 64 65 66 It is reported that dopamine
increases renin release by activating D1-like
receptors probably located on juxtaglomerular
cells,63 which in turn has been shown to
attenuate fenoldopam-induced natriuresis.64 With
use of an in vitro system, it was reported that the pretreatment of
proximal tubular preparations with dopamine decreased the expression of
AT1 receptors at the AT1
mRNA level, an effect likely mediated by increased intracellular cAMP
levels.65 This suggested that the activation of
dopamine receptors may also reset the sensitivity of the proximal
tubules to angiotensin. Similar to
D1-like receptors, the pretreatment of renal
brush border membranes with D2-like receptor
agonist has been reported to lower
[125I]angiotensin II binding
sites.67 We have shown that pretreatment of
proximal tubules with bromocriptine, a D2-like
receptor agonist, antagonized the stimulatory effect of
angiotensin II on Na,K-ATPase activity and attenuated the
inhibitory effect of angiotensin II on cAMP
accumulation.67 These effects of bromocriptine
appear to be due to reduced
[3H]angiotensin II binding sites
and an imbalance of Gs and
Gi protein ratio in the proximal tubules (T.H.,
M.F.L., unpublished observations, 1998).
The exact mechanism for the renal dopaminergic deficiency in human
primary hypertension is not known. However, a defect in
L-dopa-decarboxylase, the enzyme that catalyzes the
conversion of L-dopa to dopamine, has been suggested in
subjects with a family history of
hypertension,69 77 78 whereas in a subgroup of
salt-sensitive hypertensive patients a decrease in both renal tubular
uptake of L-dopa and its conversion to dopamine has been
reported.79 Because the suppression of renal
dopaminergic activity has been observed in young normotensives with a
family history of hypertension before the manifestation of
hypertension, it has been suggested that renal dopaminergic suppression
may contribute to the development of
hypertension.80
Rat Models of Hypertension
Spontaneously Hypertensive Rats
Because proximal tubular dopamine receptors
(D1-like receptors) contribute to 60% of the
sodium excretion under acute volume expansion, a phenomenon that is
impaired in SHR, studies have been conducted on the
D1-like receptor system in the proximal tubules
to investigate the site of impairment. In 1989, Kinoshita et
al4 reported that D1-like
receptor agonists stimulated adenylyl cyclase activity to a lesser
extent in the proximal tubules of SHR compared with normotensive WKY.
The D1-like receptor numbers and the affinity to
antagonist measured by [125I]SCH
23982, as well as forskolin- and GTP-stimulated adenylyl cyclase
activities, were similar in SHR and WKY. This suggests that the defect
resided in the coupling of the receptor with adenylyl cyclase and that
the G proteins and adenylyl cyclase per se were not defective. The
defect is specific to D1-like receptor as well as
nephron segment (only in the proximal part) and is organ specific (only
in the kidney and not in the brain striatum of
SHR).4 94 95 The stimulation of another signaling
system, PLC, by dopamine and D1-like agonist was
also reduced in SHR, suggesting a defect in the
D1-like receptor and PLC
coupling.96 Because adenylyl cyclase and PLC
serve as the primary signaling pathways in the inhibition of
Na,H-exchanger and Na,K-ATPase caused by dopamine, it was found that
dopamine failed to inhibit the activities of these sodium-transporting
proteins in the proximal tubules of SHR.39 91 The
defect in the D1-like receptor/adenylyl cyclase
and PLC may explain the decreased natriuretic effect of
dopamine and D1-like agonists in SHR.
Further studies on the solubilized D1-like
receptors in SHR revealed that the agonist displacement of
[125I]SCH 23982 showed both high and low
affinity in WKY but only low affinity in SHR,92
suggesting a defect in the high-affinity coupling between
D1-like receptor and G proteins. Other evidence
for the reduction in the agonist binding comes from the agonist
displacement of photoaffinity labeling by
[125I]SCH 23982 of
D1-like receptors.97 One
reason could be a difference in the biochemical/physical nature of
D1-like receptor between WKY and SHR. The
sulfhydryl groups are present on D1-like
receptors and regulate ligand-binding properties of the
receptor.98 The concentration of
N-ethylmaleimide (NEM, a sulfhydryl blocking agent by
alkylation) required to reduce the ligand binding
([125I]SCH 23982) by 50% was much lower
(5.2 µmol/L) in WKY than in SHR (1200
µmol/L).99 Whether the defect in the agonist
binding domain is in the primary structure because of mutation or in
the tertiary structure because of improper folding of the receptor
protein is not yet clear. Limited sequence of the
D1A mRNA (equivalent to the third cytoplasmic
loop of cloned D1A receptor, which is believed to
be G protein–interacting domain) revealed no mutation in the protein
in SHR compared with WKY.95
The defect in the D1A receptor/signal
transduction coupling is believed to exist before the development of
hypertension in SHR. The stimulation of adenylyl cyclase by
D1-like agonist is greater in WKY than in SHR at
the prehypertensive age of 3 weeks and increases with age in WKY but
not in SHR.95 100 Similarly, G protein
stimulation (measured by [35S]GTP
Recently, we reported that fenoldopam stimulated
[35S]GTP
The therapeutic application of dopamine is somewhat limited by the fact
that in addition to activating D1-like receptors,
at higher doses it also activates
D2-like, ß-, and
Fenoldopam is a preferential D1-like dopamine
receptor agonist that has been used in patients with hypertension and
heart failure. In patients with congestive heart failure, fenoldopam
increases cardiac index and decreases systemic vascular resistance and
blood pressure.105 Intravenous
administration of fenoldopam to hypertensive patients leads to an
immediate lowering of blood pressure that is accompanied by increases
in RBF as well as sodium and water excretion, and these effects of the
compound are maintained throughout the infusion
period.106 A comparative study of fenoldopam with
nitroprusside in patients with hypertensive crisis revealed that while
both of these compounds caused a prompt lowering of blood pressure, the
additional beneficial effect seen with fenoldopam was that it promoted
natriuresis and diuresis in these
patients.107 Because RBF was not measured in this
study, it is not clear whether natriuretic response was
secondary due to an increase in RBF or whether it resulted from the
direct tubular action of fenoldopam on D1-like
dopamine receptors. It is reported that activation of
D1-like receptors located on the
juxtaglomerular cells causes an increase in renin
release,63 and we have shown in animal
experiments that the natriuretic and diuretic
effect of fenoldopam is markedly potentiated by pretreatment with
angiotensin-converting enzyme inhibitors and
losartan.64 108 Therefore, the
renin-releasing effect of fenoldopam and subsequent formation of
angiotensin II counteracts the natriuretic and
diuretic effects of fenoldopam. The clinical significance of
this finding in hypertensive patients remains to be determined.
Recently, fenoldopam (Corlopam) has been approved by the Food and Drug
Administration for use in hospitalized patients for short-term
management of hypertension when rapid but quickly reversible emergency
reduction of blood pressure is clinically indicated, including
malignant hypertension with deteriorating end-organ function. Although
fenoldopam is orally active and effective in lowering blood pressure,
because of its poor bioavailability, which necessitates frequent
dosing, it is not used for the chronic treatment of hypertension.
Dopexamine is a dopamine analogue with a complex pharmacological
profile. In therapeutic dose range, it activates
D1-like receptors and
ß2-adrenoceptors and inhibits neuronal reuptake
of norepinephrine.109 The latter two
effects account for the mild positive inotropic effect seen in patients
with congestive heart failure.110 Dopexamine is
reported to be effective in the treatment of acute heart failure,
during cardiac surgery, and in general intensive
care.111 Also, as it relates to its dopaminergic
action, it is reported that dopexamine is effective for the protection
of renal function in patients undergoing orthotopic liver
transplantation112; in patients suffering chronic
renal dysfunction, dopexamine infusion caused increases in total
cortical and medullary RBF and in renographic clearance
rate.113 These actions of dopexamine at the level
of the kidney are most likely due to the action of the compound on
D1-like dopamine receptors located at various
regions within the kidney, including the blood vessels and renal
tubules. However, because of its action at multiple receptors and the
fact that it must be administered intravenously, it is
likely that dopexamine will be used only in intensive care. This
compound is approved for use in acute cardiac failure patients in
certain European countries, but it is not yet approved for use within
the United States.
Ibopamine is an orally active diisobutyrate ester
of N-methyldopamine or epinine. Ibopamine is a prodrug,
and after absorption it is hydrolyzed in plasma to its active
metabolite, epinine.18 Epinine has a
pharmacological and receptor profile similar to that of dopamine, but
the main advantage is that ibopamine, the prodrug, has oral
bioavailability and hence is administered orally. While ibopamine was
initially shown to be effective in patients with congestive heart
failure during short-term administration lasting for a few
days,113 its effects were not persistent in
patients when administered for 8 weeks.114
However, a recent clinical trial115 with
ibopamine in patients with heart failure had to be terminated early
because of the excess mortality seen in the ibopamine group (25%)
compared with the placebo group (20%). Although the reasons for the
excess mortality are not clear, a mechanism involving increased
extracellular calcium resulting from ß-adrenoceptor stimulation may
play a role in the increased mortality in the ibopamine
group.116 These findings have led to restrictions
on the use of ibopamine in patients with severe heart failure in
countries where the drug is approved as a therapeutic agent. It should
be noted that ibopamine is not approved for use in the United
States.
Compounds acting on D2-like dopamine receptors
have been shown to lower blood pressure and heart rate in experimental
animals.117 As shown in the Table
The therapeutic potential of dopamine and D1-like
receptor agonists in the treatment of cardiovascular
diseases is currently limited to the treatment of hypertensive
emergencies only, because of the lack of availability of compounds that
have extended bioavailability after oral administration. However,
compounds such as fenoldopam, in addition to causing rapid lowering of
blood pressure during hypertensive emergencies, are also found to be
effective in animal experiments in preserving and protecting RBF and
renal function under various pathological
conditions.121 122 Dopexamine also has been
reported to improve blood flow to several important organs and protect
organ function during hemorrhagic shock and injury caused by oxygen
free radicals.123 124 Therefore, it is likely
that the therapeutic potential of currently available dopamine receptor
agonists lies in the area of protection and preservation of blood flow
to vital organs such as the heart, mesentary, and kidney, and
eventually the function of these organs, for patients receiving
treatment in intensive care units.
