Renal Dopamine Receptors in Health and Hypertension

Pharmacol. Ther. Vol. 80, No. 2, pp. 149–182, 1998Copyright © 1998 Elsevier Science Inc.

ISSN 0163-7258/98 $19.00PII S0163-7258(98)00027-8

Associate Editor: D. R. Sibley

Renal Dopamine Receptors in Health and Hypertension

Pedro A. Jose,

*

§

Gilbert M. Eisner

†

and Robin A. Felder

‡

*DEPARTMENT OF PEDIATRICS, GEORGETOWN UNIVERSITY MEDICAL CENTER, 3800 RESERVOIR ROAD, NW,WASHINGTON, DC 20007, USA

†

DEPARTMENT OF MEDICINE, GEORGETOWN UNIVERSITY MEDICAL CENTER AND WASHINGTON HOSPITAL CENTER,WASHINGTON, DC 20007, USA

‡

UNIVERSITY OF VIRGINIA HEALTH SCIENCES CENTER, CHARLOTTESVILLE, VA 22908, USA

ABSTRACT. During the past decade, it has become evident that dopamine plays an important role in theregulation of renal function and blood pressure. Dopamine exerts its actions via a class of cell-surfacereceptors coupled to G-proteins that belong to the rhodopsin family. Dopamine receptors have been classifiedinto two families based on pharmacologic and molecular cloning studies. In mammals, two D

1

-like receptorsthat have been cloned, the D

1

and D

5

receptors (known as D

1A

and D

1B

, respectively, in rodents), are linkedto stimulation of adenylyl cyclase. Three D

2

-like receptors that have been cloned (D

2

, D

3

, and D

4

) are linkedto inhibition of adenylyl cyclase and Ca

2

1

channels and stimulation of K

1

channels. All the mammaliandopamine receptors, initially cloned from the brain, have been found to be expressed outside the centralnervous system, in such sites as the adrenal gland, blood vessels, carotid body, intestines, heart, parathyroidgland, and the kidney and urinary tract. Dopamine receptor subtypes are differentially expressed along thenephron, where they regulate renal hemodynamics and electrolyte and water transport, as well as reninsecretion. The ability of renal proximal tubules to produce dopamine and the presence of receptors in thesetubules suggest that dopamine can act in an autocrine or paracrine fashion; this action becomes most evidentduring extracellular fluid volume expansion. This renal autocrine/paracrine function is lost in essentialhypertension and in some animal models of genetic hypertension; disruption of the D

1

or D

3

receptorproduces hypertension in mice. In humans with essential hypertension, renal dopamine production inresponse to sodium loading is often impaired and may contribute to the hypertension. The molecular basis forthe dopaminergic dysfunction in hypertension is not known, but may involve an abnormal post-translational

modification of the dopamine receptor.

pharmacol. ther.

80(2):149–182, 1998.

© 1998 Elsevier Science Inc.

KEY WORDS.

Dopamine, dopamine receptors, kidney,

Na

1

/H

1

exchanger,

Na

1

K

1

-ATPase, hypertension.

CONTENTS1. I

NTRODUCTION

. . . . . . . . . . . . . 1502. C

LASSIFICATION

OF

D

OPAMINE

R

ECEPTORS

. . . . . . . . . . . . . . . . 1502.1. H

ISTORICAL

PERSPECTIVE

. . . . . 1502.2. D

1

-

LIKE

RECEPTORS

. . . . . . . . 1502.3. D

2

-

LIKE

RECEPTORS

. . . . . . . . 1503. P

ERIPHERAL

D

OPAMINE

R

ECEPTORS

. . 1513.1. H

ISTORICAL

PERSPECTIVE

. . . . . 1513.2. R

ENAL

DOPAMINE

RECEPTORS

. . . 1523.2.1. V

ASCULAR

RECEPTORS

. . . 1523.2.2. G

LOMERULARRECEPTORS

. . . . . . . . . 1523.2.3. T

UBULAR

RECEPTORS

. . . 1524. R

EGULATION

OF

R

ENAL

F

UNCTION

BY

D

OPAMINE

. . . . . . . . . . . . . . . . 1534.1. R

ENAL

BLOOD

FLOW

. . . . . . . . 1534.1.1. D

1

-

LIKE

RECEPTORS

. . . . . 1534.1.2. D

2

-

LIKE

RECEPTORS

. . . . . 1544.1.3. M

EDIATORS

OFVASODILATION

. . . . . . . 1544.1.4. S

UMMARY

. . . . . . . . . . 1554.2. G

LOMERULAR

FILTRATION

. . . . . 1554.3. T

UBULAR

EFFECT

. . . . . . . . . . 1564.3.1. I

NDIRECT

EVIDENCE

. . . . 1564.3.2. D

IRECT

EVIDENCE

. . . . . 1564.3.3. S

UMMARY

. . . . . . . . . . 1605. R

ENAL

D

OPAMINE

P

RODUCTION

. . . . 1605.1. S

OURCE

OF

RENAL

DOPAMINE

. . . 160

5.2. F

ACTORS

INFLUENCING

RENAL

DOPAMINE

PRODUCTION

. . . . . . 1615.2.1. E

FFECT

OF

SODIUMCHLORIDE

. . . . . . . . . . 1615.2.2. E

FFECT

OF

OTHER

DIETARY

CONSTITUENTS

. . . . . . . 1626. P

ARACRINE

R

EGULATION

OF

R

ENAL

F

UNCTION

. . . . . . . . . . . . . . . . 1626.1. M

ETHODS

TO

STUDY

PARACRINE

REGULATION

OF

RENALFUNCTION

. . . . . . . . . . . . . . 1626.1.1. I

NHIBITION

OF

RENALDOPAMINE

PRODUCTION

. . 1626.1.2. S

TIMULATION

OF

RENAL

ENDOGENOUS

DOPAMINE

PRODUCTION

. . . . . . . . 1626.1.3. I

NHIBITION

OF

DOPAMINE

BREAKDOWN

. . . . . . . . . 1626.1.4. D

OPAMINE

RECEPTORBLOCKADE

. . . . . . . . . . 1626.1.5. M

OLECULAR

BIOLOGICAL

METHODS

. . . . . . . . . . 1626.2. N

EURAL

DOPAMINE . . . . . . . . . 1636.3. TUBULAR DOPAMINE . . . . . . . . 163

6.3.1. EFFECT OF SODIUMCHLORIDE INTAKE . . . . . . 163

7. ROLE OF DOPAMINE IN ESSENTIAL HYPERTENSION . . . . . . . . . . . . . . 1637.1. SYSTEMIC VASCULAR FUNCTION . . 1647.2. RENAL VASCULAR FUNCTION . . . 1647.3. RENAL TUBULAR FUNCTION . . . . 164§Corresponding author.

150 P. A. Jose et al.

1. INTRODUCTION

Dopamine is an endogenous neurotransmitter catechola-mine that also serves as a biochemical precursor of norepi-nephrine and epinephrine. Dopamine is well known as aneurotransmitter in the CNS. During the past decade, how-ever, dopamine has been characterized as an importantmodulator of blood pressure, sodium balance, and renal andadrenal function through an independent peripheraldopaminergic system. Because dopamine is synthesized byrenal proximal tubules and is both vasodilatory and natri-uretic, it plays an important paracrine/autocrine role in theregulation of renal function during volume expansion (Joseet al., 1992, 1996). During conditions of moderate sodiumloading (2–10% of body weight), dopamine is responsiblefor more than 50% of sodium excreted (Felder, R. A. et al.,1990b; Hansell and Fasching, 1991; Hegde et al., 1989a;Jose et al., 1986; Pelayo et al., 1983; Siragy et al., 1989).

2. CLASSIFICATION OF DOPAMINE RECEPTORS2.1. Historical Perspective

Dopamine exerts its actions via a class of cell surface recep-tors that belongs to the rhodopsin-like family of G-protein-coupled receptors; these receptors have in common seventransmembrane domains (Schwartz, 1996). The pharmaco-logical classification of dopamine receptors by Kebabianand Calne (1979) into the D1-like and the D2-like subtypeshas been borne out by molecular cloning studies (Table 1)(Bunzow et al., 1988; Chio et al., 1990; Dal Toso et al.,1989; Dearry et al., 1990; Giros et al., 1989; Grandy et al.,1991; Monsma et al., 1989, 1990; Sokoloff et al., 1990; Su-nahara et al., 1990, 1991; Tiberi et al., 1991; Van Tol et al.,1991; Zhou et al., 1990).

2.2. D1-like Receptors

In mammals, two D1-like receptors linked to stimulation ofadenylyl cyclase (AC) have been cloned, the D1 and D5 re-ceptors, which are known as D1A and D1B in rodents, re-spectively (Dearry et al., 1990; Grandy et al., 1991; Mon-sma et al., 1990; Sunahara et al., 1990, 1991; Tiberi et al.,1991; Weinshank et al., 1991; Zhou et al., 1990). D1C andD1D receptors have also been described in nonmammalianspecies (Demchyshyn et al., 1995; Lamers et al., 1996; Suga-mori et al., 1994) (Table 1).

There is evidence for the existence of an as yet unclonedD1-like receptor that is linked to phospholipase C (PLC),specifically PLCb, through a pertussis toxin insensitiveG-protein, Gq (Felder, C. C. et al., 1989a,b,c; Hussain andLokhandwala, 1997; Mahan et al., 1990; Undie and Fried-man, 1990; Undie et al., 1994; Wang et al., 1995; Yu et al.,1995). It is distinct from the D5 receptor because this recep-tor has not been reported to be linked with PLC (Jaber etal., 1996; Sokoloff and Schwartz, 1995). Although the D1

receptor has been shown to be linked to PLC in some celllines (e.g., LTK2), the linkage is with PLCg and not withPLCb (Liu et al., 1992; Yu et al., 1995, 1996b). The D1-likereceptor linked to PLCb is distinct from the cloned D1 re-ceptor because an antibody directed against the D1 receptorco-precipitates with GSa, but not with Gq (Wang et al.,1995). Indeed, in mice without functional D1A receptors,D1-like agonists increase PLC activity even though AC nolonger could be stimulated (Friedman et al., 1997). The re-lation of this putative dopamine receptor to a D1-like re-ceptor cloned from Drosophila melanogaster remains to bedetermined (Reale et al., 1997). This D1-like receptor,DopR99B, has been shown to couple to a pertussis toxin-insensitive G-protein and to increase intracellular calcium.Drugs that distinguish D1-like from D2-like receptors havebeen developed, but there are currently no D1 subtype-selective drugs (Table 1).

2.3. D2-like Receptors

Three D2-like receptors that have been cloned (D2, D3, andD4) are linked to inhibition of AC (Bunzow et al., 1988;Chio et al., 1990; Dal Toso et al., 1989; Giros et al., 1989;Jaber et al., 1996; Monsma et al., 1989; Robinson and Ca-ron, 1997; Sibley and Monsma, 1992; Sokoloff et al., 1990;Van Tol et al., 1991) and inhibition of Ca21 channels(Jaber et al., 1996; Mei et al., 1996; Brown and Seabrook,1995; Seabrook et al., 1994; Wilke et al., 1998b). All theD2-like receptors have been shown to stimulate K1 chan-nels (Jaber et al., 1996; Werner et al., 1996; Sibley andMonsma, 1992), although these receptors have also beenreported to inhibit potassium currents (Liu et al., 1996;Wilke et al., 1998a). Several group-selective drugs can dis-tinguish D2-like from D1-like receptors. More recently,drugs that can distinguish among the D2-like receptors havebeen developed (Table 1).

ABBREVIATIONS. AADC, aromatic amino acid decarboxylase; AC, adenylyl cyclase; cAMP, cyclic AMP;AT1, angiotensin II Type 1; CCD, cortical collecting duct; COMT, catechol-O-methyl transferase; DARPP-32,dopamine- and cAMP-regulated phosphoprotein-32; GRK, G-protein-related kinase; l-DOPA, levodopa;mTAL, medullary thick ascending limb of Henle; NHE, Na1/H1 exchanger; PCT, proximal convoluted tubule;PKA, protein kinase A; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; PST, proximalstraight tubule; SHR, spontaneously hypertensive rat; WKY, Wistar-Kyoto.