Received January 27, 1998;
first decision March 3, 1998;
accepted March 19, 1998.
2.
2. Yoshimura M, Ikegaki I, Nishimura M, Takahashi H.
Role of dopaminergic mechanisms in the kidney for the pathogenesis of
hypertension. J Auton Pharmacol. 1990;10:67S–72S.
3.
3. Aoki K, Kikuchi K, Yamaji I. Attenuated renal
production of dopamine in patients with low renin essential
hypertension. Clin Exp Hypertens. 1989;A11:403–409.
4.
4. Kinoshita S, Sidhu A, Felder RA. Defective
dopamine-1 receptor adenylate cyclase coupling in the
proximal convoluted tubule from the spontaneously hypertensive rat.
J Clin Invest. 1989;84:1849–1856.
5.
5. Hussain T, Lokhandwala MF. Renal dopamine-1 receptor
coupling with Gs and Gq/11 proteins in spontaneously hypertensive rats.
Am J Physiol. 1997;272:F339–F346.
6.
6. Horiuchi A, Albrecht FE, Eisner GM, Jose PA, Felder
RA. Renal dopamine receptors and pre- and post-cAMP-mediated Na
transport defect in spontaneously hypertensive rats. Am J
Physiol. 1992;263:F1105–F1111.
7.
7. Albrecht FE, Drago J, Felder RA, Printz MP, Eisner
GM, Robillard JE, Sibley DR, Westphal HJ, Jose PA. Role of the
D1A dopamine receptor in the pathogenesis of
genetic hypertension. J Clin Invest. 1996;97:2283–2288.[Medline]
[Order article via Infotrieve]
8.
8. Asico LD, Fuchs S, Accili D, Carey RM, Eisner GM,
Jose PA. Disruption of the dopamine D3 receptor gene produces
renin-dependent hypertension. J Am Soc Nephrol. 1997;8:295A. Abstract.
9.
9. Sibley DR, Monsma FJ Jr. Molecular biology of
dopamine receptors. Trends Pharmacol Sci. 1992;13:61–69.[Medline]
[Order article via Infotrieve]
10.
Lokhandwala MF, Barrett RJ.
Cardiovascular dopamine receptors:
physiological, pharmacological and therapeutic
implications. J Auton Pharmacol. 1982;3:181–186.
11.
Goldberg LI, Kohli JD, Glock D. Conclusive evidence
of two subtypes of peripheral dopamine receptors. In:
Woodruff GN, Poat JA, Roberts PJ, eds. Dopaminergic Systems and
Their Regulation. London, UK: Macmillan; 1986:195–212.
12.
Felder CC, McKelvey AM, Gitler MS, Eisner GM, Jose
PA. Dopamine receptor subtypes in renal brush border and basolateral
membrane. Kidney Int. 1989;36:183–193.[Medline]
[Order article via Infotrieve]
13.
Lokhandwala MF, Amenta F. Anatomical distribution and
function of dopamine receptors in the kidney. FASEB J. 1991;5:3023–3030.[Abstract]
14.
Yamaguchi I, Jose PA, Mouradian MM, Canessa LM,
Monsma FJ Jr, Sibley DR, Takeyasu K, Felder RA. Expression of dopamine
D1A receptor gene in proximal convoluted tubule
of rat kidneys. Am J Physiol. 1993;264:F280–F285.
15.
Nash SR, Godinot N, Caron MG. Cloning and
characterization of the opossum kidney cell D1 dopamine receptor:
expression of D1A and D1B
receptor mRNAs in opossum kidney and brain. Mol Pharmacol. 1993;44:918–925.[Abstract]
16.
Sokoloff P, Giros B, Martres MP, Bouthenet ML,
Schwartz JC. Molecular cloning and characterization of a novel dopamine
receptor (D3) as a target for neuroleptics.
Nature. 1990;347:146–151.[Medline]
[Order article via Infotrieve]
17.
Willems JL, Buylaert WA, Leferve RA, Bogaert MG.
Neuronal dopamine receptors on autonomic ganglia and sympathetic nerves
and dopamine receptors in gastrointestinal system. Pharmacol
Rev. 1985;37:165–216.[Medline]
[Order article via Infotrieve]
18.
Lokhandwala MF. Cardiovascular and
renal effects of dopamine receptor agonists. ISI Atlas of
Science: Pharmacology. 1988;2:261–266.
19.
Felder RA, Blecher M, Eisner GM, Jose PA. Cortical
tubular and glomerular dopamine receptors in the rat
kidney. Am J Physiol. 1984;246:F557–F568.
20.
Huo T, Healy DP. Autoradiographic
localization of dopamine DA1 receptors in rat kidney with
[3H]SCH 23390. Am J Physiol. 1989;257:F414–F423.
21.
Missale C, Pizzi M, Memo M, Picotti GB, Carruba MO.
Postsynaptic D1 and D2 dopamine receptors are present in rabbit
renal and mesenteric arteries. Neurosci Lett. 1985;61:207–211.[Medline]
[Order article via Infotrieve]
22.
McDonald RH, Goldberg LI, McNay JL, Tuttle EP. Effect
of dopamine in man: augmentation of sodium excretion,
glomerular filtration rate and renal plasma flow.
J Clin Invest. 1964;43:1116–1124.
23.
van Veldhuisen DK, Gribes ARJ, deGraeff PA, Lie KI.
Effects of dopaminergic agents on cardiac and renal function in normal
man and in patients with congestive heart failure. Int J
Cardiol. 1992;37:293–300.[Medline]
[Order article via Infotrieve]
24.
Jose PA, Raymond JR, Bates MD, Aperia A, Felder RA,
Carey RM. The renal dopamine receptors. J Am Soc
Nephrol. 1992;2:1265–1278.[Abstract]
25.
Lokhandwala MF, Chen CJ. Peripheral
dopamine receptors. In: Niznik HB, ed. Dopamine Receptors and
Transporters. New York, NY: Marcel Dekker Inc; 1994:89–102.
26.
Hegde SS, Ricci A, Amenta F, Lokhandwala MF. Evidence
from functional and autoradiographic studies for the
presence of tubular dopamine-1 receptors and their involvement in the
renal effects of fenoldopam. J Pharmacol Exp Ther. 1989;251:1237–1245.
27.
Ball SG, Oates HS, Lee MR. Urinary dopamine in man
and rat: effect of inorganic salts on dopamine excretion. Clin
Sci Mol Med. 1978;55:167–173.[Medline]
[Order article via Infotrieve]
28.
Romero-Vacchione E, Vasquez J, Lema G, Guerrero H,
Rosa F, Bermudez M. Low urinary dopamine excretion associated to low
sodium excretion in normotensive Piaroa Amazonian ethnia compared to
urban subjects. Invest Clin. 1995;36:61–71.[Medline]
[Order article via Infotrieve]
29.
Chen CJ, Lokhandwala MF. Role of renal dopamine in
the natriuretic response to different degrees of volume
expansion in rats. Clin Exp Hypertens. 1991;13:1117–1126.
30.
Hegde SS, Jadhav AL, Lokhandwala MF. Role of kidney
dopamine in the natriuretic response to volume expansion in
rats. Hypertension. 1989;13:828–834.
31.
Oates NS, Ball SG, Perkins CM, Lee MR. Plasma and
urine dopamine in man given sodium chloride in the diet. Clin
Sci. 1979;56:261–264.[Medline]
[Order article via Infotrieve]
32.
Vyas SJ, Jadhav AL, Eichberg J, Lokhandwala MF.
Dopamine receptor-mediated activation of phospholipase C is associated
with natriuresis during high salt intake. Am J Physiol. 1992;262:F494–F498.
33.
Bertorello A, Hokfelt T, Goldstein M, Aperia A.
Proximal tubule Na,K-ATPase activity is inhibited during high salt
diet: evidence for DA-mediated effect. Am J Physiol. 1988;254:F795–F801.
34.
Goldstein M, Fuxe K, Hokfelt T. Characterization and
tissue localization of catecholamine synthesizing enzymes.
Pharmacol Rev. 1972;24:293–308.[Abstract]
35.
Baines AD, Chan W. Production of urine free
dopamine from DOPA: a micropuncture study. Life Sci. 1980;26:253–259.[Medline]
[Order article via Infotrieve]
36.
Zimlichman R, Levinson PP, Kelly G, Stull R, Keiser
HR, Goldstein DS. Derivation of urinary dopamine from plasma dopa.
Clin Sci. 1988;75:515–520.[Medline]
[Order article via Infotrieve]
37.
Gesek FA, Schoolwerth AC. Hormonal interaction with
the proximal Na,H-exchanger. Am J Physiol. 1990; 258:
F514–F521.
38.
Felder CC, Campbell T, Albrecht F, Jose PA. Dopamine
inhibits Na-H exchanger activity in renal BBMV by stimulation of
adenylate cyclase. Am J Physiol. 1990;259:F297–F303.
39.
Chen CJ, Beach RE, Lokhandwala MF. Dopamine fails to
inhibit renal tubular sodium pump in hypertensive rats.
Hypertension. 1993;21:364–372.
40.
Chen CJ, Lokhandwala MF. Inhibition of Na,K-ATPase in
renal proximal tubule by dopamine involves DA-1 receptor activation.
Naunyn Schmiedebergs Arch Pharmacol. 1993;347:289–295.[Medline]
[Order article via Infotrieve]
41.
Satoh T, Cohen HT, Katz AI. Different mechanisms of
renal Na,K-ATPase regulation by protein kinases in the proximal and
distal nephron. Am J Physiol. 1993;265:F399–F405.
42.
Horiuchi A, Takeyasu K, Mouradian MM, Jose PA, Felder
RA. D1A dopamine receptor stimulation inhibits
Na,K-ATPase activity through protein kinase A. Mol
Pharmacol. 1993;43:281–285.[Abstract]
43.
Bertorello A, Aperia A. Inhibition of proximal tubule
Na,K-ATPase activity requires simultaneous activation of
DA1 and DA2 receptors.
Am J Physiol. 1990;259:F924–F928.
44.
Hussain T, Abdul-Wahab R, Lokhandwala MF.
Bromocriptine stimulates Na,K ATPase in renal proximal tubules via cAMP
pathway. Eur J Pharmacol. 1997;321:259–263.[Medline]
[Order article via Infotrieve]
45.
Yamaguchi I, Walk SF, Jose PA, Felder RA. Dopamine
D2L receptors stimulate Na,K-ATPase activity in
murine LTK- cells. Mol Pharmacol. 1996;46:373–378.
46.
Siragey HM, Felder RA, Howell NL, Chevalier RL, Peach
MJ, Carey RM. Evidence that dopamine-2 mechanisms control renal
function. Am J Physiol. 1990;259:F793–F800.
47.
Vlanchoyannis J, Weismuller G, Schoeppe W. Effects of
dopamine on kidney function and on the adenylyl cyclase
phosphodiesterase system in man. Eur J Clin Invest. 1976;6:131–137.[Medline]
[Order article via Infotrieve]
48.
Felder CC, Albrecht FE, Campbell T, Eisner GM, Jose
PA. cAMP-independent, G protein-linked inhibition of Na/H-exchange in
renal brush border by D1 dopamine agonist. Am J
Physiol. 1993;264:F1032–F1037.
49.
Aperia A, Fryckstedt J, Svensson L, Hemmings HC Jr,
Nairn AC, Greengard P. Phosphorylated Mr 32,000
dopamine- and cAMP regulated phosphoprotein inhibits Na,K-ATPase
activity in renal tubule cells. Proc Natl Acad Sci U S A. 1991;88:2798–2801.
50.
Felder CC, Jose PA, Axelrod J. The dopamine-1
agonist, SKF 82526, stimulates phospholipase C activity independent of
adenylate cyclase. J Pharmacol Exp Ther. 1989;248:171–175.
51.
Felder CC, Blecher M, Jose PA. Dopamine-1 mediated
stimulation of phospholipase C activity in rat renal cortical
membranes. J Biol Chem. 1989;264:8739–8745.
52.
Vyas SJ, Eichberg J, Lokhandwala MF. Characterization
of receptors involved in dopamine-induced activation of phospholipase C
in rat renal cortex. J Pharmacol Exp Ther. 1992;260:134–139.
53.
Kansra V, Chen CJ, Lokhandwala MF. Dopamine causes
stimulation of protein kinase C in rat renal proximal tubules by
activating dopamine D1 receptors. Eur J Pharmacol. 1995;289:391–394.[Medline]
[Order article via Infotrieve]
54.
Gopalakrishnan SM, Chen C, Lokhandwala MF.
55.
Bertorello A, Aperia A. Na,K-ATPase is an effector
protein for protein kinase C in renal proximal tubule cells.
Am J Physiol. 1989;256:F370–F373.
56.
Yu PY, Asico LD, Eisner GM, Jose PA. Differential
regulation of renal phospholipase C by catecholamines.
J Clin Invest. 1995;95:304–308.
57.
Yu PY, Yamaguchi I, Mouradian MM, Felder RA, Jose PA.
D1A dopamine receptor regulation of phospholipase
C (PLC) isoforms expression. Pediatr Res. 1994;35:377A.
Abstract.
58.
Bertorello A, Aperia A. Regulation of Na,K-ATPase
activity in the kidney proximal tubules: involvement of GTP binding
proteins. Am J Physiol. 1989;256:F57–F62.
59.
Undie AS, Weinstock J, Saran HM, Friedman E. Evidence
for a distinct D1-like dopamine receptor that
couples to activation of phosphoinositide
metabolism in brain. J Neurochem. 1994;62:2045–2048.[Medline]
[Order article via Infotrieve]
60.
Friedman E, Jin LQ, Cai GP, Hollon TR, Drago J,
Sibley DR, Wang HY. D1-like dopaminergic
activation of phosphoinositide hydrolysis is
independent of D1A dopamine receptors: evidence
from D1A knockout mice. Mol Pharmacol. 1997;51:6–11.
61.
Hussain T, Lokhandwala MF. Altered
arachidonic acid metabolism contributes to
the failure of dopamine to inhibit Na,K-ATPase in kidney of
spontaneously hypertensive rats. Clin Exp Hypertens. 1986;18:963–974.
62.
Nowicki S, Cheng XJ, Ohtomo Y, Aperia A. Regulation
of renal Na,K-ATPase (NKA) activity by
20-hydroxyeicosatetraenoic acid
(20-HETE) is mediated by protein kinase C. J Am Soc
Nephrol. 1995;6:760. Abstract.
63.
Antonipillai I, Broess MI, Lang D. Evidence that
specific dopamine-1 receptor activation is involved in dopamine-induced
renin release. Hypertension. 1989;13:463–468.
64.
Chen CJ, Apparsundarum S, Lokhandwala MF.
Intrarenally produced angiotensin II opposes the
natriuretic effect of the dopamine-1 receptor agonist
fenoldopam in rats. J Pharmacol Exp Ther. 1991;256:486–491.
65.
Cheng HF, Becker BN, Harris RC. Dopamine decreases
expression of type-1 angiotensin II receptors in renal
proximal tubules. J Clin Invest. 1996;97:2745–2752.[Medline]
[Order article via Infotrieve]
66.
Sheikh-Hamad D, Wang YP, Jo OD, Yanagawa N. Dopamine
antagonizes the actions of angiotensin II in renal brush
border membrane. Am J Physiol. 1993;264:F737–F743.
67.
Hussain T, Abdul-Wahab R, Lokhandwala MF. Dopamine-2
(DA-2) receptor modulates angiotensin II response on renal
Na,K-ATPase through heterologous desensitization. J Am Soc
Nephrol. 1996;7:1678. Abstract.
68.
Shikuma R, Yoshimura M, Kambra S, Yamazaki H,
Takashina R, Takahashi H, Takeda K, Ijichi H. Dopaminergic modulation
of salt-sensitivity in patients with essential hypertension. Life
Sci. 1986;38:915–921.[Medline]
[Order article via Infotrieve]
69.
Iimura O, Shimamoto K, Ura N. Dopaminergic activity
and water-sodium handling in the kidneys of essential hypertensive
subjects: is renal dopaminergic activity suppressed at the
prehypertensive stage? J Cardiovasc Pharmacol. 1990;16:56S–58S.
70.
Iimura O. The role of renal dopaminergic activity in
the pathophysiology of essential hypertension. Jpn Heart
J. 1996;37:815–828.[Medline]
[Order article via Infotrieve]
71.
Iimura O, Kikuchi K, Takigami Y, Mito T, Tsuzuki M,
Shibata S. Enhanced natriuretic response to dopamine
infusion in low renin essential hypertension. N Z Med J. 1983;96:860–863.
72.
Schoors DF, Dupont AG. Increased dopamine-induced
nephrogenous cAMP formation in hypertension. Am J
Hypertens. 1991;4:494–499.[Medline]
[Order article via Infotrieve]
73.
Kikuchi K, Miyama A, Nakao T.
Hemodynamic and natriuretic response to
intravenous infusion of dopamine in patients with essential
hypertension. Jpn Circ J. 1982;46:486–493.[Medline]
[Order article via Infotrieve]
74.
Andrejak M, Hary L. Enhanced dopamine renal
responsiveness in patients with hypertension. Clin Pharmacol
Ther. 1986;40:610–614.[Medline]
[Order article via Infotrieve]
75.
O'Connell DP, Ragsdale NV, Boyd DG, Felder RA, Carey
RM. Differential human tubular responses to dopamine type 1 receptor
stimulation are determined by blood pressure status.
Hypertension. 1997;29:115–122.
76.
Sanada H, Jose PA, Yu PY, Hazen-Martin D, Carey RM,
Bruns D, Felder R. Human hypertensive subjects have a renal proximal
tubular defect in dopamine-1 receptor/adenylyl cyclase coupling.
J Am Soc Nephrol. 1997;8:307A. Abstract.
77.
Kuchel O, Shigetomi S. Defective dopamine generation
from dihydroxyphenyl-alanine in stable essential hypertensive patients.
Hypertension. 1992;19:634–638.
78.
Clark BA, Rosa RM, Epstein FH, Young JB, Landsberg L.
Altered dopaminergic responses in hypertension.
Hypertension. 1992;19:589–594.
79.
Gill JR, Grossman E, Goldstein DS. High urinary dopa
and low urinary dopamine to dopa ratio in salt-sensitive hypertension.
Hypertension. 1991;18:614–621.
80.
Muldoon MF, Terrell DF, Bunker CH, Manuck SB. Family
history studies in hypertension research: review of the literature.
Am J Hypertens. 1993;6:76–88.[Medline]
[Order article via Infotrieve]
81.
DeWardner HE. The primary role of the kidney and salt
intake in the aetiology of essential hypertension. Clin Sci. 1990;79:193–200.[Medline]
[Order article via Infotrieve]
82.
DeFeo ML, Jadhav AL, Lokhandwala MF. Dietary sodium
intake and urinary dopamine and sodium excretion during the course of
blood pressure development in Dahl salt-sensitive and
salt-resistant rats. Clin Exp Hypertens. 1987;12:2049–2060.
83.
Sakamoto T, Chen C, Lokhandwala MF. Lack of renal
dopamine production during acute volume expansion in Dahl
salt-sensitive rats. Clin Exp Hypertens. 1994;16:197–206.
84.
Felder RA, Kinoshita S, Sidhu A, Ohbu K, Kaskel FJ. A
renal dopamine-1 receptor defect in two genetic models of hypertension.
Am J Hypertens. 1990;3:96S–99S.[Medline]
[Order article via Infotrieve]
85.
Nishi A, Eklof AC, Bertorello A, Aperia A. Dopamine
regulation of renal Na,K-ATPase activity is lacking in Dahl
salt-sensitive rats. Hypertension. 1993;21:767–771.
86.
Ohbu K, Kaskel FJ, Kinoshita S, Felder RA. Dopamine-1
receptors in the proximal convoluted tubule of Dahl rats: defective
coupling to adenylate cyclase. Am J
Physiol. 1995;268:R231–R235.
87.