7.3.1. RENAL DOPAMINESYNTHESIS . . . . . . . . . . 164

7.3.2. SODIUM TRANSPORTERS . . 1647.3.3. D1 RECEPTOR . . . . . . . . 165

7.3.4. D3 RECEPTOR . . . . . . . . 1678. CONCLUSIONS . . . . . . . . . . . . . . 167REFERENCES . . . . . . . . . . . . . . . . . 168

Renal Dopamine Receptors 151

3. PERIPHERAL DOPAMINE RECEPTORS3.1. Historical Perspective

As in the CNS, the actions of dopamine and dopamine ag-onists outside the CNS cannot be explained by a singledopamine receptor (Goldberg et al., 1979). To contrast re-ceptor subtype classification by physiological criteria withthe classification using biochemical and radioligand bind-ing data, Goldberg et al. (1986) classified peripheraldopamine receptors into the DA1 and DA2 subtypes. Therewas initial justification for mimicking the classificationscheme of dopamine receptors in the CNS because boththe D1-like and DA1 receptors and the D2-like and DA2 re-ceptors share common pharmacological properties (e.g., ag-

onists and antagonists, linkage to cyclic AMP [cAMP]).However, there was also justification for distinguishingdopamine receptors in the CNS from those outside theCNS because the affinity of the D1-like (DA1) receptor inthe kidney to D1-like ligands is lower than in the brain(Nakajima and Kuruma, 1980; Felder et al., 1984a,b; Felderand Jose, 1988; Sidhu et al., 1990; Zdilar and Lackovic,1989). Subsequently, all the mammalian dopamine recep-tors, initially cloned from the brain, have been found to beexpressed outside the CNS in such sites as the adrenalgland, blood vessels, carotid body, kidney and urinary tract,heart, intestines, and parathyroid gland (Aherne et al.,1997; Felder, R. A. et al., 1993; Gauda et al., 1996; Gre-

TABLE 1. Classification of Dopamine Receptors

Pharmacological class D1-like group D2-like group

Molecular biological class D11 D5

2 D2 D3 D4

Amino acidsHuman 446 477 443 400 387Rat 446 475 444 446 387

Effector Gs1AC/PLC

Gs1AC

Gi/Go2AC

1/2K1 channel2Ca21 channel

Gi/Go2AC

1K1 channel3

2Ca21 channel

Gi/Go2AC

1/2K1 channel2Ca21 channel

Group selective agonists SKF 383934,5,6,7

Fenoldopam4,5,6,7Bromocriptine5,6,7,8,9,10

Apomorphine5,6,7,8,11

Group selective antagonists SCH 233904,5,6,7 YM-091518,12

Subtype selective agonists None None U91356A11 PD12890710,13

Quineralone10,14

Pramipexole16

(1)-N-propyl-norapomorphine15

PD16807717

Subtype selective antagonists None None L741,62618 Nafadotride10,19

U-99,194A21

(1)-AJ7623

U-10195820

L-745,87922

NGD-9424

RBI-25725

Mesoridazine26

1Also know as D1A in rodents.2Also known as D1B in rodents.3Not established.4Selective for D1-like group, but cannot distinguish D1 from D5.5Seeman and Van Tol (1994).6Gingrich and Caron (1993)7Jaber et al. (1996).8Selective for D2-like group, but cannot distinguish subtypes.9100-fold less affinity to D4.10Sokoloff and Schwartz (1995).11Piercey et al. (1996b).12Tang et al. (1994a).13Pugsley et al. (1995).14Accili et al. (1996).15Lahti et al. (1996).16Piercey et al. (1996a).17Glase et al. (1997)18Bowery et al. (1996).19Sautel et al. (1995).20Schlachter et al. (1997).21Kling-Petersen et al. (1995).22Kulagowski et al. (1996).23Waters et al. (1993).24Tallman (1998).25Kula et al. (1997)26Roth et al. (1995).1, stimulatory; 2, inhibitory. Modified from Jose and Felder (1996).


nader et al., 1995; Marmon et al., 1993; Matsumoto et al.,1995; Mezey et al., 1996; Nash et al., 1993; Niznik et al.,1989; O’Connell et al., 1995; O’Malley et al., 1992; Ozonoet al., 1996, 1997; Pupilli et al., 1994; Sanada et al.,1997a,b; Sokoloff et al., 1990; Yamaguchi et al., 1993, 1997;Yao et al., 1995, 1997). Although the reason for the differ-ence in ligand affinities between the brain and the kidneyremains to be determined, there appears to be no differencein the coding sequence between central and peripheraldopamine receptors. Furthermore, no novel “peripheral”dopamine receptors have been cloned thus far. However,there is differential regulation of the D1 receptor in neuraltissues and the kidney. Although a short and a long isoformof D1 receptor mRNA is present in neural tissue, only theshort variant is expressed in renal tissue. Lee et al. (1997)suggest that the differential expression of the short and longD1 transcripts is due, in part, to tissue-specific expression ofan activator protein driving transcription from a promoterat nucleotide positions 21154 and 21136. The D2-likedopamine receptor subtypes have several isoforms; how-ever, there is no evidence that a particular isoform is specif-ically expressed in peripheral tissues (Chio et al., 1990; DalToso et al., 1989; Giros et al., 1989, 1991; Monsma et al.,1989; Seeman and Van Tol, 1994; Van Tol et al., 1992).

3.2. Renal Dopamine Receptors

Renal dopamine receptor subtypes have been studied exten-sively in the rat kidney. Radioligand binding and autorad-iography studies have demonstrated the presence of D1-likeand D2-like receptors in renal vessels and renal cortex,whereas only D2-like receptors are noted in glomeruli andrenal medulla (Amenta, 1990, 1997; Felder, C. C. et al.,1989c; Felder and Jose, 1988; Felder, R. A. et al., 1984a,b;Hegde et al., 1989b; Huo and Healy, 1989; Huo et al., 1991;Missale et al., 1988; Nakajima and Kuruma, 1980; Take-moto et al., 1991).

3.2.1. Vascular receptors. Autoradiography studies in bloodvessels have demonstrated that D1-like receptors are lo-cated mainly in the tunica media, whereas D2-like receptorsare located mainly in the intima and adventitia (Amenta,1990). D1-like receptor density is greatest in the renal ar-tery among arterial beds expressing dopamine receptors(e.g., mesenteric, pulmonary, femoral) (Jin et al., 1995). Inrenal microvessels, the D1B receptor mRNA is 2–3 timesgreater than is the D1A receptor mRNA (Yao et al., 1995).In agreement with the autoradiography studies, immuno-histochemistry studies in rat kidney show that the D1A re-ceptor in renal blood vessels is in the tunica media (O’Con-nell et al., 1995); the D3 receptor is also expressed in thetunica media, as well as the adventitia (O’Connell et al.,1998b). In the human kidney, the D5, but not the D1, recep-tor is expressed in small renal vessels (Ozono et al., 1997;unpublished studies). These studies suggest that the D1A re-ceptor is mainly post- or extrasynaptic, the D3 receptor islocated at both presynaptic and post- or extrasynaptic sites,

and the D2 receptor may be mainly at presynaptic sites(Barili et al., 1997b). Indeed, destruction of renal nerveswith 6-hydroxydopamine does not affect the binding of D1

ligands; the failure of sympathetic denervation to affect “D3

receptor” binding may be related to the low sensitivity ofthe autoradiographic method to detect small differences(Amenta, 1990). Radioligand binding studies also suggest theexpression of D4 receptors in renal arterioles (Amenta, 1997).

Immunohistochemistry has revealed the presence of D1A

(O’Connell et al., 1995), but not D3 receptors in juxtaglom-erular cells of the rat kidney (O’Connell et al., 1998b). Inagreement with the immunohistochemistry studies of kid-ney slices, rat juxtaglomerular cells in culture also express theD1A receptor (Yamaguchi et al., 1997). D1B receptor mRNAwas not detected, but D3 and D4 receptor mRNA were alsonoted in rat juxtaglomerular cells in primary culture (San-ada et al., 1997b; Yamaguchi et al., 1997). The discrepancybetween the studies of the kidney and the studies in juxta-glomerular cells in culture suggests that the expression ofthese receptors is conditional (e.g., culture dependent).

3.2.2. Glomerular receptors. Glomeruli mainly expressD2-like receptors, specifically the D2Long and D3 receptorsubtypes (Amenta, 1997; Felder, R. A. et al., 1984b; Gao,D.-Q. et al., 1994). There is no expression of D1, D1A, D1B,and D5 receptors in rat or human glomeruli (O’Connell etal., 1995; Ozono et al., 1997; unpublished studies). However,rat glomeruli express D1-like receptors after culture, but thesubtype has not been determined (Barnett et al., 1986; Bry-son et al., 1992; Shulz et al., 1987). The predominant D2-like receptor is probably the D3 subtype (Amenta, 1997;O’Connell et al., 1998b); they are expressed in podocytes,but not in mesangial cells (O’Connell et al., 1998b).

3.2.3. Tubular receptors. Nephron segments expressingD1-like receptors include the proximal convoluted tubule(PCT), proximal straight tubule (PST) (Felder, R. A., etal., 1984a,b, 1988a, 1993; Kinoshita et al., 1989, 1990),medullary thick ascending limb of Henle (mTAL) (Take-moto et al., 1991), macula densa (Ricci et al., 1993; Amentaand Ricci, 1990), and cortical collecting duct (CCD)(Takemoto et al., 1991; Ohbu and Felder, 1991). D2-like re-ceptors are expressed mainly in the proximal tubule andmedullary collecting ducts (Amenta, 1990; Barili et al.,1997a; Felder, C. C. et al., 1989c; Huo and Healy, 1989).Except for the D3 receptor (Sokoloff et al., 1990), the lowexpression of the dopamine receptors in the kidney has pre-cluded the detection of their mRNA by Northern blot.

3.2.3.1. Proximal tubule. Relative to the other nephronsegments, the expression of D1-like receptors (determinedby radioligand binding) is greatest in the PCT (Felder, R. A.,et al., 1984a; Kinoshita et al., 1990; Ohbu and Felder, 1991;Takemoto et al., 1991), but D1 receptor density in thisnephron segment is only about 25% of that noted in thebrain striatum (Yamaguchi et al., 1995). Both D1A and D1B

receptors are expressed in renal proximal tubules (Yao et al.,


1997). In agreement with the radioligand binding studies inthe rat, the D1A and D1B receptor mRNA and protein areexpressed to a greater extent in renal PCT than in CCD(Yao et al., 1997). D1-like receptors are present in luminal(brush border) and basolateral membranes (Felder, C. C. etal., 1989c). In the rat proximal tubule, more D1A receptormRNA and protein are present in luminal than in basolat-eral membranes (O’Connell et al., 1995, 1998a). The rat,opossum, and human kidney express more D1A or D1 thanD1B or D5 receptors (Nash et al., 1993; Sanada et al., 1997a;Yao et al., 1997), the converse of the profile in the renalvasculature (Yao et al., 1995); in the opossum kidney cellline, the D1B receptor is no longer expressed (Nash et al.,1993). A pig renal proximal tubule cell line, LLC-PK1, alsoexpresses a receptor that is homologous to the rat D1A re-ceptor (Grenader et al., 1995).

D2-like receptors are also expressed in renal proximal tu-bules at the luminal and basolateral membranes (Felder,C. C. et al., 1989c). Although the mRNAs for both D2Long

and D3 receptors have been shown in the rat cortex(Sokoloff et al., 1990; Gao, D.-Q. et al., 1994), only the D3

receptor protein has been detected in rat proximal tubules(O’Connell et al., 1998b). As with the D1A receptor, thereis expression of the D3 receptor at the luminal membrane;unlike the D1A receptor, however, the D3 receptor is not ex-pressed in the basolateral membrane, at least in the rat(O’Connell et al., 1998b).

3.2.3.2. Loop of Henle. D1-like receptors have been dem-onstrated in the mTAL by radioligand binding and autora-diography (Takemoto et al., 1991; Ricci et al., 1993). Therat and human mTAL express the D1B (or D5), but not theD1A (or D1), receptor (Ozono et al., 1997; Yamaguchi et al.,1997; unpublished studies). There are probably no func-tional dopamine receptors in the cortical thick ascendinglimb of Henle (Felder, R. A. et al., 1984a).

3.2.3.3. Distal convoluted tubule. Radioligand binding stud-ies have not detected D1-like receptors in the rat distal con-voluted tubule (Kinoshita et al., 1990). However, autora-diographic studies have demonstrated D1-like receptors inthe rat distal tubule (Ricci et al., 1993). D1A (O’Connell etal., 1995) and D3 receptors (O’Connell et al., 1998b) alsohave been detected in rat distal tubules, including the mac-ula densa, by immunostaining; the D1 receptor is alsopresent in human distal tubules (Ozono et al., 1997).

3.2.3.4. Cortical collecting duct. D1-like receptor density ismuch lower in the CCD than in the PCT, but probablygreater than in the mTAL (Felder, R. A. et al., 1984a;Ohbu and Felder, 1991; Takemoto et al., 1991). Quantita-tive reverse transcriptase/polymerase chain reaction andWestern blotting studies confirmed that the expression ofthe D1-like receptors is about 10-fold less in the CCD thanin the PCT. Unlike the pattern in the PCT, in the CCDthe D1B receptor is expressed to a similar extent as the D1A

receptor (Yao et al., 1997). The rat CCD also expresses the

D3 (O’Connell et al., 1998b) and D4 receptors (Sun et al.,1997).

3.2.3.5. Medullary collecting duct and papilla. The inner me-dulla expresses two D2-like receptors, the D2Long and D3 re-ceptors (Gao, D-Q. et al., 1994). However, the D3 receptorprotein is not present in the medulla (O’Connell et al.,1998b). The inner medullary collecting duct also expressesa D2-like receptor linked to prostaglandin E (Huo et al.,1991; Huo and Healy, 1991). The medullary collectingducts in rats do not express D1-like receptors; however,both the D1 (Ozono et al., 1997) and D5 receptors (unpub-lished studies) are expressed in medullary collecting ductsof human kidneys. The function of these receptors in themedulla remains to be established (Maeda et al., 1992).

The presence of dopamine receptor subtypes in the kid-ney studied by radioligand binding has been described notonly in rodents, but also in sheep (Felder, R. A. et al.,1988b), dogs (Felder, C. C. et al., 1989c), guinea pigs (Mar-cou et al., 1982), and humans (Ricci et al., 1993). The auto-radiographic distribution of dopamine receptors in the hu-man kidney is similar to that reported in the rat kidney,except that the human kidney has D1-like receptors in dis-tal tubules, but not in CCD (Ricci et al., 1993). Immuno-histochemistry and Western blotting studies have alsoshown the presence of D1, D5, and D3 receptors in proximaland distal tubules of the human kidney (Ozono et al., 1997;Sanada et al., 1997a; unpublished studies). However, incontrast with the rat kidney, in the human kidney, the D5,but not the D1, receptor is expressed in small blood vesselsand juxtaglomerular cells (O’Connell et al., 1995, 1998a;Ozono et al., 1997; unpublished studies).

4. REGULATION OF RENAL FUNCTION BY DOPAMINE4.1. Renal Blood Flow4.1.1. D1-like receptors. Dopamine, given systemically orinto the renal artery at low doses, increases renal blood flowand decreases renal vascular resistance (Goldberg, 1972;Felder, R. A. et al., 1989). As with most vasodilators, theincrease in renal blood flow occurs to the greatest extent inthe inner cortex and medulla (Heyman et al., 1995;Neiberger and Passmore, 1979). The dopamine-mediatedrenal vasodilation is effected at postsynaptic receptors, be-cause it occurs even when a- and b-adrenergic receptorsare blocked (Frederickson et al., 1985). Under these condi-tions, the renal vasodilatory effect of dopamine is exerted atD1-like receptors because it is blocked by the D1-like antag-onist SCH 23390 (Frederickson et al., 1985). Moreover, therenal vasodilatory effect is mimicked by D1-like agonists(Hahn and Wardell, 1980; Hegde et al., 1989b; Jose et al.,1987; Lang and Woodman, 1982; Stote et al., 1983; Yatsu etal., 1997a,b). Dopamine and D1 agonists dilate afferent andefferent arterioles to the same degree (Edwards, 1985, 1986;Takenaka et al., 1993). However, in some disease stateswith decreased renal blood flow, dopamine may preferen-tially dilate afferent arterioles (Steinhausen et al., 1986; ter


Wee and Donker, 1994). In agreement with the receptordensity data (Jin et al., 1995), dopamine vasodilates thekidney more than the mesenteric or coronary artery (Seri etal., 1987; Lang and Woodman, 1982).