Stier CT Jr, Itskovitz HD, Chen YH. Urinary dopamine
and sodium excretion in spontaneously hypertensive rats. Clin Exp
Hypertens. 1993;15:105–123.
88.
Kambra S, Yoshimura M, Takahashi H, Ijichi H.
Enhanced synthesis of renal dopamine and impaired natriuresis in
spontaneously hypertensive rats. Jpn Heart J. 1987;28:594. Abstract.
89.
Felder RA, Seikaly MG, Cody P, Eisner GM, Jose PA.
Attenuated renal response to dopaminergic drugs in spontaneously
hypertensive rats. Hypertension. 1990;15:560–569.
90.
Chen CJ, Lokhandwala MF. An impairment of tubular
DA-1 receptor function as a causative factor for diminished natriuresis
to volume expansion in spontaneously hypertensive rats. Clin Exp
Hypertens. 1992;14:615–628.
91.
Gesek FA, Schoolwerth AC. Hormone response to
proximal Na+, H+-exchanger
in spontaneously hypertensive rats. Am J Physiol. 1991;261:F526–F536.
92.
Sidhu A, Vachvamichsanong P, Jose PA, Felder RA.
Persistent defective coupling of dopamine-1 receptors to G proteins
after solubilization from kidney proximal tubules of hypertensive rats.
J Clin Invest. 1992;89:789–793.
93.
Kansra V, Chen CJ, Lokhandwala MF. Dopamine fails to
stimulate protein kinase C activity in renal proximal tubules of
hypertensive rats. Clin Exp Hypertens. 1995;17:837–845.
94.
Ohbu K, Felder RA. Nephron specificity of dopamine
receptor-adenylyl cyclase defect in spontaneous hypertension.
Am J Physiol. 1993;264:F274–F279.
95.
Felder RA, Kinoshita S, Ohbu K, Mouradian MM, Sibley
DR, Monsma FJ Jr, Minowa T, Minowa MT, Canessa LM, Jose PA. Organ
specificity of the dopamine receptor/adenylyl cyclase coupling defect
in spontaneously hypertensive rats. Am J Physiol. 1993;264:R726–R732.
96.
Chen CC, Vyas SJ, Eichberg J, Lokhandwala MF.
Diminished phospholipase-C activation by dopamine in spontaneously
hypertensive rats. Hypertension. 1992;19:102–108.
97.
Vachvamichsanong P, Kimura K, Sidhu A. Differences in
photolabeling of DA1 receptors in renal proximal tubules from
normotensive rats and SHR. Am J Physiol. 1995;268:F1009–F1016.
98.
Sidhu A, Kassis S, Kebabian J, Fishman PH. Sulfhydryl
group(s) in the ligand binding of the D-1 dopamine receptor: specific
protection by agonist and antagonist.
Biochemistry. 1986;25:6695–6701.[Medline]
[Order article via Infotrieve]
99.
Sela S, Sidhu A. Sulfhydryl groups of renal
D1A dopamine receptors: differential sensitivity
of receptors to N-ethylmaleimide in normotensive and
hypertensive rats. J Hypertens. 1996;14:615–622.[Medline]
[Order article via Infotrieve]
100.
Kinoshita S, Felder RA. Ontogeny of DA1
receptor-adenylate cyclase coupling in proximal convoluted
tubules. Am J Physiol. 1990;259:F971–F976.
101.
Gurich RW, Beach RE. Abnormal regulation of renal
proximal tubule Na,K-ATPase by G proteins in spontaneously hypertensive
rats. Am J Physiol. 1994;267:F1069–F1075.
102.
Goldberg LI. The role of dopamine receptors in the
treatment of congestive heart failure. J Cardiovasc
Pharmacol. 1989;14(suppl 5):s19–s27.
103.
Smit AJ, Meijer S, Wesseling H, Reitsma WD, Donkeer
AJM. Impaired renal hemodynamic but conserved
natriuretic response to dopamine in patients with renal
disease. Nephron. 1989;52:338–346.[Medline]
[Order article via Infotrieve]
104.
Olsen NV, Olsen MH, Bonde J, Kanstrup IL, Plum I,
Strangaard S, Leyssac PP. Dopamine natriuresis in salt-repleted,
water-loaded humans: a dose response study. Br J Clin
Pharmacol. 1997;43:509–520.[Medline]
[Order article via Infotrieve]
105.
Francis GS, Wilson BC, Rector TS.
Hemodynamic, renal and neurohumoral effects of
selective oral DA1 receptor agonist (Fenoldopam) in patients with
congestive heart failure. Am Heart J. 1988;116:473–479.[Medline]
[Order article via Infotrieve]
106.
Murphy MB, McCoy CE, Weber RR, Fredrickson ED,
Douglas FL, Goldberg LI. Augmentation of renal blood flow and sodium
excretion in hypertensive patients during blood pressure reduction by
intravenous administration of dopamine-1 agonist,
fenoldopam. Circulation. 1987;76:1312–1318.
107.
Elliot WJ, Weber RR. Nelson KS. Renal and
hemodynamic effects of intravenous
fenoldopam versus nitroprusside in severe hypertension.
Circulation. 1990;81:970–977.
108.
Chen CJ, Lokhandwala MF. Potentiation by
enalaprilat of fenoldopam-evoked natriuresis is due to blockade of
intrarenal production of angiotensin II in rat.
Naunyn Schmiedebergs Arch Pharmacol. 1995;352:194–200.[Medline]
[Order article via Infotrieve]
109.
Goldberg LI, Bass AS. Relative significance of
dopamine receptors, beta adrenoceptors and norepinephrine
uptake inhibition in the cardiovascular actions of
dopexamine hydrochloride. Am J Cardiol. 1988;62:37C–40C.[Medline]
[Order article via Infotrieve]
110.
Lang RM, Borow KM, Neumann A, Carroll JD, Weinert L,
Murphy MB, Ghali J, Rajfer SI. Role of beta2-adrenoceptors in mediating
positive inotropic activity in the failing heart and its relation to
the hemodynamic actions of dopexamine hydrochloride.
Am J Cardiol. 1988;62:46C–52C.[Medline]
[Order article via Infotrieve]
111.
Vincent JL. Towards improving vital organ function:
assessing the role of dopexamine hydrochloride in intensive care
medicine. Clin Int Care. 1991;2(suppl):5–54.
112.
Gray PA, Bodeham AR, Park GR. A comparison of
dopexamine and dopamine to prevent renal impairment in patients
undergoing orthotopic liver transplantation.
Anesthesia. 1991;46:438–441.[Medline]
[Order article via Infotrieve]
113.
Atallah MM, Saied MMA, El-Diasty TA, Gray PA, Park GR.
Renal effect of dopexamine hydrochloride in patients with chronic renal
dysfunction. Urol Res. 1992;20:419–424.[Medline]
[Order article via Infotrieve]
114.
Rajfer SI, Rossen JD, Douglas FL, Goldberg LI,
Karrison J. Effects of long-term therapy with oral ibopamine on resting
hemodynamics and exercise capacity in patients with
heart failure: relationship to the generation of
N-methyldopamine and to plasma norepinephrine
levels. Circulation. 1988;73:740–748.
115.
Hampton JR, van Veldhuisen DJ, Kleber FX, Cowley AJ,
Ardia A, Block P, Cortina A, Cserhalmi L, Follath F, Jensen G,
Kayanakis J, Lie KI, Mancia G, Skene MM. Randomized study of effect of
ibopamine on survival in patients with advanced severe heart failure.
Lancet. 1997;349:971–977.[Medline]
[Order article via Infotrieve]
116.
Niebaver J, Coates AJS. Treating chronic heart
failure: time to take stock. Lancet. 1997;349:966–967.[Medline]
[Order article via Infotrieve]
117.
Chen CJ, Lokhandwala MF. Dopamine receptor agonists in
cardiovascular pharmacotherapy. Indian J
Pharmacol. 1992;24:72–81.
118.
Lohse MJ, Benovic JL, Caron MG, Lefkowitz RJ. Multiple
pathways of rapid ß2-adrenergic receptor
desensitization, delineation and specific inhibitors.
J Biol Chem. 1990;265:3202–3211.
119.
O'Dowd BF, Hnatowich M, Caron MG, Lefkowitz RJ,
Bouvier M. Palmitoylation of the human
ß2-adrenergic receptor: mutation of Cys341 in
the carboxy tail leads to an uncoupled nonpalmitoylated form of the
receptor. J Biol Chem. 1989;264:7564–7569.
120.
Ng GYK, Mouillac B, George SR, Caron M, Dennis M,
Bouvier M, O'Dowd BF. Desensitization, phosphorylation
and palmitoylation of the human dopamine D1 receptor. Eur J
Pharmacol. 1994;267:7–19.[Medline]
[Order article via Infotrieve]
121.
Nicholas AJ, Koster PF, Brooks DP, Ruffolo RR. Effect
of fenoldopam on the acute and subacute nephrotoxicity produced by
amphotericin B in dogs. J Pharmacol Exp Ther. 1992;260:269–274.
122.
Wang YX, Gellai M, Brooks DP. Dopamine DA1 receptor
agonist, fenoldopam, reverses glycine-induced hyperfiltration in rats.
Am J Physiol. 1992;262(6 pt 2):F1055–F1060.
123.
Jacinto SM, Lokhandwala MF, Jandhyala BS. Studies on
the pharmacological intervention to prevent oxygen free radical
mediated toxicity: effects of dopexamine, a DA1 receptor and
ß2-adrenoceptor agonist. Naunyn
Schmiedebergs Arch Pharmacol. 1994;350:277–283.[Medline]
[Order article via Infotrieve]
124.
Chintala MS, Moore RJ, Lokhandwala MF, Jandhyala
BS. Evaluation of the effects of dopexamine, a novel
DA1 and ß2-adrenoceptor
agonist on cardiac function and splanchnic circulation in a canine
model of hemorrhagic shock. Naunyn Schmiedebergs Arch
Pharmacol. 1993;347:296–300.[Medline]
[Order article via Infotrieve]
© 1998 American Heart Association, Inc.
Review
Renal Dopamine Receptor Function in Hypertension
Abstract
Abstract—Dopamine plays an important
role in the regulation of renal sodium excretion. The synthesis of
dopamine and the presence of dopamine receptor subtypes
(D1A, D1B as D1-like and
D2, and D3 as D2-like) have been
shown within the kidney. The activation of D1-like
receptors located on the proximal tubules causes inhibition of tubular
sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase
activity. The D1-like receptors are linked to the multiple
cellular signaling systems (namely, adenylyl cyclase, phospholipase C,
and phospholipase A2) in the different regions of the
nephron. Defective renal dopamine production and/or dopamine
receptor function have been reported in human primary hypertension as
well as in genetic models of animal hypertension. There may be a
primary defect in D1-like receptors and an altered
signaling system in the proximal tubules that lead to reduced
dopamine-mediated effects on renal sodium excretion in hypertension.
Recently, it has been shown in animal models that the disruption of
either D1A or D3 receptors at the gene level
causes hypertension in mice. Dopamine and dopamine receptor agonists
also provide therapeutic potential in treatment of various
cardiovascular pathological conditions, including
hypertension. However, because of the poor bioavailability of the
currently available compounds, the use of D1-like agonists
is limited to the management of patients with severe hypertension when
a rapid reduction of blood pressure is clinically indicated and in
acute management of patients with heart failure. In conclusion, there
is convincing evidence that dopamine and dopamine receptors play an
important role in regulation of renal function, suggesting that a
defective dopamine receptor/signaling system may contribute to the
development and maintenance of hypertension. Further studies
need to be directed toward establishing a direct correlation between
defective dopamine receptor gene in the kidney and development of
hypertension. Subsequently, it may be possible to use a therapeutic
approach to correct the defect in dopamine receptor gene causing
the hypertension.
Key Words: dopamine • receptors, dopamine • kidney tubules, proximal • kidney • hypertension, renal
Introduction
Dopamine is known to
play an important role in the control of renal sodium excretion.
Specific receptors for dopamine have been identified in various regions
of the nephron, and it is reported that dopamine is synthesized within
the renal proximal tubules. Endogenously produced dopamine,
as well as exogenously administered dopamine, exerts pronounced effects
on renal function. There are reports suggesting that a defect in renal
dopamine receptor function and/or dopamine production may play
a role in the pathogenesis of hypertension. For example, reduced
urinary dopamine/sodium excretion is reported in some forms of human
primary hypertension.1 2 3 It is reported that a
defect in dopamine receptor–G protein coupling and alterations in the
signaling components may be responsible for the failure of dopamine to
promote sodium excretion in hypertensive
animals.4 5 6 Furthermore, recently it was shown
that mice lacking D1A receptors developed
hypertension.7 Also, in another study it was
discovered that mice lacking D3 receptors
developed renin-dependent hypertension.8 This
article will review our knowledge of dopamine receptor–mediated
cellular signaling mechanisms in the kidney and discuss evidence
supporting the concept that defective renal dopamine production
and receptor function may play a role in hypertension. Furthermore, the
therapeutic potential of dopamine and other dopamine receptor agonists
in the management of cardiovascular disorders will also
be discussed.
Dopamine Receptor Classification and Localization in the
Kidney
The biological effects of dopamine are mediated through at least 5
genetically distinct dopamine receptors: D1,
D2, D3,
D4, and
D5.9 These receptors are
classified into two major families as D1-like
(includes D1 and D5, whose
rat homologues are D1A and
D1B) and D2-like (includes
D2, D3, and
D4) dopamine receptors based on the stimulation
and inhibition of adenylyl cyclase,
respectively.9 With pharmacological means of
receptor characterization, the peripheral dopamine
receptors were initially classified as DA1 and
DA2 subtypes.10 11 Within
the kidney, ligand binding and autoradiographic studies
have revealed the presence of both DA1 and
DA2 receptors.12 13 14 Of the
cloned dopamine receptors, D1A,
D1B, D2Long, and
D3 have been identified in the
kidney.14 15 16 In this review, we will use the
nomenclature D1-like receptors and
D2-like receptors to describe the dopamine
receptors linked to the stimulation and the inhibition of adenylyl
cyclase, respectively.
Physiological Role of Dopamine in the
Kidney
In 1964 the natriuretic and diuretic effects
of dopamine were first observed in humans.22
Although the concept of a specific receptor for dopamine had not been
proposed at that time, it is now known that dopamine exerts pronounced
cardiovascular and renal actions by activating both
D1-like and D2-like
dopamine receptors located at various sites within the cardiac,
vascular, and renal regions.13 18 19 At higher
doses, dopamine also activates ß- and
-adrenoceptors.23 Several studies have shown
that selective agonists at D1-like receptors
cause hypotension, increase in blood flow to certain organs,
diuresis, and natriuresis, whereas
D2-like receptor agonists produce hypotension,
bradycardia, a decrease in afterload, and vasodilation in certain
vascular beds
(Table
).24 25 It
has been shown that D1-like receptor agonists
cause an increase in RBF and glomerular filtration rate, as
well as increase in urinary excretion of sodium and
water.24 26 Studies from our laboratory and
others have shown that the natriuretic and diuretic
response elicited by D1-like receptor agonist
involves changes in intrarenal hemodynamics and direct
tubular action. At lower doses, it is the direct action on the renal
tubules that accounts for the natriuresis and diuresis induced
by selective D1-like receptor
agonists.13 24 26 These effects of agonists can
be antagonized by SCH 23390, a selective D1-like
receptor antagonist, further substantiating the role of
D1-like receptors in these actions of dopamine
and D1-like agonists.
View this table:
[in a new window]
Table 1. Peripheral Dopamine Receptors in Cardiovascular
System
Dopamine Receptor–Linked Cellular Signaling Mechanisms
Regulation of sodium transport across the proximal tubules occurs
through the involvement of two key proteins: Na,H-exchanger, located on
the brush border membrane, and Na,K-ATPase, located on the basolateral
membrane of the proximal tubule.33 37 38 39 These
two proteins have been identified as the target for the action of
dopamine. Dopamine produces inhibition in the activities of these
proteins, a mechanism by which dopamine affects tubular sodium
transport. In the proximal tubules, both D1-like
and D2-like receptors are
coexpressed.12 13 The activation of
D1-like receptors by dopamine produces inhibition
in Na,K-ATPase activity in the proximal tubules and in other parts of
the nephron, such as mTAL and CCD.40 41 Also,
using in vitro transfection of D1A receptor in
fibroblast LTK- cells, Horiuchi et
al42 showed inhibition of Na,K-ATPase activity by
fenoldopam, a D1-like receptor agonist. The
activation of D1-like receptor by dopamine and
D1-like agonist also produces inhibition of
Na,H-exchanger activity in the proximal segments of the nephron, as
well as in brush border membrane vesicle
preparations.37 38 As it relates to the effects
of D2-like receptor activation, according to one
study, the inhibition of Na,K-ATPase activity by dopamine requires
simultaneous activation of D1-like
and D2-like receptors in the proximal
tubules.43 On the other hand, we and others
recently demonstrated in vitro that D2-like
receptor activation may lead to the stimulation of Na,K-ATPase activity
in the proximal tubules44 and the
LTK- murine cells transfected with
D2Long cDNA.45 The
stimulation of Na,K-ATPase activity by the
D2-like receptor agonists involves pertussis
toxin–sensitive, G protein–linked inhibition of cAMP. Although it is
suggested that activation of D2-like receptors
produces antidiuresis and
antinatriuresis,46 whether tubular
D2-like receptors are directly involved in the
regulation of tubular sodium absorption and contribute to the basal
level of sodium transport through the mechanism of Na,K-ATPase is yet
to be determined. The activation of D2-like
receptor does not affect the activity of Na,H-exchanger in the proximal
tubule.38 1-receptor activation also leads to the
stimulation of PLC activity but activates Na,K-ATPase activity
in the proximal tubules.55 This phenomenon is
explained by the differential regulation of PLC activity and isoform
expression by D1-like and
1-receptors.56
D1-like receptor and
1-receptor agonists were intrarenally infused
in rats, and the expression and activity of various PLC isoforms in the
cortical membranes were studied. The intrarenal infusion of
D1-like receptor agonist increased
PLC-ß1 expression and activity but decreased
PLC-
1 expression and activity in the membranes
of renal cortex.56 Similar observations on the
changes in PLC-ß1 and
PLC-1 expression and activity by
D1-like receptor agonist were also made in
LTK- cells heterologously expressing the rat
D1A receptor.57 Similar to
D1-like agonist, phenylephrine
(1-adrenoceptor agonist) also increased the
expression of PLC-ß1 protein but had no effect
on the expression of PLC-1 in the cortical
membranes. The two signaling pathways, adenylyl cyclase and PLC, were
proposed to be linked to D1-like receptors
through the coupling of Gs and
Gq/11 proteins in the proximal
tubules.50 51 52 More direct evidence came from our
recent study using [35S]GTPS binding
stimulated by fenoldopam (a D1-like receptor
agonist) and antagonism by specific anti-G in
the basolateral membranes.5 Bertorello et
al58 have reported that pertussis
toxin–sensitive G proteins
(Gi/Go family) also play a
role in dopamine-mediated inhibition of Na,K-ATPase activity. This
supports their study showing that simultaneous activation
of both D1- and D2-like
receptors is required to inhibit Na,K-ATPase by
dopamine.43 D2-like
receptors have been shown to be linked to pertussis toxin–sensitive
proteins.44 45 Despite the evidence based on the
transfection of cells with D1A receptor and
showing that activation of D1A receptors could
stimulate both adenylyl cyclase and PLC, recent studies suggest the
existence of two different molecular entities that are linked
independently to adenylyl cyclase and PLC in the
brain.59 Recently, with the use of
D1A knockout mice, it was reported that the
D1-like receptor agonist SKF 38393 and dopamine
clearly did not generate cAMP but stimulated inositol phosphate
production in the brain regions (striatum and frontal
cortex).60 This suggested that the inositol
formation (PLC-linked pathway) was independent of
D1A receptor. However, similar studies have yet
to be performed in the kidney to investigate whether adenylyl cyclase
and PLC are linked to the same D1A receptor or to
two different D1-like receptor proteins. Of the
D1-like receptors, D1B
dopamine receptors are also expressed in the proximal
tubules.15 It is also possible that
D1B receptors are linked to the PLC pathway.