4.1.2. D2-like receptors. In the CNS, both D2 and D3 re-ceptors can function as autoreceptors (Tepper et al., 1997;Gobert et al., 1995; Tang et al., 1994b). In the kidney, pre-synaptic D2-like receptors have been shown to inhibit nore-pinephrine release (Rump et al., 1992, 1993; Lokhandwalaand Steenberg, 1984). Dopamine can vasodilate the renalvasculature via presynaptic D2-like receptors (Dupont et al.,1986; Goldberg et al., 1979, 1986; Rump et al., 1993; Seri etal., 1987; Szabo et al., 1992). This effect is mainly evidentwhen renal nerve activity is increased (Bass and Robie, 1984;Lokhandwala et al., 1979), a situation that is seen duringanesthesia and sodium-depleted states. Action at presynap-tic D2-like receptors to inhibit norepinephrine release mayexplain the ability of bromocriptine, a D2-like agonist, toincrease renal blood flow and glomerular filtration rate inthe anesthetized rat (Stier et al., 1982; Seri and Aperia,1988; Seri et al., 1987). A similar mechanism may explainthe renal vasodilatory effect of endogenous dopamine inhumans on a low-sodium diet (Bughi et al., 1994).

The effect of postsynaptic D2 receptors on the renal vas-culature is still controversial. In the dog kidney, when botha- and b-adrenergic receptors are blocked, the renal va-sodilatory effect of dopamine is antagonized by a D1-likeantagonist (SCH 23390), but not by a D2-like antagonist(domperidone) (Frederickson et al., 1985). In a similar prep-aration, Horn and Kohli (1991) reported that bromocrip-tine, a D2-like agonist with some selectivity for the D2 andD3 receptors over the D4 receptor (Seeman and Van Tol,1994; Seeman, 1993; Sokoloff and Schwartz, 1995; Ging-rich and Caron; 1993), but also with D1-like antagonisticproperties (Kebabian and Calne, 1979; Hess and Creese,1987), decreases renal blood flow. Because the effect wasnot influenced by a-adrenergic blockade, vasoconstrictoraction at a postsynaptic D2-like receptor is possible (Hornand Kohli, 1991; Lang and Woodman, 1982). Of interest isthe fact that in another maximally dilated kidney prepara-tion such as that seen in the conscious, chronically instru-mented dog on a moderate sodium intake (40 mmol/day),low concentrations of quinpirole (picomolar), a D2-like ag-onist with some selectivity for the D3 and D4 receptors overthe D2 receptor (Freedman et al., 1994; Gingrich and Caron,1993; MacKenzie et al., 1994; Patel et al., 1996; Seabrook etal., 1992; Seeman, 1993; Sokoloff and Schwartz, 1995),also produces vasoconstriction (Siragy et al., 1992). The ef-fect was exerted at a D2-like receptor because it is blockedby low concentrations (picomolar) of the D2-like antago-nist YM-09151 (Siragy et al., 1992).

In apparent contrast, in the preconstricted isolated per-fused rat kidney, bromocriptine has been shown to inducevasodilation via postsynaptic D2-like receptors (Barthelmebset al., 1991; Schmidt and Imbs, 1979; Woodman et al.,1980). This renal vasodilatory effect of D2-like receptors in

the rat is similar to the renal vasodilatory effect of quin-pirole in the dog kidney treated with a- and b-adrenergicblockers (Horn and Kohli, 1991; Felder, R. A. et al.,1988a). It is not surprising that D2-like receptors may havesome vasodilatory effects at postsynaptic receptors becauseD2-like receptors can block Ca21 channels and open K1

channels (see Table 1) (Jaber et al., 1996; Liu et al., 1996;McGroarty and Greenfield, 1997; Sibley and Monsma,1992; Surmeier and Kitai, 1993; Werner et al., 1996). Ca21-channel blockers and K1-channel agonists are powerful va-sodilators (Brayden, 1997; Bühler, 1995; Lenz and Wagner,1995; Scholz, 1997). However, the effect of quinpirole maynot have been mediated by D2-like receptors because highconcentrations of the agonist were used (.10-8 M) and theeffect could not be blocked consistently by D2-like antago-nists (YM-09151, domperidone, [2]-sulpiride), but wasblocked by histamine antagonists (Horn and Kohli, 1991;Felder, R. A. et al., 1988a). These studies need to be re-evaluated, because domperidone and (2)-sulpiride have agreater affinity for the D2 and D3 receptor than for the D4

receptor (Freedman et al., 1994; Gingrich and Caron, 1993;Patel et al., 1996; Seeman, 1993; Seeman and Van Tol,1994; Sokoloff et al., 1992), and the D3 and D4 receptorsmay be preferentially expressed over the D2 receptor in re-nal arterioles (Amenta, 1997; O’Connell et al., 1998b;Sanada et al., 1997b). Although YM-09151 has a similar af-finity for the D2, D3, and D4 receptors, it has a high affinityfor nondopaminergic receptors (Tang et al., 1994a; See-man, 1993), and the high concentrations used by Horn andKohli (1991) may have obfuscated the results. In addition,to properly interpret the experiment, the sodium intake ofthe study subjects should be known, because the renal va-sodilatory effect of D2-like receptors in humans is reducedduring sodium loading and increased during sodium restric-tion (Bughi et al., 1994). In contrast, the renal vasodilatoryeffect of D1-like receptors is not affected by sodium loading(Ragsdale et al., 1990). Nevertheless, the aforementionedstudies suggest that when renal vascular resistance is high(e.g., sodium restriction), a D2-like receptor blockade ofcalcium influx and stimulation of potassium efflux could re-sult in renal vasodilation. We have reported that dopaminestimulates K1 channels in the mTAL and Ca21-channelblockers inhibit Na1/K1-ATPase activity in renal proximaltubules (Aoki et al., 1996; Eisner et al., 1997). However, itremains to be determined whether dopamine receptors canregulate K1 and Ca21 channels in vascular smooth muscles.

4.1.3. Mediators of vasodilation. The vasodilator effectof dopamine via D1-like receptors is mediated mainly bycAMP/protein kinase A (PKA) (Alkadhi et al., 1986;Chatziantoniou et al., 1995; Gao, Y. J. et al., 1995; Hegdeand Lokhandwala, 1988; Missale et al., 1988; Murthy et al.,1976; Tamaki et al., 1989). Prostacyclins may also contrib-ute to dopamine- and D1-mediated renal vasodilation (Ma-noogian et al., 1988; Minuz et al., 1989). In cultured renalvascular smooth muscles, a dopamine-mediated stimulation


of protein kinase C (PKC) is associated with up-regulationof D1-like receptors, which results in an enhancement incAMP production (Yasunari et al., 1993).

A complicated effect of D1-like receptors has been de-scribed in nonrenal vessels (rat tail artery and aorticsmooth muscles). Borin (1997) has reported that in rataorta smooth muscle cells, dopamine decreases both sodiuminflux and efflux by inhibition of Na1/H1 exchanger(NHE) and Na1/K1-ATPase activity, respectively, in partvia PKA. This dual inhibition of sodium influx and effluxmay or may not result in a change in intracellular sodium.A predominant inhibitory effect on NHE activity would re-sult in a decrease in intracellular sodium and a decrease invessel tone, whereas a predominant inhibitory effect onNa1/K1-ATPase activity would result in an increase in in-tracellular sodium and an increase in vascular tone (Borin,1997). The latter situation may explain the apparent vaso-constrictor action of a D1-like agonist in the rat tail artery(Rashed and Songu-Mize, 1995, 1996). In these studies,dopamine and SKF 38393, a D1-like agonist, inhibited Na1/K1-ATPase and increased vascular tone, an effect that wasassociated with activation of PLC (Rashed and Songu-Mize, 1995, 1996). Because the effects were abolished bypertussis toxin, the receptor involved is different from thePLC that is stimulated by D1-like agonists in renal proximaltubules. This form of PLC is pertussis-toxin resistant andlinked to Gq (Felder, C. C. et al., 1989b; Hussain and Lok-handwala, 1997). When PLCb1 is not expressed, D1-agonistscan be indirectly linked to PLCg1 via PKA (Yu et al., 1995,1996b). It is possible that the effect of dopamine on resis-tance vessels may not be the same as that in conduit vessels(e.g., aorta) and in the rat tail artery, which may subserve athermoregulatory function.

4.1.4. Summary. In the renal vasculature, D1-like recep-tors are linked to vasodilation. The effect of D2-like recep-tors on the renal vasculature is probably dependent on thestate of renal nerve activity. Stimulation of postsynapticD2-like receptors (D3 and/or D4 subtypes) can result in ei-ther vasodilation or vasoconstriction. With chronic sodiumchloride loading, basal reactivity of renal vessels may be en-hanced by increased levels of endogenous Na1/K1-ATPaseinhibitor and increased intracellular sodium (Yuan et al.,1992). Under these conditions, dopamine can further in-crease intracellular sodium by stimulating NHE activity viaD2-like receptors (Felder, C. C. et al., 1993; Neve et al.,1992). The increase in intracellular sodium increases vascu-lar reactivity and thus, dopamine via D2-like receptors canthen elicit vasoconstriction. When renal nerve activity isincreased, as seen in renal nerve stimulation, low-sodiumdiet, hypovolemia, or during anesthesia, the vasodilator ef-fect of dopamine occurs via presynaptic D2-like receptors,presumably of the D3 subtype. In addition, when the renalvascular resistance is increased, the D2-like effect at postsyn-aptic sites is that of vasodilation, because D2-like receptorsinhibit Ca21 channels and stimulate K1 channels. Both of

these reactions can lead to vasorelaxation. Under theseconditions, a synergistic effect between D1- and D2-like re-ceptors may become evident (Hahn and Wardell, 1980;Seri et al., 1987; Seri and Aperia, 1988). The effect ofdopamine on vascular tone may differ between conduit(e.g., aorta) and resistance (e.g., mesenteric and renal arte-riole) vessels. The increase in vascular tone produced byD1-like agonists in conduit vessels may serve to increaseperfusion in downstream vessels dilated by D1-like receptors.

4.2. Glomerular Filtration

The dopamine-induced increase in renal blood flow is notconsistently associated with an increase in glomerular fil-tration rate. This inconsistent action may be due in partto failure of transglomerular pressure to increase as a conse-quence of equal vasodilation of afferent and efferent arteri-oles (Edwards, 1985, 1986). However, dopamine can ame-liorate the reduction in glomerular filtration rate caused byamphotericin B (Reiner and Thompson, 1979) and in hy-povolemic states (ter Wee and Donker, 1994). This actioncould be a direct effect on glomerular cells, because dopa-mine has been shown to attenuate the contractile responseto angiotensin II in isolated glomeruli (Barnett et al., 1986).The mechanism by which dopamine exerts its direct effecton glomerular filtration rate is not clear. An increase inglomerular cAMP is unlikely because D2-like, but not D1-like, receptors are expressed in glomeruli (Amenta, 1997;Felder, R. A. et al., 1984b; O’Connell et al., 1995, 1998b).Only after culture do glomeruli express D1-like receptors(Barnett et al., 1986; Shulz et al., 1987). In isolated glomer-uli, dopamine decreases AC activity, in keeping with thepresence of D2-like receptors (Felder, R. A. et al., 1984b). Ifthe isolated glomeruli are not contaminated with arterioles,the ability of dopamine to attenuate the vasoconstrictor ef-fect of angiotensin II in vitro may be due to the ability ofD2-like receptors to inhibit Ca21 channels; angiotensin IIproduces mesangial contraction, in part, by increasing in-tracellular calcium (Jensen et al., 1997). In vivo, D2-like re-ceptors can decrease or increase glomerular filtration rate,depending upon the state of renal vascular D2-like receptoractivation (see Section 4.1.2). When the interaction of D1-and D2-like receptors results in a greater vasodilatory effecton afferent than efferent arterioles, glomerular filtrationrate can increase (Seri and Aperia, 1988). D2-like receptorsare thought to be involved in the increase in glomerular fil-tration rate associated with amino acid infusion (Mendezet al., 1991; Mühlbauer et al., 1994, 1997b). This actionapparently is mediated by renal nerves because it is abol-ished by renal denervation (Mühlbauer et al., 1997b).Baines and Drangova (1986) previously have reported thatneural dopamine regulates glomerular filtration rate. WhenD2-like receptors decrease renal blood flow, there is greaterafferent than efferent constriction, a result producing agreater decrease in glomerular filtration rate than renalblood flow and a fall in filtration fraction (Siragy et al.,1990, 1992).


4.3. Tubular Effect4.3.1. Indirect evidence. The renal vasodilation inducedby dopamine and D1-like agonists is associated with an in-crease in urine flow, sodium, phosphate, calcium, and mag-nesium excretion, with variable effects on potassium excretion(Albrecht et al., 1996; Bhat et al., 1986; Cadnapaphornchai etal., 1977; Cuche et al., 1976; Felder, R. A. et al., 1989,1990b; Girbes et al., 1990; Goldberg, 1972; Lee, 1982; Massryand Kleeman, 1972; McDonald et al., 1964; McGrath et al.,1985; Olsen et al., 1990; Pendleton et al., 1978; Stote et al.,1983; Yatsu et al., 1997b). However, the natriuretic and di-uretic effects of dopamine and D1-like agonists can only bepartially explained by renal vasodilation; the natriuresisand diuresis can be dissociated from changes in renal bloodflow (Albrecht et al., 1996; Hegde et al., 1989b; Hughes etal., 1986). Moreover, when the renal vasodilation withfenoldopam, a D1-like agonist, is abrogated, natriuresis anddiuresis persist, albeit at a reduced level (Jose et al., 1987).