However, such a plausible explanation may not be tested using the
conventional approach because of the unavailability of selective
agonist or antagonist. D1B receptor
knockout animals may provide a model to resolve the issue. shows a hypothetical diagram of
dopamine receptor–mediated cellular signaling mechanisms in the
nephron.
View larger version (39K):
[in a new window]
Figure 1. Schematic hypothetical presentation of
D1-like dopamine receptor and associated cellular
signaling mechanisms in the nephron that mediate the inhibition of
sodium-transporting proteins and thereby increase in renal sodium
excretion. PKC (same or different isoforms), directly or via the
stimulation of PLA2, may phosphorylate
Na,K-ATPase. D1-like receptor and its coupling with G
proteins are believed to be defective, which leads to diminished renal
sodium excretion in hypertension. IP3 indicates inositol triphosphate;
DAG, diacylglycerol; Cyt P450, cytochrome P450
monoxygenase; and Pi,
phosphorylation.
Renal Dopaminergic System in Hypertension
Human Primary Hypertension
There are reports of a deficiency in the renal dopamine synthesis
and/or secretion in various forms of human hypertension. Depressed
urinary dopamine excretion has been reported in salt-sensitive
hypertensive patients compared with normal subjects or
non–salt-sensitive patients,68 as well as in
low-renin primary hypertension compared with normotensive normal-renin
and high-renin hypertensive patients.2 The
depressed renal dopamine in low-renin primary hypertension is commonly
associated with increase in renal vascular resistance, decrease in
renal plasma flow, and expansion of extracellular fluid
volume.2 Suppressed dopaminergic activity has
also been shown in the prehypertensive stage of primary
hypertension.1 69 Because endogenous
kidney dopamine plays an important role in maintaining body sodium
homeostasis, renal dopaminergic deficiency may contribute to the
development and maintenance of high blood pressure, at least in
a subpopulation of humans with essential hypertension. Suppression of
dopaminergic activity was also observed in young normotensive subjects
with an apparent family history of hypertension before any evidence of
hypertension emerged.69 70 The infusion of
exogenous dopamine leads to the augmentation of sodium excretion in the
subjects with low-renin hypertension and in the subjects with family
history of hypertension.70 71 In another study,
increased urinary sodium excretion in response to exogenous dopamine
infusion in patients with essential hypertension was accompanied by
increased urinary and nephrogenous cAMP contents compared with the
normotensive control subjects.72 These studies
are in agreement with the hypothesis of an upregulation of dopamine
receptor and/or change in receptor affinity in patients with essential
hypertension, secondary to decreased endogenous intrarenal
dopamine production.71 73 74 The notion
of D1-like receptor upregulation has been
recently supported by another study.75 According
to this study in hypertensive subjects,75 the
upregulation of D1-like receptor function takes
place in the distal tubules and not in the proximal tubules, and such
an upregulation in the distal tubules D1-like
receptor offsets the defect in the proximal tubule, leading to
natriuresis and diuresis in response to the
D1-like agonist fenoldopam. However, thus far,
direct measurements of renal dopamine receptor population or agonist
affinity in subjects with primary hypertension have not been reported.
A defect in the coupling of D1-like receptors and
adenylyl cyclase system was recently reported in primary cultured cells
of hypertensive human proximal tubules.76 This
defect is receptor specific, since adenylyl cyclase stimulation by
parathyroid hormone was found to be similar in the cells from both
normotensive and hypertensive subjects. Furthermore, a
D1-like receptor/adenylyl cyclase defect in human
cells was suggested to be similar to the defects found in the proximal
tubules from animal models of genetic hypertension (discussed
below).
Dahl Salt-Sensitive Rats
There are several lines of evidence suggesting a defective
dopaminergic system in the kidneys of the Dahl salt-sensitive strain of
rats. Dahl salt-sensitive rats excrete sodium poorly with increased
sodium load.81 There is decreased kidney dopamine
content in salt-sensitive rats fed a high salt
diet,82 a lack of increased urinary dopamine
excretion in salt-sensitive rats subjected to acute volume
expansion,83 and reduced urinary dopamine and
cAMP excretion in young normotensive salt-sensitive rats compared with
control Wistar rats fed a normal salt diet.2 In
addition to a decreased urinary dopamine excretion, a defect in the
D1-like receptor has been reported in the
proximal tubules of Dahl salt-sensitive rats. In an experimental study,
endogenous dopamine was allowed to accumulate by inhibition
of its conversion to norepinephrine by a dopamine
ß-hydroxylase inhibitor. This led to downregulation of
proximal tubular D1-like receptors and complete
ablation of D1-like agonist stimulation of
adenylyl cyclase activity in the normotensive rats, while the
D1-like receptors in salt-sensitive rats were
resistant to such regulation.83 84 In
another study,85 high salt intake (10 days)
downregulated Na,K-ATPase activity in the proximal tubules of
salt-resistant rats that was reversed by benserazide (dopamine
synthesis inhibitor), suggesting a role of
endogenous dopamine in the regulation of Na,K-ATPase. In
contrast, high salt intake did not affect Na,K-ATPase activity, and
benserazide also had no effect on the enzyme in salt-sensitive rats.
This suggested the inability of the D1-like
receptor to regulate the Na,K-ATPase activity that results from a
defective D1-like receptor-mediated cellular
signaling mechanism in salt-sensitive rats. The notion of defective
coupling of D1-like receptor with adenylyl
cyclase is supported by another study.86 It was
discovered that D1-like receptor agonists were
unable to stimulate adenylyl cyclase in the proximal tubules from Dahl
salt-sensitive rats, whereas forskolin (a direct stimulator of adenylyl
cyclase) stimulation of the enzyme was not different between Dahl
salt-sensitive and salt-resistant rats.86
A defective coupling would be expected to lead to a reduced
D1-like receptor-mediated inhibition of
Na,H-exchanger and hence a reduced sodium excretion, which has yet to
be demonstrated in Dahl salt-sensitive rats.
In SHR, dopamine production and excretion is normal or
even increased,87 88 but dopamine- and
fenoldopam-mediated natriuretic and diuretic
responses are diminished under normal conditions, as well as during
acute volume expansion (5% body weight), compared with those in
normotensive control WKY.83 89 90 We and others
have performed extensive studies to investigate the site(s) of defect
in the D1-like receptor system in the
SHR.4 39 91 92 93 S binding)
by D1-like agonist was reduced in the basolateral
membranes from 3-week-old SHR compared with WKY.5
Compelling evidence showing a relationship of defective
D1A receptor/signaling system with hypertension
comes from two sets of experiments published recently: one on the
cross-breeds of normotensive and hypertensive rats and the second on
mice lacking functional D1A
receptors.7 In the F2 generation from female WKY
and male SHR crosses, the inability of D1-like
receptor to inhibit Na,H-exchanger in the proximal tubules cosegregated
with increased systolic blood pressure (>160 mm Hg) and
decreased ability of renal sodium excretion in response to
D1-like agonist infused in the renal arteries of
the rats. The activation of D1-like receptors was
able to inhibit the Na,H-exchanger in rats of the same F2 generation
with systolic blood pressure <140 mm Hg. In another set
of experiments, mutant mice lacking functional
D1A receptors were generated. Compared with
control mice, both homozygous and heterozygous mice had greater
systolic, diastolic, and mean arterial
pressures. The renal tubules from homozygous mice had no
[125I]SCH 23982 (a
D1-like ligand) binding sites and had no
stimulation of cAMP by dopamine.7 In addition to
the observation made with D1A receptor, the
disruption of D3 receptor (a member of
D2-like receptors present on proximal
tubules) has also been shown recently to cause renin-dependent
hypertension.8 However, the mechanism of
hypertension caused by the disruption of D3
receptors is different than that caused by D1A
receptors. The renal renin activity was much greater in the mice
lacking D3 receptors (both homozygous and
heterozygous) than in the wild-type control group. A single-bolus dose
of the AT1 receptor antagonist
losartan decreased systolic blood pressure to a greater
extent and for a longer time in the homozygous mice than in the
wild-type mice. During acute volume expansion, blood pressure was
unchanged, glomerular filtration rates were similar, and
urine flow was increased to similar extents in the wild-type and the
mutant mice (both homozygous and heterozygous). However, increase in
sodium excretion was attenuated in homozygous mice compared with
control.8 There is evidence showing that a
physiological and biochemical interaction exists
between dopamine and angiotensin II receptors in the
kidney.64 66 Intrarenally produced
angiotensin has been shown to counteract fenoldopam-induced
sodium excretion.64 Also, it has been shown that
both D1-like and D2-like
receptor agonists cause a decrease in AT1
receptor binding sites in proximal tubular
preparations.65 66 Although the
AT1 receptor binding sites have not been measured
in the D3 mutant mice, it is possible that the
absence of D3 receptors might have caused an
increase in AT1 receptors in the proximal tubules
along with the higher renin production. S binding to a lesser extent in the
basolateral membranes of SHR than WKY.5 Moreover,
of the two coupled G proteins (Gs and
Gq/11), a reduction in the quantities of
Gq/11 was found in the basolateral membranes
of SHR compared with WKY.5 In another
study,101 dopamine and cholera toxin
(Gs protein activator) were reported
to inhibit Na,K-ATPase activity in the proximal tubules from WKY but
had no effect in SHR. When the proximal tubules were pretreated with
pertussis toxin (Gi protein
inactivator), both dopamine and cholera toxin produced
significant inhibition in Na,K-ATPase activity in SHR. Because
arachidonic acid metabolites mediate dopamine-induced
inhibition of Na,K-ATPase activity in the proximal tubules, a reduced
inhibition in Na,K-ATPase activity by arachidonic acid
was observed in SHR compared with WKY.61 As we
discussed earlier, the response of adenylate cyclase and
Na,H-exchanger to D1-like agonist undergoes
ontogenesis in WKY but not in SHR; a similar ontogenesis takes place
with the action of cAMP on Na,H-exchanger in WKY but not in SHR.