The phosphaturic effect of dopamine and fenoldopamsuggests action at the proximal tubule. However, the natri-uretic effect is much greater than its phosphaturic, calci-uretic, or kaliuretic action, a finding suggesting that inhibi-tion of sodium transport occurs in nephron segmentsbeyond the proximal tubule. Indeed, the natriuresis follow-ing fenoldopam administration has been shown to becaused by inhibition of both proximal and distal sodium re-absorption (Hughes et al., 1986; Ragsdale et al., 1990;Blumberg et al., 1988). The natriuretic effect of dopamineand fenoldopam is influenced by sodium balance, in con-trast to the neutral effect of sodium balance on dopamine-mediated renal vasodilation. For example, the natriureticeffect of dopamine or fenoldopam is evident in euvolemicand in volume-expanded states, but not in sodium-depletedstates (Agnoli et al., 1987; Ragsdale et al., 1990); in this sit-uation, dopamine actually decreases sodium excretion (Ag-noli et al., 1987). The ability of dopamine to increase ionand water excretion is generally mimicked by D1-like ago-nists (e.g., fenoldopam, SKF 38393, YM435) and blockedby D1-antagonists (e.g., SCH 23390, cis-flupenthixol). Thisresult suggests action at D1-like receptors (Girbes et al.,1990; Felder, R. A. et al., 1990b; Frederickson et al., 1985;Hegde et al., 1989b; Hughes et al., 1986; Jose et al., 1987;Pelayo et al., 1983; Ragsdale et al., 1990; Stote et al., 1983).

The effect of renal D2-like receptors on ion and watertransport remains unsettled. Bromocriptine, a D2-like ago-nist with D1-like antagonistic properties (Kebabian andCalne, 1979; Hess and Creese, 1987), has no effect on so-dium excretion, but increases renal blood flow in anesthe-tized rats (Stier et al., 1982). In conscious, chronically in-strumented dogs on a sodium intake of 40 mmol/day,quinpirole, a D2-like agonist, decreases sodium excretion asa consequence of both a decrease in renal blood flow and anincrease in tubular sodium reabsorption (Siragy et al.,1992). The effect of D2 antagonists on renal function iseven more controversial. It ranges from no effect (Freder-ickson et al., 1985) to an attenuation of sodium excretion(Bennett et al., 1982; Coruzzi et al., 1986), and even an in-

crease in sodium excretion (Siragy et al., 1990). The appar-ent discrepancies between these two studies may be relatednot only to the effect of volume expansion (Bughi et al.,1994), but also to the D2-like receptor expressed in the kid-ney. For example, in hypovolemic or euvolemic stateswhere vasopressin levels are elevated, the ability of D2-likeagonists to inhibit the effects of vasopressin (Muto et al.,1985; Sun and Schafer, 1996) may obscure the stimulatoryeffect of D2-like receptors on water and ion transport inmore proximal parts of the nephron. The predominantD2-like receptors expressed in glomeruli, renal arterioles,and tubules may be the D3 subtype, whereas the D4 subtypemay also be expressed in the renal vasculature and theCCD (Amenta, 1997; O’Connell et al., 1998b; Sanada etal., 1997b; Sun and Schafer, 1996; Sun et al., 1997). Theaffinity of bromocriptine to D2-like receptor subtypes has arank order potency of D2 . D3 . D4 (Freedman et al., 1994;Gingrich and Caron, 1993; Seeman, 1993; Seeman andVan Tol, 1994; Sokoloff and Schwartz, 1995), whereasquinpirole has a greater affinity for the D3 and D4 receptors(D3 . D4) than for the D2 receptor (Freedman et al., 1994;Gingrich and Caron, 1993; MacKenzie et al., 1994; Patel etal., 1996; Seabrook et al., 1992; Seeman, 1993; Sokoloff andSchwartz, 1995). Domperidone also has a greater affinity forthe D2 and D3 receptors than for the D4 receptor (Freedmanet al., 1994; Patel et al., 1996; Gingrich and Caron, 1993;Seeman, 1993; Seeman and Van Tol, 1994; Sokoloff et al.,1992). It would be expected that a ligand with a greater af-finity for the D3 and D4 receptors would have a greater ef-fect on sodium transport than would a ligand with a greateraffinity for the D2 and D3 receptors. These speculations nowcan be confirmed with the availability of D2-like selectiveligands (Table 1). Unlike the important role of renal nerveson dopamine-induced changes in glomerular filtration rate,renal nerves have minimal effect on dopamine-mediatedtubular sodium transport (Asico et al., 1998; Wang et al.,1997).

4.3.2. Direct evidence4.3.2.1. Proximal tubule. Dopamine and dopamine agonistshave been shown to inhibit sodium and phosphate trans-port in the isolated perfused rabbit PST, but not PCT(Bello-Reuss et al., 1982; Kaneda and Bello-Reuss, 1983).However, in the rat, dopamine decreases fluid and sodiumtransport in PCT following microperfusion of peritubularcapillaries in vivo and in microdissected PCT studied in vitro(Aperia et al., 1987; Chan et al., 1986; Slobodyansky et al.,1995). Dopamine has also been shown to inhibit organicacid secretion in renal proximal tubules of the flounder(Halpin and Renfro, 1996) and sodium, hydrogen, and cal-cium transport in the proximal tubule of the bullfrog (Hagi-wara et al., 1990).

4.3.2.1.1. Na1/H1 exchanger. The inhibitory effects ofdopamine on ion transport are exerted at the luminal (brushborder) and basolateral membrane. For example, dopamine,via D1-like receptors, inhibits NHE (Felder, C. C. et al.,


1990a,b, 1993; Gesek and Schoolwerth, 1990; Horiuchi etal., 1992; Jadhav and Liu, 1992) and Na1/Pi co-transport ac-tivity at the luminal membrane (Debska-Slizien et al., 1994a;Glahn et al., 1993). The inhibitory effect of dopamine andD1-like receptors on luminal ion transport is mainly due toactivation of the cAMP/PKA pathway (Debska-Slizien etal., 1994a; Felder, C. C. et al., 1990a,b; Glahn et al., 1993;Perrichot et al., 1995). (In humans, intravenous dopamineinduces a natriuresis that is associated with an increase inplasma and urinary cAMP excretion [Vlachoyannis et al.,1976]). In addition, luminal proximal tubular NHE activityis also inhibited via a cAMP-independent, G-protein-depen-dent mechanism (Felder, C. C. et al., 1993; Jadhav and Liu,1992). The ability of dopamine to attenuate the stimulatoryeffect of angiotensin II on NHE activity in luminal mem-branes apparently is mediated by eicosanoids generated bythe phospholipase A2 (PLA2) and cytochrome P450 path-way. This effect is independent of PLC activation (Sheikh-Hamad et al., 1993); D1 receptor-mediated inhibition ofluminal NHE activity is also independent of PLC (Felder,C. C. et al., 1990a).

4.3.2.1.2. Na1/K1-ATPase. Dopamine also inhibits Na1/K1-ATPase activity at the renal proximal tubular basolat-eral membrane (Aperia et al., 1987; Baines et al., 1992;Chen and Lokhandwala, 1993; Satoh et al., 1992, 1993a;Seri et al., 1988; Soares-da-Silva et al., 1996; Takemoto etal., 1991, 1992), but the responsible dopamine receptor andthe mechanism by which it inhibits Na1/K1-ATPase activ-ity in the kidney remain to be settled. In the rat proximaltubule, D1-like receptors play a role, either alone (Baines etal., 1992; Chen and Lokhandwala, 1993) or in conjunctionwith D2-like receptors (Bertorello and Aperia, 1990; Satohet al., 1993b; Takemoto et al., 1991). The cellular mecha-nism by which dopamine inhibits Na1/K1-ATPase activityis also a matter of controversy. In many cells, Na1/K1-AT-Pase activity can be inhibited indirectly by a decreasein intracellular sodium secondary to reduced sodium entry(Borin, 1997; Shahedi et al., 1995); thus, inhibition of NHEactivity (Felder, C. C. et al., 1990a,b, 1993; Gesek andSchoolwerth, 1990; Horiuchi et al., 1992; Jadhav and Liu,1992) may indirectly inhibit Na1/K1-ATPase activity.However, Na1/K1-ATPase activity in the proximal tubulecan be inhibited by dopamine (agonists) even when intrac-ellular sodium concentration is clamped (Ibarra et al., 1993;Slobodyansky et al., 1995).

Dopamine and D1-like agonists generate second/thirdmessengers by stimulation of AC (Baldi et al., 1988; Felder,C. C. et al., 1989c; Felder, R. A. et al., 1984a,b, 1993;Gesek and Schoolwerth, 1991; Kinoshita et al., 1989, 1990;Nakajima et al., 1977), PLC (Felder, C. C., 1989a,b,c; Kansraet al., 1995; Sheikh-Hamad et al., 1993; Vyas et al., 1992a,b),and PLA2 (Hussain and Lokhandwala, 1996; Ominato et al.,1996; Satoh et al., 1992, 1993a,b; Sheikh-Hamad et al.,1993). The mechanism(s) by which Na1/K1-ATPase activ-ity is regulated by the second messengers generated by theseeffector enzymes is not completely understood. In rat renal

proximal tubules, in opossum kidney cells expressing theendogenous aNa1/K1-ATPase, and in COS cells trans-fected with amphibian aNa1/K1-ATPase, the phosphory-lation of Na1/K1-ATPase by PKA and PKC has been vari-ously reported to inhibit or stimulate sodium pump activity(Beguin et al., 1996; Bertorello et al., 1991; Carranza et al.,1996a,b, 1997; Chibalin et al., 1997a,b; Féraille et al., 1995,1997; Fisone et al., 1994, 1995; Logvinenko et al., 1996;Middleton et al., 1993). In a pig kidney cell line (LLC-PK1), no effect of PKC on the phosphorylation or activityof Na1/K1-ATPase was found (Middleton et al., 1993). Incontrast, in an opossum kidney cell line expressing a func-tional rodent aNa1/K1-ATPase, PKC was reported to stim-ulate rather than inhibit Na1/K1-ATPase activity (Pede-monte et al., 1997a,b). Moreover, in an amphibian kidneycell line (A6), the ability of phorbol esters (which stimulatePKC activity) to inhibit Na1/K1-ATPase activity was inde-pendent of its PKC phosphorylation site (Beron et al., 1997;Feschenko and Sweadner, 1997); rather, it was related to itswithdrawal from the basolateral cell surface (Beron et al.,1997; Chibalin et al., 1997b). PKC may also inhibit Na1/K1-ATPase activity by an alternate route, by stimulation ofPLA2 activity. Production of eicosanoids generated by cyto-chrome P450, e.g., 20-hydroxyeicosa-tetraenoic acid, in-hibits Na1/K1-ATPase activity (Hussain and Lokhandwala,1996; Ominato et al., 1996; Nowicki et al., 1997; Satoh etal., 1992, 1993a,b). Nitric oxide and cyclic GMP have alsobeen reported to inhibit Na1/K1-AT-Pase activity in ratrenal medullary tissue slices (McKee et al., 1994).

Several investigators have also reported that PKA phos-phorylation of Na1/K1-ATPase (Beguin et al., 1996) actu-ally inhibits its activity in COS cells heterologously ex-pressing aNa1/K1 ATPase (Fisone et al., 1994; Cheng etal., 1997a,b) and in ventricular myocytes when intracellu-lar calcium is low (Gao, J. et al., 1994). The involvement ofPKA in the dopamine-mediated effect on Na1/K1-ATPaseactivity is also supported by studies in fibroblasts trans-fected with either the rat D1A or D2Long cDNA; the inhibi-tion or stimulation of Na1/K1-ATPase activity is linked tostimulation or inhibition of cAMP production, respectively(Horiuchi et al., 1993; Yamaguchi et al., 1996). In addition,the ability of the D2-like agonist bromocriptine to stimulateNa1/K1-ATPase activity in renal proximal tubules has alsobeen linked to inhibition of AC activity (Hussain et al.,1997).

The discrepancies about signal transducer involvementand importance of phosphorylation in the inhibition ofNa1/K1-ATPase activity could be due to differences in ex-perimental protocols, species, or cell lines used (see above).Differences in the degree of phosphorylation of Na1/K1-ATPase between the rat on the one hand and the dog andthe pig kidney on the other have been shown to be due tothe absence of Ser-18 in the dog and pig kidney; Ser-18 isthe amino acid residue that is more abundantly phosphory-lated by PKC (Feschenko and Sweadner, 1995). Appar-ently, rat Na1/K1-ATPase phosphorylation by PKC ismodulated by its prior phosphorylation with PKA (Cheng


et al., 1997b). However, the differences in reports of secondmessenger action on Na1/K1-ATPase in the rat kidney re-main to be resolved (Bertorello et al., 1991; Carranza et al.,1996a,b, 1997; Chibalin et al., 1997a,b; Féraille et al., 1995,1997). Adequacy of tissue oxygenation (Féraille et al.,1995) and levels of intracellular calcium and sodium mayvariably affect Na1/K1-ATPase activity (Yingst, 1988; Gaoet al., 1992). PKA may stimulate or inhibit Na1/K1-AT-Pase activity depending upon the concentration of in-tracellular calcium; low intracellular calcium (,150 nM) isassociated with an inhibition, whereas high intracellularcalcium (.150 nM) is associated with stimulation (Chenget al., 1997a; Gao, J. et al., 1992, 1994). Apparently, the in-hibitory effect of PKC on rat renal proximal tubule Na1/K1-ATPase activity becomes apparent under hypoxic con-ditions (Féraille et al., 1995). The method used to stimulatePKC activity (e.g., phorbol esters) is another factor to con-sider. Studies on the phosphorylation of Na1/K1-ATPasehave utilized PKCs using mixtures of PKCa, b, and g (Fes-chenko and Sweadner, 1997). However, PKCb and PKCgare not expressed in renal tubules; PKCa is not a target offenoldopam, a D1-like agonist in this tissue (Yao et al.,1997) (see Section 4.3.2.1.3), and one of its targets, PKCz,is not phorbol-ester sensitive.

The timing of experiments adds another dimension ofcomplexity to the interpretation of the effect of secondmessengers on Na1/K1-ATPase activity. Unpublished stud-ies from our laboratory show that dopamine has a biphasiceffect on Na1/K1-ATPase activity in microdissected rat re-nal proximal tubules; there is an initial stimulatory effect,followed by a more prolonged inhibitory effect. A combi-nation of PKA and PKC agonists simulates the biphasiceffect of dopamine (unpublished studies). PKC has beenshown to initially stimulate and subsequently inhibit Na1/K1-AT-Pase activity (Bertorello and Aperia, 1989; Ber-torello, 1992). Longer-term inhibition of Na1/K1-ATPaseactivity by dopamine apparently involves both PKC andPKA (Cheng et al., 1997b; Pinto-do-O et al., 1997). Thephosphorylation of Na1/K1-ATPase by dopamine corre-lates with a decrease in activity in early, but not in later,time points (Chibalin et al., 1997a). The conformation ofNa1/K1-ATPase is also an important determinant in itsphosphorylation by PKA (Feschenko and Sweadner, 1994).Finally, the effects on endogenously expressed Na1/K1-AT-Pase may not be mimicked by heterologously expressedNa1/K1-ATPase in cells that may not have the same cellmachinery and polar expression as the renal proximal tubule.

There is also evidence that the primary mechanism bywhich dopamine inhibits transport in renal proximal tu-bules may be one of decreasing luminal sodium entry. Sucha mechanism has been shown to be important in the overallinhibitory effect of dopamine on Na1/K1-ATPase activityin the Madin Darby canine kidney epithelial cells, a cellline with distal tubular characteristics (Shahedi et al.,1995). In the rat proximal tubule, the increase in NHE ac-tivity following inhibition of dopamine synthesis precedesby several hours a stimulatory effect on Na1/K1-ATPase

activity (Debska-Slizien et al., 1994a). Of interest is the ob-servation that epinephrine stimulates Na1/K1-ATPase ac-tivity in renal proximal tubules, in part by increasing lumi-nal NHE activity (Baines et al., 1990).

In light of all of these studies into account, dopamineprobably inhibits Na1/K1-ATPase activity by two mecha-nisms: indirectly, by decreasing luminal sodium entry by in-hibition of NHE activity, and directly, possibly by inhibi-tion of the sodium pump itself. Such a mechanism for theinhibitory effect of dopamine on sodium transport has alsobeen proposed by Borin (1997) in aortic smooth muscles.The mechanism(s) by which second messengers and therole of phosphorylation regulate Na1/K1-ATPase activityremains to be settled.

4.3.2.1.3. Phospholipase C isoforms. Another dilemma thatmust be resolved about the role of PLC in the dopamine-mediated inhibition of sodium transport stems from the ob-servations that neurohumoral agents that stimulate PLCand PKC activity, such as angiotensin II and norepineph-rine, stimulate rather than inhibit sodium transport (Baineset al., 1990; Beach et al., 1987; Gopalakrishnan et al., 1995;Houillier et al., 1996; Ibarra et al., 1993; Schelling et al.,1994; Slivka et al., 1988). We have tried to resolve this di-lemma by comparing the effect of fenoldopam and norepi-nephrine on PLC activity in rat kidneys. We found that thenatriuretic effect of fenoldopam was associated with stimu-lation of PLCb and inhibition of PLCg activity and expres-sion in the proximal tubular membrane. In contrast, the an-tinatriuretic effect of norepinephrine was associated withan increase in PLCb activity and expression without an ef-fect on PLCg (Yu et al., 1995).

In a subsequent study, we found that fenoldopam, in theshort term, inhibited PKCd and PKCz, but stimulatedPKCu, expression (Yu et al., 1997). This finding is in con-trast to the linkage of the D2 receptor to PKCe (Senogles,1994). The effect of the D1-like agonist on PKC isoform ex-pression is also different from those reported for norepi-nephrine and angiotensin II. Norepinephrine increasedPKCa, b, g, d, and e expression in thyroid cells (Wang etal., 1996) and methoxamine, and a1-adrenergic agonistincreased PKCd and z in human tracheal epithelial cells(Liedtke et al., 1997), whereas angiotensin II increasedPKCa, d, e, and z in renal tubules (Karim et al., 1995; Pog-gioli et al., 1995). Indeed, inhibition of PKCd translationprevents the a1-adrenergic stimulation of sodium transportin human airway epithelial cells (Liedtke and Cole, 1997).Einephrine and a-adrenergic agonists have also been shownto stimulate renal tubular Na1/K1-ATPase activity by acti-vating a protein kinase that is insensitive to phorbol esters(Baines et al., 1990), a result suggesting involvement of anovel PKC (Hoffman, 1997). PKCd has also been reportedto stimulate an amiloride-sensitive NHE, presumably NHE-1,in C6 glioma cells (Chen and Wu, 1995). It remains to bedetermined whether the differential regulation of PKC iso-forms by D1 agonists and norepinephrine can explain thedifferential effects on ion transport.


The effect of D2-like receptors, independent of D1-likereceptors, on tubular function remains to be settled (Siragyet al., 1992; Stier et al., 1982). Dopamine or D2-like ago-nists, via D2-like receptors, increase transport in the renalproximal tubule (Felder, C. C. et al., 1993; Laradi et al.,1986; Perrichot et al., 1995) and other tissues (Donowitz etal., 1983). D2-like receptors have no effect on PLC activity(Felder, C. C. et al., 1989b,c; Sheikh-Hamad et al., 1993;Vyas et al., 1992a). However, apomorphine and bromocrip-tine, D2-like agonists, decrease basal or forskolin-stimulatedAC activity in rat renal proximal tubules and a proximaltubular cell line (Felder, R. A. et al., 1984a; Hussain et al.,1997; Perrichot et al., 1995). In mouse fibroblasts trans-fected with the rat D2Long cDNA, quinpirole, a D2-like ago-nist, increases Na1/K1-ATPase activity, the opposite of theeffect observed in cells expressing the D1A receptor (Horiu-chi et al., 1993; Yamaguchi et al., 1996). In rat renal proxi-mal tubules, bromocriptine also increases Na1/K1-ATPaseactivity (Hussain et al., 1997). The stimulatory effect ofD2-like agonists (bromocriptine and quinpirole) on Na1/K1-ATPase activity may be mediated by a decrease in cAMPproduction (Yamaguchi et al., 1996; Hussain et al., 1997).

However, under certain conditions, D2-like receptorsmay enhance the ability of D1-like agonists to inhibit Na1/K1-ATPase activity (Bertorello and Aperia, 1989; Satoh etal., 1993b; Takemoto et al., 1991). The attenuating actionof dopamine on the stimulatory effect of angiotensin II onNHE activity in renal brush border membranes is also me-diated by both D1- and D2-like receptors (Sheikh-Hamad etal., 1993). Studies in transfected cells and in brain striatalcells suggest that the D2-like receptor (e.g., D2) may facili-tate the ability of the D1-like receptor (e.g., D1) to stimu-late AC and inhibit Na1/K1-ATPase activity (Bertorello etal., 1990; Piomelli et al., 1991). The D1 and D2 receptorsheterologously expressed in Chinese hamster ovary cells(D2 . D1) act synergistically to increase arachidonic acidrelease (Piomelli et al., 1991). In these Chinese hamsterovary cells, stimulation of PKC directs the preferential cou-pling of the transfected D2 receptor from inhibition of ACto stimulation of arachidonic acid release (Di Marzo et al.,1993; Kanterman et al., 1991). This mechanism may be op-erative in renal proximal tubules, because D1-like, but notD2-like, receptors stimulate PLC and PKC activity (Felder,C. C. et al., 1989a,b,c; Sheikh-Hamad et al., 1993; Vyas etal., 1992a; Yu et al., 1995, 1996c). Another mechanismmay involve the inhibition of Ca21 channels by D2-like re-ceptors (Brown and Seabrook, 1995; Jaber et al., 1996; Meiet al., 1996; Seabrook et al., 1994). Some isoforms of AC (Vand VI), which are expressed in the kidney, are inhibitedby low concentrations of calcium (Cooper et al., 1995; Su-nahara et al., 1996); a low intracellular calcium concentra-tion could enhance the ability of D1-like agonists to stimu-late AC activity. Ca21-channel blockers have been shownto inhibit Na1/K1-ATPase activity and increase sodium ex-cretion, effects mediated by D1-like receptors (Eisner et al.,1994, 1997). More recently, low levels of intracellular cal-cium were reported to inhibit Na1/K1-ATPase activity in

COS cells transfected with the rat Na1/K1-ATPase(Cheng et al., 1997a); high intracellular calcium stimulatesNa1/K1-ATPase activity (Cheng et al., 1997a; Gao, J. etal., 1992, 1994). However, dopamine has not been reportedto increase intracellular calcium in immortalized renalproximal tubular cells of the opossum (Perrichot et al.,1995).

4.3.2.1.4. Receptor subtypes. Two D1-like receptors are ex-pressed in renal proximal tubules and cells (Yamaguchi etal., 1993; Felder, R. A. et al., 1993; O’Connell et al., 1995;Yao et al., 1997; Nash et al., 1993); the D1A receptor is ex-pressed to a much greater extent than is the D1B receptor(Nash et al., 1993; Yao et al., 1997). It is not known whichD1-like receptor mediates the actions of dopamine on trans-port. Presumably, D1B receptors are not essential becausethese receptors are not expressed in opossum kidney celllines, yet D1-like receptor stimulation of AC activity stilloccurs (Cheng et al., 1990; Nash et al., 1993). Two D2-likereceptors are expressed in renal proximal tubules, the D2Long

and D3 receptors (Gao, D.-Q. et al., 1994); the D3 receptoris probably expressed in greater abundance than is theD2Long (Sokoloff et al., 1990; O’Connell et al., 1998b).

4.3.2.2. Loop of Henle. In the mTAL, dopamine via D1-likereceptors actually stimulates Na1/K1/2Cl activity; how-ever, the overall action in the mTAL is a decrease in trans-port because Na1/K1-ATPase activity is also inhibited viaactivation of K1 channels and PKA (Aoki et al., 1996).The D1-like effect is probably exerted at the D1B receptor,because the D1B, but not the D1A, receptor is expressed inmTAL (Yamaguchi et al., 1997). Luminal NHE-3 is alsopresent in mTAL, but the effect of dopamine on this trans-porter in this nephron segment has not been evaluated(Amemiya et al., 1995; Biemesderfer et al., 1997). Dopa-mine via D1-like receptors inhibits Na1/K1-ATPase activ-ity caused by an increase in AC and PKA activity (Aoki etal., 1996; Meister et al., 1989; Nishi et al., 1993c; Satoh etal., 1993b). In contrast to that noted in proximal tubules,PKC is not necessary for the inhibitory effect of dopamineto occur (Satoh et al., 1993b). However, as in the proximaltubule, PKA-mediated stimulation of PLA2 activity is alsoinvolved (Satoh et al., 1993b). The role of phosphorylationin the function of Na1/K1-ATPase is controversial (seeSection 4.3.3.1.2). In some (Beguin et al., 1996; Bertorelloet al., 1991; Fisone et al., 1994; Logvinenko et al., 1996),but not in all, studies (Féraille et al., 1995; Carranza et al.,1996a,b), the phosphorylation of Na1/K1-ATPase in renalproximal tubules (see Section 4.3.3.1.2) reduces its activitywhereas its dephosphorylation increases its activity.Dopamine has been shown to increase a dopamine- andcAMP-regulated phosphoprotein-32 (DARPP-32) that in-hibits protein phosphatase-1 activity in the mTAL;DARPP-32 is expressed in the mTAL, but not in the PCT(Meister et al., 1989). The nephron segment-specific local-ization of DARPP-32 may explain the nephron segment-specific inhibition of phosphatase activity by dopamine; it


is evident in mTAL, but not in proximal tubules (Li et al.,1995; Meister et al., 1989; Slobodyansky et al., 1995).

4.3.2.3. Cortical collecting duct. In the rat CCD, D1-like, butnot D2-like, receptors (186,249) inhibit Na1/K1-ATPase ac-tivity (Satoh et al., 1992, 1993a,b; Takemoto et al., 1992);both D1A and D1B receptors (D1A.D1B) are expressed, butto a much lesser extent than those found in PCTs (Yao etal., 1997). In the rat CCD, as in the rat mTAL, the D1-likereceptor exerts its action by stimulation of AC, PKA, andPLA2 activity (Ohbu and Felder, 1991, 1993; Satoh et al.,1992, 1993a,b). The D1-like receptor stimulation of AC ac-tivity and inhibition of Na1/K1-ATPase activity are greaterin the rat CCD than in the rat PCT (Ohbu and Felder,1991; Takemoto et al., 1992). In the Madin Darby caninekidney epithelial cells, a dog kidney cell line that retainsdifferentiated properties of renal collecting tubules, dopa-mine also inhibits Na1/K1-ATPase activity, but PKA, PKC,and eicosanoid mechanisms are involved (Cohen-Luriaet al., 1994; Shahedi et al., 1992, 1995; Takemoto et al.,1992). However, the predominant effect of dopamine inthe CCD and distal nephron may be the inhibition of thehydro-osmotic effect of vasopressin (Deis and Alonso,1970; Koyama et al., 1985; Muto et al., 1985; Sun and Scha-fer, 1996), an effect mediated by a D2-like receptor the D4

receptor (Matsumoto et al., 1995; Sun and Schafer, 1996;Sun et al., 1997). Dopamine also inhibits the hydro-osmoticeffect of vasopressin in the toad bladder, a homologue of thedistal tubule in mammalian nephrons (Arruda and Saba-tini, 1982). Dopamine has additional effects in the CCD; itmay exert a modulatory influence on renal aldosterone ac-tion. Dopamine, via D1-like receptors, antagonizes the ac-tion of aldosterone in the CCD (Muto et al., 1985); theD1-like action may be enhanced by the ability of D2-like re-ceptors to inhibit aldosterone release in sodium-repletestates (Carey and Sen, 1986). In contrast, in rats on a highK1 or low Na1 diet, D2-like receptors facilitate aldosteroneeffects (Adam, 1979; Adam and Goland, 1979). This maybe another example of the sodium-retaining effect ofdopamine in sodium-depleted states (see Section 4.3.2.1.2)(Agnoli et al., 1987). The paradoxical effect is unexplainedat this time.