Horiuchi et al6 have shown that the effect of
cAMP on Na,H-exchanger activity is lost with maturation in the proximal
tubules of SHR. On the basis of these studies, it is reasonable to
propose that the alterations in these signaling components may also
contribute to the failure of dopamine and D1-like
agonists to inhibit Na,K-ATPase and Na,H-exchanger activity in the
proximal tubules from SHR.
Dopamine Receptor Agonists in Treatment of Cardiovascular
Diseases
Dopamine receptors located at various regions within the
cardiovascular system, including the kidneys, serve as
important target sites for the actions of several compounds acting at
either D1-like and/or
D2-like receptors. The location and
cardiovascular changes caused by the activation of
these receptors are shown in the Table
. -adrenergic receptors.
However, at low doses ranging from 1 to 3 µg ·
kg-1 · min-1,
dopamine predominantly activates D1-like
receptors and causes increases in RBF, glomerular
filtration rate, and sodium and water excretion. Dopamine in low doses
is used in acute treatment of heart failure in patients to promote
natriuresis and diuresis via selective
D1-like dopamine receptor
stimulation.102 It was shown in another study
that in patients with renal disease, while the renal vasodilatory
response to dopamine was reduced compared with that in healthy
volunteers, the natriuretic response in these patients was
still evident. In a recent study, dose-response analysis of
dopamine in water-loaded individuals was
performed.103 It was found that the
natriuretic and renal vasodilating effect of dopamine was
maximal at a dose of 3 µg · kg-1
· min-1. At higher doses, increased
-adrenergic stimulation caused attenuation of the renal vasodilation
seen with D1-like receptor
stimulation.104 Therefore, while dopamine is
effective as a renal vasodilator and natriuretic agent, its
clinical use is limited because of its ability to activate
-adrenoceptors, and this effect may sometimes be exaggerated
depending on the clinical condition of the patient. , activation of
D2-like receptors located on sympathetic nerve
terminals and ganglia leads to inhibition of norepinephrine
release; the subsequent reduction in afterload and vasodilation is what
accounts for the antihypertensive action of compounds such as
bromocriptine and quinpirole.117 However, these
compounds are not used in hypertensive patients because of several
unwanted and complicating effects. For example, because these agents
enter the brain, activation of D2-like receptors
in this region produces many undesirable effects, including emesis and
endocrine changes. Also, a reduction in sympathetic tone leads to
conditions such as postural hypotension. Therefore, although
D2-like dopamine receptor agonists have
contributed to our understanding of the pharmacology of
peripheral prejunctional dopamine receptors and their role
in the regulation of sympathetic neurotransmission under pathological
conditions, they do not offer any therapeutic potential in the
treatment of cardiovascular diseases, including
hypertension.
Summary and Future Directions
Several physiological, biochemical, and
molecular studies suggest the importance of endogenous
dopamine and renal D1A receptor in the regulation
of sodium and body volume homeostasis. Although there is evidence that
a defective renal dopaminergic system contributes to the development
and maintenance of hypertension, it is not yet clear what is
the triggering factor that causes the defect selectively in the renal
dopaminergic system. In the animal model of genetic hypertension, the
precise defect in D1A receptor leading to reduced
affinity to the agonist and impaired signal transduction has not yet
been defined. Certain biochemical properties of renal
D1A receptor in SHR, such as buried sulfhydryl
groups,99 indicate that a defect may lie in the
posttranslational and receptor-folding machinery. Similar to
ß-adrenoceptor,118 119 various
phosphorylation sites and palmitoylation site (at
cys348) are present on the D1A
receptor120 which may play an important role in
the coupling with G proteins and activation of second messenger
systems. Therefore, in addition to investigating the defects in
D1A receptor protein per se, it will be equally
important to focus on the biochemistry of posttranslational steps
involved in D1A receptor folding and expression
of the receptor protein on the cell membrane in SHR. Although the
development of hypertension in mice lacking D1A
receptor (by general knockout) suggested a causal relationship of the
D1A receptor gene with hypertension, the effect
of kidney-specific knockout of D1A receptor gene
is yet to be investigated. The question of whether
D1A receptor is the only
D1-like dopamine receptor that is linked to both
signaling pathways (PLC/PKC and adenylyl cyclase/PKA) and inhibits
Na,K-ATPase and Na,H-exchanger, respectively, in the proximal tubules
remains to be answered. The recent report using
D1A knockout mice shows that
D1-like receptors mediating stimulation of PLC
are not D1A dopamine receptors stimulating
adenylyl cyclase in the brain striatum. It is not known whether the
dopamine receptors linked to adenylyl cyclase and PLC in the kidney are
D1A subtypes or whether two different molecular
entities of D1-like receptors are expressed.
Binding of [125I[SCH 23390 in the brain
striatum and kidney proximal tubules of D1A
knockout mice suggested a heterogeneity of
D1A receptors.7 60 Brain
striatum of D1A knockout mice (homozygous) had
the remaining sites that bound to [125I[SCH
23390 and were suggested to be linked to inositol
hydrolysis,60 whereas the proximal tubules from
D1A knockout mice (homozygous) exhibited no
[125I[SCH 23390 binding
sites.7 Further biochemical and molecular
characterization of dopamine receptors in the kidney will allow us to
better understand their role in the regulation of sodium excretion and
the cause of defective dopamine receptors and associated signal
transduction mechanisms in hypertension. As related to the relationship
between increased renin-angiotensin activity and disruption
of D3 receptors in mice,8
it will also be important to examine whether the disruption of
D3 receptors led to an increase in
AT1 receptors in the kidney. In light of the
reported interactions between angiotensin and dopamine
receptors, the findings could be relevant to further explanations for
the mechanism of hypertension seen in mice lacking
D3 receptors.
Selected Abbreviations and Acronyms
AT1
=
angiotensin type 1 receptor
CCD
=
cortical collecting duct
mTAL
=
medullary thick ascending limb
PKA
=
cAMP-dependent protein kinase
PKC
=
protein kinase C
PLA2
=
phospholipase A2
PLC
=
phospholipase C
RBF
=
renal blood flow
SHR
=
spontaneously hypertensive rats
WKY
=
Wistar-Kyoto rats
Footnotes
Reprint requests to Mustafa F. Lokhandwala, PhD, College of Pharmacy, University of Houston, Houston TX 77204-5511.
References
1.
1. Iimura O, Shimamoto K. Suppressed dopaminergic
activity and water-sodium handling in kidneys at the prehypertensive
stage of essential hypertension. J Auton Pharmacol.
1990;10(suppl 1):73S–77S.1-Adrenoceptor subtypes mediating stimulation
of Na,K-ATPase activity in rat renal proximal tubules. Eur J
Pharmacol. 1995;288:139–147.[Medline]
[Order article via Infotrieve]
Top
Abstract
IntroductionThis article has been cited by other articles:
 |
|
 |
|
  A. R. Cinelli, R. Efendiev, and C. H. Pedemonte Trafficking of Na-K-ATPase and dopamine receptor molecules induced by changes in intracellular sodium concentration of renal epithelial cells Am J Physiol Renal Physiol, October 1, 2008; 295(4): F1117 - F1125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Doris Promoting Regulatory Gene Variation in Sodium Reabsorption Hypertension, October 1, 2008; 52(4): 623 - 624. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Efendiev, C. E. Budu, A. M. Bertorello, and C. H. Pedemonte G-protein-coupled Receptor-mediated Traffic of Na,K-ATPase to the Plasma Membrane Requires the Binding of Adaptor Protein 1 to a Tyr-255-based Sequence in the {alpha}-Subunit J. Biol. Chem., June 20, 2008; 283(25): 17561 - 17567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Gildea, X. Wang, P. A. Jose, and R. A. Felder Differential D1 and D5 Receptor Regulation and Degradation of the Angiotensin Type 1 Receptor Hypertension, February 1, 2008; 51(2): 360 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Vellaichamy, D. Zhao, N. Somanna, and K. N. Pandey Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A upregulates ACE and AT1 receptor gene expression and signaling: role in cardiac hypertrophy Physiol Genomics, October 19, 2007; 31(2): 193 - 202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Banday and M. F. Lokhandwala Oxidative stress reduces renal dopamine D1 receptor-Gq/11{alpha} G protein-phospholipase C signaling involving G protein-coupled receptor kinase 2 Am J Physiol Renal Physiol, July 1, 2007; 293(1): F306 - F315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Maurel, O. Spreux-Varoquaux, F. Amenta, S. K. Tayebati, D. Tomassoni, M.-H. Seguelas, A. Parini, and N. Pizzinat Vesicular monoamine transporter 1 mediates dopamine secretion in rat proximal tubular cells Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1592 - F1598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Pinho, M. P. Serrao, and P. Soares-da-Silva High-salt intake and the renal expression of amino acid transporters in spontaneously hypertensive rats Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1452 - F1463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Z. Fardoun, M. Asghar, and M. Lokhandwala Role of oxidative stress in defective renal dopamine D1 receptor-G protein coupling and function in old Fischer 344 rats Am J Physiol Renal Physiol, November 1, 2006; 291(5): F945 - F951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zeng, Y. Liu, Z. Wang, D. He, L. Huang, P. Yu, S. Zheng, J. E. Jones, L. D. Asico, U. Hopfer, et al. Activation of D3 Dopamine Receptor Decreases Angiotensin II Type 1 Receptor Expression in Rat Renal Proximal Tubule Cells Circ. Res., September 1, 2006; 99(5): 494 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Marwaha and M. F. Lokhandwala Tempol reduces oxidative stress and restores renal dopamine D1-like receptor- G protein coupling and function in hyperglycemic rats Am J Physiol Renal Physiol, July 1, 2006; 291(1): F58 - F66. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Sanada, J. Yatabe, S. Midorikawa, T. Katoh, S. Hashimoto, T. Watanabe, J. Xu, Y. Luo, X. Wang, C. Zeng, et al. Amelioration of Genetic Hypertension by Suppression of Renal G Protein-Coupled Receptor Kinase Type 4 Expression Hypertension, June 1, 2006; 47(6): 1131 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zeng, Z. Wang, H. Li, P. Yu, S. Zheng, L. Wu, L. D. Asico, U. Hopfer, G. M. Eisner, R. A. Felder, et al. D3 Dopamine Receptor Directly Interacts With D1 Dopamine Receptor in Immortalized Renal Proximal Tubule Cells Hypertension, March 1, 2006; 47(3): 573 - 579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Bek, X. Wang, L. D. Asico, J. E. Jones, S. Zheng, X. Li, G. M. Eisner, D. K. Grandy, R. M. Carey, P. Soares-da-Silva, et al. Angiotensin-II Type 1 Receptor-Mediated Hypertension in D4 Dopamine Receptor-Deficient Mice Hypertension, February 1, 2006; 47(2): 288 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Efendiev and C. H. Pedemonte Contrary to Rat-Type, Human-Type Na,K-ATPase Is Phosphorylated at the Same Amino Acid by Hormones that Produce Opposite Effects on Enzyme Activity J. Am. Soc. Nephrol., January 1, 2006; 17(1): 31 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zeng, Z. Wang, U. Hopfer, L. D. Asico, G. M. Eisner, R. A. Felder, and P. A. Jose Rat Strain Effects of AT1 Receptor Activation on D1 Dopamine Receptors in Immortalized Renal Proximal Tubule Cells Hypertension, October 1, 2005; 46(4): 799 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zeng, Z. Yang, Z. Wang, J. Jones, X. Wang, J. Altea, A. J. Mangrum, U. Hopfer, D. R. Sibley, G. M. Eisner, et al. Interaction of Angiotensin II Type 1 and D5 Dopamine Receptors in Renal Proximal Tubule Cells Hypertension, April 1, 2005; 45(4): 804 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Hakam and T. Hussain Renal Angiotensin II Type-2 Receptors Are Upregulated and Mediate the Candesartan-Induced Natriuresis/Diuresis in Obese Zucker Rats Hypertension, February 1, 2005; 45(2): 270 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yang, L. D. Asico, P. Yu, Z. Wang, J. E. Jones, R.-k. Bai, D. R. Sibley, R. A. Felder, and P. A. Jose D5 dopamine receptor regulation of phospholipase D Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H55 - H61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zeng, H. Sanada, H. Watanabe, G. M. Eisner, R. A. Felder, and P. A. Jose Functional genomics of the dopaminergic system in hypertension Physiol Genomics, November 17, 2004; 19(3): 233 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Banday, T. Hussain, and M. F. Lokhandwala Renal dopamine D1 receptor dysfunction is acquired and not inherited in obese Zucker rats Am J Physiol Renal Physiol, July 1, 2004; 287(1): F109 - F116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zeng, D. Wang, L. D. Asico, W. J. Welch, C. S. Wilcox, U. Hopfer, G. M. Eisner, R. A. Felder, and P. A. Jose Aberrant D1 and D3 Dopamine Receptor Transregulation in Hypertension Hypertension, March 1, 2004; 43(3): 654 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zeng, D. Wang, Z. Yang, Z. Wang, L. D. Asico, C. S. Wilcox, G. M. Eisner, W. J. Welch, R. A. Felder, and P. A. Jose Dopamine D1 Receptor Augmentation of D3 Receptor Action in Rat Aortic or Mesenteric Vascular Smooth Muscles Hypertension, March 1, 2004; 43(3): 673 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Asghar, T. Hussain, and M. F. Lokhandwala Overexpression of PKC-{beta}I and -{delta} contributes to higher PKC activity in the proximal tubules of old Fischer 344 rats Am J Physiol Renal Physiol, December 1, 2003; 285(6): F1100 - F1107. [Abstract] [Full Text]
|
|
|
|
|
|
C. Zeng, Y. Luo, L. D. Asico, U. Hopfer, G. M. Eisner, R. A. Felder, and P. A. Jose Perturbation of D1 Dopamine and AT1 Receptor Interaction in Spontaneously Hypertensive Rats Hypertension, October 1, 2003; 42(4): 787 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Pinho, P. Gomes, M. P. Serrao, M. J. Bonifacio, and P. Soares-da-Silva Organ-Specific Overexpression of Renal LAT2 and Enhanced Tubular L-DOPA Uptake Precede the Onset of Hypertension Hypertension, October 1, 2003; 42(4): 613 - 618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Efendiev, C. E. Budu, A. R. Cinelli, A. M. Bertorello, and C. H. Pedemonte Intracellular Na+ Regulates Dopamine and Angiotensin II Receptors Availability at the Plasma Membrane and Their Cellular Responses in Renal Epithelia J. Biol. Chem., August 1, 2003; 278(31): 28719 - 28726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Banday, M. Asghar, T. Hussain, and M. F. Lokhandwala Dopamine-Mediated Inhibition of Renal Na,K-ATPase Is Reduced by Insulin Hypertension, June 1, 2003; 41(6): 1353 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zheng, P. Yu, C. Zeng, Z. Wang, Z. Yang, P. M. Andrews, R. A. Felder, and P. A. Jose G{alpha}12- and G{alpha}13-Protein Subunit Linkage of D5 Dopamine Receptors in the Nephron Hypertension, March 1, 2003; 41(3): 604 - 610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zeng, L. D. Asico, X. Wang, U. Hopfer, G. M. Eisner, R. A. Felder, and P. A. Jose Angiotensin II Regulation of AT1 and D3 Dopamine Receptors in Renal Proximal Tubule Cells of SHR Hypertension, March 1, 2003; 41(3): 724 - 729. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Narkar, T. Hussain, and M. F. Lokhandwala Activation of D2-like receptors causes recruitment of tyrosine-phosphorylated NKA alpha 1-subunits in kidney Am J Physiol Renal Physiol, December 1, 2002; 283(6): F1290 - F1295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. N. Umrani, A. A. Banday, T. Hussain, and M. F. Lokhandwala Rosiglitazone Treatment Restores Renal Dopamine Receptor Function in Obese Zucker Rats Hypertension, December 1, 2002; 40(6): 880 - 885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Asghar, T. Hussain, and M. F. Lokhandwala Higher basal serine phosphorylation of D1A receptors in proximal tubules of old Fischer 344 rats Am J Physiol Renal Physiol, August 1, 2002; 283(2): F350 - F355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Efendiev, A. M. Bertorello, R. Zandomeni, A. R. Cinelli, and C. H. Pedemonte Agonist-dependent Regulation of Renal Na+,K+-ATPase Activity Is Modulated by Intracellular Sodium Concentration J. Biol. Chem., March 22, 2002; 277(13): 11489 - 11496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. LUIPPOLD, C. ZIMMERMANN, M. MAI, D. KLOOR, D. STARCK, G. GROSS, and B. MUHLBAUER Dopamine D3 Receptors and Salt-Dependent Hypertension J. Am. Soc. Nephrol., November 1, 2001; 12(11): 2272 - 2279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. NARKAR, T. HUSSAIN, C. PEDEMONTE, and M. F. LOKHANDWALA Dopamine D2 Receptor Activation Causes Mitogenesis via p44/42 Mitogen-Activated Protein Kinase in Opossum Kidney Cells J. Am. Soc. Nephrol., September 1, 2001; 12(9): 1844 - 1852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. X. Li, M. Bek, L. D. Asico, Z. Yang, D. K. Grandy, D. S. Goldstein, M. Rubinstein, G. M. Eisner, and P. A. Jose Adrenergic and Endothelin B Receptor-Dependent Hypertension in Dopamine Receptor Type-2 Knockout Mice Hypertension, September 1, 2001; 38(3): 303 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Gomes, M. A. Vieira-Coelho, and P. Soares-da-Silva Ouabain-insensitive acidification by dopamine in renal OK cells: primary control of the Na+/H+ exchanger Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R10 - R18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. ASGHAR, V. KANSRA, T. HUSSAIN, and M. F. LOKHANDWALA Hyperphosphorylation of Na-Pump Contributes to Defective Renal Dopamine Response in Old Rats J. Am. Soc. Nephrol., February 1, 2001; 12(2): 226 - 232. [Abstract] [Full Text]
|
|
|
|
 |
|
 E. Feraille and A. Doucet Sodium-Potassium-Adenosinetriphosphatase-Dependent Sodium Transport in the Kidney: Hormonal Control Physiol Rev, January 1, 2001; 81(1): 345 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Therien and R. Blostein Mechanisms of sodium pump regulation Am J Physiol Cell Physiol, September 1, 2000; 279(3): C541 - C566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. N. Thomas, B. Tomlinson, and J. A. J. H. Critchley Modulation of Blood Pressure and Obesity With the Dopamine D2 Receptor Gene TaqI Polymorphism Hypertension, August 1, 2000; 36(2): 177 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sato, M. Soma, T. Nakayama, and K. Kanmatsuse Dopamine D1 Receptor Gene Polymorphism Is Associated With Essential Hypertension Hypertension, August 1, 2000; 36(2): 183 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Lucas-Teixeira, M. A. Vieira-Coelho, and P. Soares-da-Silva Food Intake Abolishes the Response of Rat Jejunal Na+,K+-ATPase to Dopamine J. Nutr., April 1, 2000; 130(4): 877 - 881. [Abstract] [Full Text]
|
|
|
|
|
|
L. J. Millatt and H. M. Siragy Age-Related Changes in Renal Cyclic Nucleotides and Eicosanoids in Response to Sodium Intake Hypertension, February 1, 2000; 35(2): 643 - 647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yang, C. K. Hwang, E. Junn, G. Lee, and M. M. Mouradian ZIC2 and Sp3 Repress Sp1-induced Activation of the Human D1ADopamine Receptor Gene J. Biol. Chem., December 1, 2000; 275(49): 38863 - 38869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Narkar, T. Hussain, and M. Lokhandwala Role of tyrosine kinase and p44/42 MAPK in D2-like receptor-mediated stimulation of Na+, K+-ATPase in kidney Am J Physiol Renal Physiol, April 1, 2002; 282(4): F697 - F702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Gomes and P. Soares-da-Silva Role of cAMP-PKA-PLC signaling cascade on dopamine-induced PKC-mediated inhibition of renal Na+-K+-ATPase activity Am J Physiol Renal Physiol, June 1, 2002; 282(6): F1084 - F1096. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||