In the CCD, sodium transport across the luminal mem-brane to a large extent occurs via Na1 channels. The effectof dopamine on Na1 channels in the CCD has not beenstudied. However, in an amphibian distal renal tubular cellline (A6), dopamine has been reported to decrease the ac-tivity of the Na1 channel by a non-PKC-mediated mecha-nism (Schlager et al., 1998). In the striatum and the hip-pocampus, D1-like agonists decrease the amplitude ofsodium currents more frequently than do D2-like agonists(Cantrell et al., 1997; Schiffmann et al., 1995; Surmeierand Kitai, 1993). The inhibition of sodium currents is me-diated by cAMP-dependent phosphorylation of the a-sub-unit of the Na1 channel (Cantrell et al., 1997). In contrast,D2-like, but not D1-like, agonists increase the amplitude ofsodium current (Surmeier and Kitai, 1993).

4.3.2.4. Inner medulla. The rat inner medulla expresses themRNA of two D2-like receptors, the D2Long and D3 receptors(Gao, D.-Q. et al., 1994); however, the D3 protein is not de-tected by immunohistochemistry (O’Connell et al., 1998b).The inner medullary collecting duct also expresses a D2-likereceptor linked to prostaglandin E (Huo and Healy, 1991;Huo et al., 1991), but the receptor subtype involved or itsfunction remains to be established (Maeda et al., 1992).

4.3.3. Summary. Under conditions of positive sodiumbalance, D1-like receptors alone, or combined with a syner-gistic effect of D2-like receptors, decrease ion transport inrenal proximal tubules, mTAL, and CCD. This inhibitoryeffect involves direct effects in the proximal tubule, mTALand CCD; an antagonism of aldosterone action in the CCDmay also contribute to the inhibition of ion transport. D1-likereceptors may also indirectly decrease water reabsorption byinhibiting vasopressin release. The effect of D2-like recep-tors, independent of D1-like receptors, on ion and watertransport is complex. During volume expansion, D2-like re-ceptors may facilitate diuresis by antagonizing the hydro-osmotic effect of vasopressin in CCD and may facilitatenatriuresis in this nephron segment by inhibiting aldoster-one secretion. In sodium-depleted states, D2-like receptorsmay decrease ion and water excretion directly by increasingproximal tubular reabsorption and indirectly by stimulatingvasopressin release. In normal sodium-replete states, mostof the inhibitory effect of dopamine on sodium transport isprobably exerted in the proximal tubule by actions of D1-likereceptors. When D1-like receptor (e.g., D1A) function is im-paired, as in hypertension, D5 (D1B) receptor function inthe mTAL and more distal segments may become apparent(see Section 7.3). The ability of dopamine to inhibit tubu-lar transport at multiple sites may explain the marked natri-uretic effect of dopamine compared with its inhibitory ef-fect on sodium transporters in specific nephron segments(e.g., 20% inhibition of Na1/K1-ATPase activity, 30–40%inhibition of NHE activity). The natriuresis caused by thedirect inhibitory effect of tubular transport by dopamine isaugmented by the additional effects of increased renalblood flow that is sometimes accompanied by an increase inglomerular filtration rate.

5. RENAL DOPAMINE PRODUCTION5.1. Source of Renal Dopamine

Although there are dopaminergic nerves in the kidney(Dinnerstein et al., 1979; Bell et al., 1988), they contributeless than 10% of renal dopamine production (Akama et al.,1995; Adam and Adams, 1985; Baines, 1982; Berndt et al.,1994; Morgunov and Baines, 1981; Stephenson et al., 1982;Hegde and Lokhandwala, 1992; Wang et al., 1997). More-over, vagal afferents can stimulate the renal release of dopa-mine (Morgunov and Baines, 1985; Hegde and Lokhand-wala, 1992). The major source of renal dopamine is theconversion of levodopa (L-DOPA) (taken up by renal tu-bules from the circulation or from the glomerular filtrate)


(Ball et al., 1982; Boren et al., 1980; Suzuki et al., 1984) todopamine by aromatic amino acid decarboxylase (AADC)(Baines and Chan, 1980; Baines et al., 1985; Hagege andRichet, 1985; Seri et al., 1990; Suzuki et al., 1984; Wahbe etal., 1982). This conversion occurs mainly in proximal tu-bules because AADC activity is highest in this nephronsegment (Hayashi et al., 1990). Its activity decreases pro-gressively along the nephron; thus, 75% of renal AADC ispresent in the cortex and 25% in the medulla (Hayashi etal., 1990; Soares-da-Silva, 1994). Renal dopamine can alsocome from the deconjugation of sulfated and glucu-ronidated dopamine (Kuchel, 1995; Yoshimuzi et al., 1992)and the demethylation of 3-O-methyl DOPA (Ibarra et al.,1996). Dopamine is not converted to norepinephrine in ei-ther dopaminergic nerves or renal tubules because they lackdopamine b-hydroxylase (Bell et al., 1988).

5.2. Factors Influencing Renal Dopamine Production

Renal dopamine production reflected in urinary dopamineexcretion is influenced by several factors, including sub-strate (L-DOPA) delivery to renal tubular cells (filtered andperitubular uptake), AADC activity, filtered dopamine,dopamine degradation, and tubular secretion of dopamine.Filtered dopamine does not contribute much to urinarydopamine because the concentration of dopamine in theplasma is in the picomolar range (Van Loon and Sole, 1980),in the nanomolar range in the interstitial space, inside theproximal tubule cell, and tubular fluid (Häberle et al., 1991;Ibarra et al., 1996; Stephenson et al., 1982), and in the mi-cromolar range in the urine (Baines, 1982; Goldstein et al.,1989; Lee, 1982; Soares-da-Silva, 1994; Stephenson et al.,1982; Wang et al., 1997).

5.2.1. Effect of sodium chloride. Expansion of the extra-cellular fluid volume increases renal dopamine production,but the type of ion and its concentration are important de-termining factors. Thus, volume expansion with isotonic,but not hypotonic, saline or albumin increases urinarydopamine excretion (Akama et al., 1995; Alexander et al.,1974; Faucheux et al., 1977; Cuche et al., 1983; McClana-han et al., 1985; Sowers et al., 1984). A low-sodium diet isassociated with low urinary dopamine, whereas a high-so-dium diet is associated with increased urinary dopamine(Alexander et al., 1974; Akpaffiong et al., 1980; Baines,1982; Ball and Lee, 1977; Ball et al., 1978; Carey et al.,1981; Felder, R. A. et al., 1989; Goldstein et al., 1989; Ha-yashi et al., 1991; Ho et al., 1997; Lee, 1982; Oates et al.,1979; Mühlbauer and Osswald, 1993; Soares-da-Silva,1994; Wang et al., 1997). The increase in urinary dopaminein sodium-replete states is partly caused by an increase inAADC activity (Hayashi et al., 1991; Seri et al., 1990;Soares-da-Silva and Fernandes, 1990; Soares-da-Silva et al.,1993). However, the low affinity of AADC for L-DOPAmakes it unlikely to be the only factor in the regulation ofrenal dopamine production (Adam et al., 1986; Hayashi etal., 1991; Lee, 1982). The increase in urinary dopamine

with salt loading is not due to decrease in its breakdown ei-ther (Baines, 1982; Goldstein et al., 1989; Lee, 1982). Al-though salt loading does not increase the plasma levels ofthe precursor of dopamine L-DOPA (Goldstein et al., 1989;Hayashi et al., 1991), the increase in urinary dopamine isassociated with an increase in urinary excretion of L-DOPA.Therefore, the increase in urinary excretion of dopamineappears to be secondary to an increase in the uptake ofL-DOPA by renal proximal tubules, presumably from thecirculation (Ball et al., 1982; Baines and Chan, 1980; Bar-thelmebs et al., 1990; Boren et al., 1980; Chan, 1976;Soares-da-Silva, 1994). An important factor in the increasein urinary dopamine in chronic sodium loading is due tothe preferential egress of dopamine into the lumen ratherthan into the interstitium (Wang et al., 1997) through anunknown mechanism. However, inhibition of NHE activ-ity decreases efflux of dopamine to the peritubular space,an effect that presumably favors luminal outflow (Soares-da-Silva, 1993b). Thus, dopamine, by inhibiting proximaltubular luminal Na1-H1 exchange activity, may facilitateits own egress into the tubular lumen (Baines and Chan,1980; Debska-Slizien et al., 1994a; Felder, C. C. et al., 1990b,1993; Gesek and Schoolwerth, 1990; Jadhav and Liu, 1992);dopamine egresses at the apical surface by a nonsaturableprocess (Soares-da-Silva et al., 1998). In sodium-repletestates, dopamine may also stimulate its own production bystimulation of PKC activity (Soares da-Silva, 1993a). Thepreferential luminal efflux results in high nanomolar con-centrations (Häberle et al., 1991; Wang et al., 1997) ofdopamine in the tubular lumen, concentrations that ap-proach the EC50 of dopamine and D1-like agonists to stimu-late AC and PLC activity and to inhibit luminal NHE ac-tivity (Felder, C. C. et al., 1990a,b, 1993; Gesek andSchoolwerth, 1990; Jadhav and Liu, 1992; Jose et al., 1992).

However, other investigators have failed to find a rela-tion between urinary dopamine and sodium excretion(Barendregt et al., 1995a,b; Mühlbauer et al., 1997a,b;Mühlbauer and Osswald, 1994; Vieira-Coelho et al., 1996).The reason for these negative reports is not clear. Mühl-bauer and colleagues have claimed that the difference be-tween their studies and those of others is due to food intake(Mühlbauer et al., 1997a,b; Mühlbauer and Osswald, 1994).However, all the acute studies performed in the laboratoryof Jose and colleagues were performed in rats in which food,but not water, was withheld for 24 hr (Felder, R. A. et al.,1990b; Jose et al., 1987; Pelayo et al., 1983). Differences inthe amount (Hansell and Fasching, 1991; Pelayo et al.,1983) and duration (Oates et al., 1979) of the sodium loadare possible explanations. In humans, an increase in sodiumintake from 20 to .200 mmoL/day resulted in an increasein renal dopamine production peaking at the second day,followed by a gradual decline by the fifth day to 50% of thevalue on the peak day (Oates et al., 1979). In rats, sodiumchloride loading maximally increased dopamine excretionon the first few days, with the excretion decreasing close tocontrol levels at 1 week, only to gradually increase againfrom 2 to 4 weeks (Grossman et al., 1991; Jadhav and


Lokhandwala, 1990; Yoshimura et al., 1986, 1987). How-ever, after 6 weeks of long-term sodium chloride loading inrats, renal dopamine concentrations are not higher than innonloaded rats (Petrovic and Bell, 1986). Sex may also playa role, as sodium loading increases dopamine excretion inChinese females, but not in Chinese males (Chan et al.,1996). There are other modifiers of dopamine excretion,such as urban versus rural settings in humans and age in bothhumans and rats (Armando et al., 1995; Romero-Vecchioneet al., 1995; Soares-da-Silva and Fernandes, 1991; Young etal., 1992; Zemel and Sowers, 1988).

5.2.2. Effect of other dietary constituents. Chloride seemsto be an important ion in regulating renal dopamine pro-duction. An increase in the intake of chloride, with orwithout sodium, increases urinary dopamine, whereas so-dium bicarbonate does not (Akpaffiong et al., 1980; Ball etal., 1978). Calcium (Akpaffiong et al., 1980; Dazai et al.,1993), phosphate (Berndt et al., 1994; Isaac et al., 1992),and protein loading and L-DOPA production in the intes-tine also increase renal dopamine production (Clark et al.,1992; Cuche, 1988; Mühlbauer and Osswald, 1994).

6. PARACRINE REGULATION OF RENAL FUNCTION

The ability of renal proximal tubules to produce dopamineand the presence of receptors in these tubules suggest thatdopamine can act in an autocrine or paracrine fashion.

6.1. Methods to Study Paracrine Regulation of Renal Function

The paracrine regulation of renal function by dopamine hasbeen studied by using different approaches. Thus, one canstudy the effects of a decrease or an increase in the produc-tion of dopamine or dopamine receptors or a blockade ofdopamine receptors in the kidney.

6.1.1. Inhibition of renal dopamine production. Carbidopaor benserazide decreases dopamine production by inhibitingAADC. However, AADC also decarboxylates 5-hydroxy-tryptamine, the precursor of serotonin (Cooper et al.,1996). Studies using carbidopa or benserazide to inhibitAADC may make interpretation of the results difficult be-cause serotonin generally increases sodium transport andthus opposes the action of dopamine (Hafdi et al., 1996;Soares-da-Silva et al., 1996). Dopamine excretion has alsobeen found to increase in spite of continued (days) carbi-dopa administration (Ball and Lee, 1977).

6.1.2. Stimulation of renal endogenous dopamine pro-duction. Renal dopamine levels can also be increased byincreasing substrate delivery to the kidney with the use ofthe dopamine prodrug gludopa. The high levels of g-glutamyltranspeptidase (compared with other organs) allow thepreferential conversion of gludopa to L-DOPA in renal prox-

imal tubules (Jose et al., 1996; Lee, 1982, 1987; Wang et al.,1997; Wilk et al., 1978). The administration of gludopa in-hibits NHE and Na1/K1-ATPase activity and increases so-dium excretion (Eklöf et al., 1997; Jose et al., 1996; Lee,1982, 1987; Wang et al., 1997).

6.1.3. Inhibition of dopamine breakdown. Renal dopaminelevels can also be increased by decreasing the catabolism ofdopamine.

6.1.3.1. Catechol-O-methyl transferase and monoamine oxidaseinhibition. Dopamine levels can be increased by catechol-O-methyl transferase (COMT) or monoamine oxidase in-hibitors, which decrease the catabolism of dopamine. COMTor monoamine oxidase inhibitors, however, also decreasethe breakdown of other monoamines that have actions op-posite to dopamine (e.g., serotonin). Nevertheless, inhibi-tion of COMT by nitecapone has been shown to producedopamine-like effects, including natriuresis and inhibitionof Na1/K1-ATPase activity in renal PCT and PST (Eklöf etal., 1997). COMT is expressed in most nephron segments,especially in the PST (Meister et al., 1993).

6.1.3.2. Dopamine-b-hydroxylase inhibition. Renal noradre-nergic nerves, but not renal tubules, express dopamine-b-hydroxylase, the enzyme that converts dopamine to norepi-nephrine. However, inhibition of dopamine-b-hydroxylaseresults in a 3-fold increase in renal cortical dopamine levels,a down-regulation of renal D1-like receptor density, and anuncoupling of the D1-receptor from AC in renal proximalconvoluted, but not distal convoluted, tubule (Kinoshita etal., 1990). Inhibition of dopamine-b-hydroxylase not onlyresults in an increase in renal dopamine levels, but can po-tentially decrease norepinephrine levels. Although renalnerves do not contribute much to renal dopamine produc-tion, vagal afferents can increase renal dopamine produc-tion, which can produce a natriuresis (Morgunov andBaines, 1985; Hegde and Lokhandwala, 1992).

6.1.4. Dopamine receptor blockade. Another approach tostudy the role of endogenous renal dopamine is the intrare-nal administration of dopamine antagonists. Thus, block-ade of renal D1-like receptors decreases sodium excretion,whereas blockade of D2-like receptors induces the oppositeeffect (Jose et al., 1986; Felder, R. A. et al., 1989; Siragy etal., 1989, 1990).

6.1.5. Molecular biological methods. One could also pre-vent the expression of dopamine receptor subtypes in thekidney or in a specific nephron segment of cell type by mo-lecular biological means by using promoters of genes spe-cific to a nephron segment (antisense oligonucleotides,hammerhead ribozymes, or dominant negative mutants).These approaches potentially provide the most specific andselective means of studying the role of renal dopamine inrenal function.


6.2. Neural Dopamine

Renal neural endogenous dopamine is not important in theregulation of renal blood flow, except at the lower limits ofautoregulation (Kapusta and Robie, 1988; Sunn et al.,1992). Renal neural endogenous dopamine may also partic-ipate in the regulation of glomerular filtration rate, espe-cially with the hyperfiltration that occurs during aminoacid infusion (Baines and Drangova, 1986; Mühlbauer etal., 1997b).

6.3. Tubular Dopamine

When renal tubular endogenous dopamine subserves a para-crine/autocrine function, its natriuretic effect (via D1-likereceptors) is due mainly to tubular rather than glomerularor renal hemodynamic action (Ball and Lee, 1977; Felder,R. A. et al., 1990b; Hegde et al., 1989a; Jose et al., 1986,1988; Krishna et al., 1985; McClanahan et al., 1985; Pelayoet al., 1983; Siragy et al., 1989; Smit et al., 1988, 1990); theconverse is true for the antinatriuretic effect of D2-like re-ceptors (Siragy et al., 1990).

6.3.1. Effect of sodium chloride intake. Endogenous do-pamine also regulates phosphate excretion (Debska-Sliz-ien et al., 1994a; Garcia et al., 1997; Glahn et al., 1993;Isaac et al., 1992). Phosphate balance produces reciprocalchanges in phosphate excretion, changes that are second-ary to alterations in renal dopamine production (Berndtet al., 1993, 1994; Isaac et al., 1992). In contrast, the renalparacrine action of dopamine on sodium is markedly in-fluenced by the state of sodium balance, and this effect can-not be explained solely by changes in renal dopamine pro-duction.

6.3.1.1. Renal function. The natriuretic effect of intrave-nous dopamine or fenoldopam is attenuated in human sub-jects in a negative sodium balance (Agnoli et al., 1987;Ragsdale et al., 1990); indeed, in this situation, dopaminemay actually decrease sodium excretion (Agnoli et al.,1987). During hydropenia, dopamine receptor blockade inrats has no effect on sodium excretion (Pelayo et al., 1983).However, blockade of renal dopamine production by carbi-dopa or D1-like receptors decreases sodium excretion underconditions of “moderate” sodium load (5–10% of bodyweight) (Ball and Lee, 1977; Felder, R. A. et al., 1990b;Hansell and Fasching, 1991; Hegde et al., 1989a; Ho et al.,1993, 1997; Imondi et al., 1979; Jose et al., 1986, 1988;Mühlbauer and Osswald., 1993; Pelayo et al., 1983; Siragyet al., 1989). These studies suggest that a positive sodiumbalance is important in the natriuretic and diuretic effect ofdopamine. Indeed, a lesser increase in urinary dopamineproduces a greater natriuresis when the increase is due to achronic salt load than when it is due to an increase in renalproduction caused by the administration of the dopamineprodrug gludopa (Wang et al., 1997).

6.3.1.2. Effector protein. D1 receptor antagonism does notinhibit basal renal cortical AC or PLC activity (Felder, R. A.et al., 1984a; Vyas et al., 1992b) in rats on a normal-sodiumdiet, but does inhibit basal PLC activity in rats on a high-sodium diet (Vyas et al., 1992b). Inhibition of renal dopa-mine synthesis also does not affect NHE or Na1/K1-AT-Pase activity in the renal cortex in sodium-depleted states(Baines et al., 1992; Bertorello et al., 1988; Debska-Slizienet al., 1994a). However, the ability of exogenous or endoge-nous dopamine to inhibit proximal tubule Na1/K1-ATPaseor NHE activity is enhanced after chronic sodium loading(Bertorello et al., 1988; Debska-Slizien et al., 1994a; Nishiet al., 1993c). This enhanced effect of dopamine is not dueto a direct effect of sodium on Na1/K1-ATPase or NHE(Holtback et al., 1993; Nishi et al., 1993a). It is not due to aNaCl-induced change in renal dopamine receptor densityor affinity, because sodium loading actually decreases renalD1-like receptor density (Jadhav et al., 1991; Sharif et al.,1995) and sodium decreases renal D1-like receptor affinity(Felder and VanCampen, 1990). Sodium loading also de-creases the ability of dopamine to stimulate renal corticalPLC (Vyas et al., 1992b). Sodium has also been shown todecrease forskolin-stimulated cAMP production in vascularsmooth muscles (Yasunari et al., 1994), but a similar studyin kidney tissue has not been reported. Taken together, thesestudies suggest that the synergistic effect of sodium loadingon the natriuretic effect of dopamine is due to an increasedrenal production of dopamine and its accumulation at theluminal side, as well as to an increased inhibitory effect onsodium transporters. These actions cannot be accounted forby enhanced production of second messengers, but the ef-fect of sodium balance on second messenger-independentD1-mediated inhibition of sodium transport (Felder, C. C.et al., 1993) remains to be determined. It is possible thatsalt loading decreases the concentration and action of hor-monal or humoral factors that oppose D1-like receptorfunction (e.g., angiotensin II, adenosine, serotonin) (Chenet al., 1991; Chen and Lokhandwala, 1995; Clark et al.,1991; Häberle et al., 1991; Soares-da-Silva et al., 1996).The ability of dopamine to inhibit Na1/Pi co-transport is alsoaffected by phosphate balance (Baines et al., 1992; Debska-Slizien et al., 1994a,b). However, endogenous dopamine-mediated regulation of phosphate excretion may be evidenteven when sodium intake is not high, so long as the animal isin a phosphate-replete state (Debska-Slizien et al., 1994b).

7. ROLE OF DOPAMINE IN ESSENTIAL HYPERTENSION

Abnormalities in the central and peripheral dopaminergicsystem have been thought to be important in the pathogen-esis of hypertension. Our review of the literature suggeststhat the dopaminergic abnormalities in the CNS are proba-bly a response to rather than a cause of the hypertension(Jose et al., 1998). Rather, the peripheral dopaminergic ab-normalities are probably important in the causation of hy-pertension.


7.1. Systemic Vascular Function

An unusual cause of hypertension is abnormal elevation incirculating dopamine, which causes vasoconstriction ata-adrenergic receptors (Kuchel et al., 1982). However, thesystemic vasodilatory effect of D1 and D2 agonists is not im-paired in hypertension (Brooks and Weinstock, 1991;Carey et al., 1984; Harvey et al., 1986; Kaneko et al., 1990;Lappe et al., 1986; Lokhandwala et al., 1979; Weber et al.,1988).

7.2. Renal Vascular Function

The response of the renal vasculature to dopaminergicagents in genetic or essential hypertension is not settledyet. A reduced ability of fenoldopam to reverse the renalvasoconstrictor effect of angiotensin II in the spontane-ously hypertensive rat (SHR) has been reported (Chatzian-toniou et al., 1995). Fenoldopam has also been reported tofail to vasodilate the kidney of some patients with essentialhypertension (Bughi et al., 1989).

The ability of dopamine to inhibit tubuloglomerularfeedback is also impaired in the SHR (Häberle et al., 1991);an increased sensitivity of tubuloglomerular feedback hasbeen suggested as a mechanism for the increased renal vas-cular resistance in the SHR (Arendshorst, 1987; Braam etal., 1993). However, some studies suggest that the ability offenoldopam to decrease renal vascular resistance is main-tained in the SHR (Lappe et al., 1986). Indeed, the abilityof dopamine to relax renal artery strips has been reported tobe increased in stroke-prone SHRs (Gao et al., 1995). Inhumans, fenoldopam increases effective renal plasma flowto a greater extent in salt-sensitive hypertensive than innormotensive subjects (O’Connell et al., 1998a). It is pos-sible that these differences in published reports may berelated to differences in classes of hypertension being stud-ied (salt sensitive versus salt-resistant) or different experi-mental conditions (basal tone versus reactivity to vasocon-strictors).

7.3. Renal Tubular Function

In sharp contrast to the important renal paracrine/auto-crine regulation by dopamine in normotensive animals, re-nal endogenous dopamine no longer regulates sodium ex-cretion in SHRs (Chen and Lokhandwala, 1992; Felder, R. A.et al., 1990b). In the SHR, endogenous dopamine no longerregulates NHE (Debska-Slizien et al., 1994b; Jose et al.,1991, 1996) or Na1/K1-ATPase activity in renal proximaltubules (Debska-Slizien et al., 1994b; Eisner et al., 1997).More important, the renal paracrine/autocrine action of en-dogenous dopamine is no longer operative in some humansubjects with essential hypertension (Clark et al., 1992;Saito et al., 1986, 1994).

The failure of renal endogenous dopamine to regulate so-dium excretion in the human and animal models of essen-tial hypertension may arise from one of several mecha-nisms, including (a) decreased renal dopamine production,(b) abnormal dopamine receptor, (c) abnormal transduc-

tion of the renal dopamine receptor, (d) abnormal sodiumtransporters.

7.3.1. Renal dopamine synthesis. Decreased renal synthe-sis of dopamine may be involved in the pathogenesis of hy-pertension in human subjects. For example, some Blackswith salt-sensitive hypertension have a reduced renal dopa-mine production and do not increase renal dopamine pro-duction in response to a NaCl load (Lee, 1982, 1987; Sow-ers et al., 1988); some Caucasian salt-sensitive hypertensivesubjects also do not increase renal dopamine production inresponse to a NaCl or protein load (Clark et al., 1992; Gillet al., 1988, 1991). These hypertensive subjects may have adefect in the proximal tubular transport of L-DOPA, de-creased conversion of L-DOPA to dopamine by AADC, ordecreased egress of cellular dopamine into the tubule. Thefinding of a high urinary L-DOPA to dopamine ratio maysignify decreased conversion of L-DOPA to dopamine (Gillet al., 1991). Still other hypertensive patients may have adecreased production of urinary free dopamine because ofabnormally high levels of conjugated dopamine (Kuchel,1995; Kuchel and Kuchel, 1991). However, a decreased re-nal production of dopamine does not explain the impairedfunction of endogenous dopamine in other cases of essen-tial hypertension. Indeed, urinary dopamine and dopaminemetabolites have been reported to be increased in youngpatients with essential hypertension (Saito et al., 1986,1994; Kuchel and Kuchel, 1991). Decreased dopamine pro-duction is also an unlikely explanation in the SHR or inthe Dahl salt-sensitive rat because renal dopamine levels orurinary dopamine excretion rates are not decreased com-pared with their normotensive controls (Grossman et al.,1991; Racz et al., 1986). Furthermore, when renal dopa-mine production is increased (by the administration of thedopamine prodrug gludopa) in SHRs to the same level as intheir normotensive control, the Wistar-Kyoto (WKY) rat,sodium excretion and inhibition of NHE activity are stillless in SHRs than in WKY rats (Jose et al., 1996).

7.3.2. Sodium transporters. Abnormal sodium transport-ers are also an unlikely explanation for the failure of renalendogenous dopamine to affect sodium excretion in theSHR. Both luminal NHE and basolateral Na1/K1-ATPaseactivity in renal proximal tubules can be inhibited by PKAand PKC, respectively, to a similar extent in the youngWKY rat and SHRs (Chen et al., 1993; Horiuchi et al.,1992). G-protein inhibition of renal proximal tubular lumi-nal NHE renal proximal tubules is also unimpaired in theSHR (Albrecht et al., 1995), although G-protein subunitlevels and G-protein regulation of Na1/K1-ATPase, pre-sumably by b/g subunits, may be abnormal in SHRs (Gu-rich and Beach, 1994). Changes in renal G-protein subunitlevels, e.g., decreased Gq levels, and post-G-protein defectsmay occur as a consequence of hypertension (Horiuchi etal., 1992; Hussain and Lokhandwala, 1997; Michel et al.,1994).


7.3.3. D1 receptor. Because decreased renal dopamineproduction or abnormal renal sodium transporters may notbe the explanation for the failure of endogenous dopamineto engender a natriuretic effect in genetic hypertension, wehave postulated that the defect may involve the renaldopamine receptor and its cellular transduction (Jose et al.,1992, 1996, 1998; Jose and Felder, 1996).

7.3.3.1. Animal models of genetic hypertension. We and oth-ers have reported that the natriuretic effect of dopamineand D1 agonists is impaired in two animal models of hyper-tension (Chen and Lokhandwala, 1992; Felder, R. A. et al.,1990b; Hansell, 1995; Nishi et al., 1993c) and in some casesof human essential hypertension (O’Connell et al., 1997).In the SHR and in the Dahl salt-sensitive rat, the impairednatriuretic effect of dopamine and D1-like agonists is associ-ated with a decreased ability to inhibit NHE (Albrecht etal., 1996; Gesek and Schoolwerth, 1991; Horiuchi et al.,1992; Debska-Slizien et al., 1994b) and Na1/K1-ATPaseactivity (Chen et al., 1993; Debska-Slizien et al., 1994b;Eisner et al., 1997; Gurich and Beach, 1994; Nishi et al.,1993b,c) in renal proximal tubules; the mTAL may also beinvolved in Dahl salt-sensitive rats (Nishi et al., 1993c).The decreased ability of dopamine and D1 agonists to in-hibit these transporters has been related to a defectivedopaminergic stimulation of second messenger productionfrom AC, PLC, and PLA2 (Chen et al., 1992; Felder, R. A.et al., 1990a, 1993; Hussain and Lokhandwala, 1996; Kan-sra et al., 1995; Kinoshita et al., 1989; Nishi et al., 1993c;Ohbu et al., 1993, 1995; Ohbu and Felder, 1993). The de-creased ability of D1-like receptor to stimulate effector en-zymes, e.g., AC, is not due to the effector enzyme or toG-proteins because the ability of forskolin and guanine nu-cleotides to stimulate AC activity (Felder, R. A. et al.,1990a, 1993; Kinoshita et al., 1989; Ohbu et al., 1993,1995) or inhibit NHE activity (Albrecht et al., 1995) is notimpaired in the renal PCT of SHRs. Parathyroid hormonealso increases AC activity to a similar extent in the PCT ofWKY rats and SHRs, a result indicating specificity of thedefect to a D1-like receptor (Felder, R. A. et al., 1990a; Ki-noshita et al., 1989). These abnormalities are noted as earlyas 3–4 weeks of age, before the onset of hypertension, afinding indicating a primary rather than a secondary abnor-mality (Felder, R. A. et al., 1990a, 1993; Hussain andLokhandwala, 1997; Kinoshita et al., 1989; Ohbu et al.,1993, 1995). Furthermore, the attenuated natriuresis andinhibition of NHE activity in renal proximal tubules ofSHR by D1-like agonists co-segregate with high blood pres-sure. This effect indicates an important role of D1-like re-ceptors in the pathogenesis of genetic hypertension (Al-brecht et al., 1996).

Although Na1/Pi transport, like NHE activity, is regu-lated by second messengers generated by AC and PLC(Cole et al., 1987), its dopaminergic regulation is not im-paired in the SHR (Debska-Slizien et al., 1994b). The per-sistence of normal Na1/Pi regulation by dopamine in theSHR suggests that there is a defect downstream from the re-

ceptor (Debska-Slizien et al., 1994b) or that a regulator ofD1-like receptor activity is present at a site of D1-like recep-tor regulation of NHE (e.g., PCT), but not at the site ofD1-like receptor regulation of Na1/Pi activity (e.g., PST)(Isaac et al., 1992).

The ability of dopamine and D1-like agonists to stimulateAC activity is impaired in the PCT, but not in the CCD, ofrats with genetic hypertension (Ohbu and Felder, 1993).The inhibitory effect of endogenous dopamine on Na1/K1-ATPase activity in the renal medulla is also not impaired inthe SHR (Eisner et al., 1997), although the mTAL hasbeen reported to have a defective dopaminergic response inthe Dahl salt-sensitive rat (Nishi et al., 1993c). The abilityof dopamine and fenoldopam to stimulate AC activity isalso preserved in the striatum of the brain (Felder, R. A. etal., 1993). Thus, a D1-like receptor defect that is receptor-,nephron segment-, and organ-specific is present in animalmodels of genetic hypertension (Felder, R. A. et al., 1993;Jose et al., 1992, 1996, 1998; Jose and Felder, 1996; Kino-shita et al., 1989; Ohbu and Felder, 1993). Furthermore, thedefect is proximal to G-proteins and presumably at thelevel of a D1-like receptor. The defect is not due to geneticdrift or casual relation because it co-segregates with the hy-pertensive phenotype (Albrecht et al., 1996).

7.3.3.2. Human essential hypertension. The cause(s) of es-sential hypertension remains elusive, probably because itis a heterogeneous disease in which both genetics and en-vironment contributes to elevate blood pressure. The bloodpressure difference between a hypertensive strain of rat anda normotensive control has been attributed to the influenceof 2–6 genetic loci (Yen et al., 1974). Each of the individualgenetic loci that contribute incrementally to hypertensionhas specific biochemical or physiologic phenotypes. Thereis much evidence of the involvement of dopamine andgenes that regulate its function in the pathogenesis ofhypertension. Some studies have shown that the infusion ofdopamine or D1-like analogues in human hypertensive sub-jects results in enhanced natriuresis (Andrejak and Hary,1986; Kikuchi et al., 1982; Schoors and Dupont, 1991;Shigetomi et al., 1991). This effect has been assumed byothers to be due to up-regulation of renal dopamine re-ceptors secondary to decreased renal dopamine levels(Schoors and Dupont, 1991). Recent investigations haveshown that the natriuretic effect of fenoldopam indeed isenhanced in young salt-sensitive hypertensive subjects(O’Connell et al., 1997). However, the inhibitory effect offenoldopam at the proximal tubule (determined by lithiumclearance) is impaired. Furthermore, in primary cultures ofrenal proximal tubules from hypertensive subjects, dopa-mine and fenoldopam have an attenuated ability to stimu-late AC activity similar to that described in animal mod-els of genetic hypertension (Sanada et al., 1997a). Thesestudies suggest that the D1-like action in renal proximal tu-bules is defective in some humans with essential hyperten-sion and that the increased natriuresis with fenoldopam isdue to an enhanced effect at more distal sites along the


nephron (O’Connell et al., 1997; Nielsen and Pedersen,1997).

7.3.3.3. Molecular defect in genetic hypertension. Although thedata suggest a defect of a renal D1-like receptor in genetichypertension, renal D1-like receptor density and distribu-tion (determined by radioligand binding) are similar inWKY rats and SHRs (Felder, R. A. et al., 1993; Horiuchi etal., 1992; Kinoshita et al., 1989; Sidhu et al., 1992; Vach-vanichsanong et al., 1995). The expression of the twomammalian D1-like receptors D1A and D1B in renal proxi-mal tubules is also similar in these two rat strains (unpub-lished observations). However, there may be a defect of aD1-like receptor in genetic hypertension. Although theD1-like receptor exists in a low- and high-affinity state inthe renal proximal tubule of the WKY rat, it exists only inthe low-affinity state in the SHR (Felder and VanCampen,1990; Horiuchi et al., 1992; Kinoshita et al., 1989; Sidhu etal., 1992; Vachvanichsanong et al., 1995, 1996); the high-affinity state is linked with the “active” D1-like receptor(Horiuchi et al., 1992). The ability of N-ethyl maleimide toalkylate the D1-like receptor and the ability of sodium to al-ter its binding properties are no longer evident in renalproximal tubules of SHR (Felder and VanCampen, 1990;Horiuchi et al., 1992; Sela and Sidhu, 1996; Sidhu et al.,1992). Because the primary sequence (coding and noncod-ing regions) of the two D1-like mammalian receptors (D1A

and D1B) is not different between WKY rats and SHRs orbetween Dahl salt-sensitive and Dahl-salt resistant rats(Burgess et al., 1993; unpublished observations), we havetaken these studies to indicate a defect in the conformationof a D1-like receptor, probably as a result of an abnormalpost-translational modification (Jose et al., 1996; Jose andFelder, 1996).

The D1-like receptor defect in the renal proximal tubuleof rats with genetic hypertension is similar to the uncou-pling of the receptor from its G-protein/effector enzymecomplex in homologous desensitization (Chuang et al.,1996; Ferguson et al., 1996; Lefkowitz et al., 1993; Lohse etal., 1996). Heterologous desensitization (which occurswhen prolonged exposure to one agonist attenuates the re-sponse to other classes of agonists) of D1-like receptors isunlikely because b-adrenergic receptors and parathyroidhormone receptors in the kidney are not desensitized(Felder, R. A. et al., 1993; Jespersen et al., 1997; Kinoshitaet al., 1989; Michel et al., 1993; Neuser et al., 1990; Ons-gard-Meyer et al., 1994). There are studies suggesting thatreceptors other than D1-like receptors (e.g., b-adrenergicand a1-adrenergic receptors) may also be less reactive in theSHR than in WKY rats. However, these studies were per-formed after hypertension was established; the develop-ment of hypertension adversely affects the cAMP pathway(Horiuchi et al., 1992; Michel et al., 1994). Homologousdesensitization (which occurs with prolonged exposure to aspecific agonist and attenuates the response to the sameclass of agonists) (Chuang et al., 1996; Ferguson et al.,1996; Lefkowitz et al., 1993; Lohse et al., 1996) resembles

the uncoupling of the D1-like receptor from the G-protein/enzyme complex in the renal proximal tubule of the SHR.However, the uncoupling is not due to homologous desensi-tization; the “defect” is present at 3 weeks of age (Felder,R. A. et al., 1993; Hussain et al., 1997; Kinoshita et al.,1989; Ohbu et al., 1993, 1995) when renal dopamine levelsdo not differ in hypertensive and normotensive rats (Racz etal., 1986). The “defect” is also present in immortalized PCTcells from SHRs (Yu et al., 1996c) and primary cultures ofhuman renal proximal tubules from patients with essentialhypertension (Sanada et al., 1997a), a setting in which nodopamine is being made (exogenous L-DOPA is needed fordopamine synthesis in proximal tubules). Furthermore,when renal dopamine levels are increased over a 12-hr pe-riod in WKY, renal D1-like receptor density decreases (Ki-noshita et al., 1990); renal D1-like receptor density is simi-lar in WKY rats and SHR (Felder, R. A. et al., 1993;Horiuchi et al., 1992; Kinoshita et al., 1989; Sidhu et al.,1992; Vachvanichsanong et al., 1995). Preliminary studiessuggest that the renal proximal tubular D1A receptor (butnot the D1B receptor) is “hyper”-serine-phosphorylated inthe SHR compared with the WKY rat (Yu et al., 1996a).Because G-protein-related kinases (GRKs) are involved inthe phosphorylation of receptors and result in their desensi-tization, it is of interest that GRK activity and GRK2 ex-pression are increased in lymphocytes of patients with es-sential hypertension (Gros et al., 1997). GRK2 is involvedin the phosphorylation of several G-protein-coupled recep-tors, including D1 receptors (Tiberi et al., 1996). Whetherthese changes are secondary or primary is not known. How-ever, hypertension caused by chronic administration of an-giotensin II or norepinephrine is associated with increasedactivity and expression of GRK5 in rat aortic smooth mus-cles (Ishizaka et al., 1997). Although the molecular mecha-nism of the uncoupling of the D1-like receptor is notknown, the D1A receptor is important in the pathogenesisof hypertension because disruption of this gene in mice in-creases blood pressure and produces diastolic hypertension(Albrecht et al., 1996). Of interest is the observation ofcomplete suppression of D1-like receptor expression and theinability of dopamine to stimulate AC activity in tubules ofmice homozygous to the mutant D1A receptor. This resultmay indicate that the D1B receptor is “silent” in renal prox-imal tubules. If the impaired transduction of the D1-like sig-nal can be equated to sodium retention in these mutantmice, then an abnormal regulation of D1-like receptors maylead to salt-sensitive hypertension. Because D1-like recep-tors may positively regulate renin secretion, decreased ac-tivity of these receptors may produce low or normal reninhypertension.

7.3.3.4. Interaction with the renin-angiotensin system. In therat, the D1A, but not the D1B, receptor positively regulatesrenin release from juxtaglomerular cells (Yamaguchi et al.,1997). However, the D1 receptor is not expressed in juxta-glomerular cells in humans (Ozono et al., 1997); the D5 re-ceptor (unpublished studies) may correspond to the D1-like


receptors identified by radioligand binding (Ricci et al.,1993). Aberrant regulation of D1-like receptors may haveeffects on other systems that adversely affect renal regula-tion of fluid and electrolyte balance and blood pressure. Forexample, dopamine via cAMP has been shown to be impor-tant in the regulation of angiotensin II Type 1 (AT1)mRNA and protein levels in the kidney (Cheng et al.,1996, 1998; Harris et al., 1997). The ability of high L-DOPAto decrease AT1 mRNA and protein levels in the youngSHR (4 weeks) suggests that D1-like action is preserved(Cheng et al., 1998). Because the ability of D1-like agoniststo increase cAMP production in renal proximal tubule cellsis already impaired in the young SHR (3–4 weeks) (Felder,R. A., et al., 1993; Kinoshita et al., 1989), a high dose ofL-DOPA may overcome such a defect in the young, but notin the older, SHR. Dopamine on the one hand and angio-tensin II and norepinephrine on the other have contrastingeffects on renal tubular transport, the former decreasing so-dium transport and the latter producing the opposite effect(Chen et al., 1991; Chen and Lokhandwala, 1993; Clarket al., 1991; Gesek and Schoolwerth, 1990; Nord et al.,1987; Sheikh-Hamad et al., 1993). An unopposed effect ofAT1 receptors and norepinephrine may explain the en-hanced effect of angiotensin II and adrenergic nerves (andother ligands) on renal proximal tubular transport in theSHR (Beach, 1992; DiBona and Kopp, 1997; Kato et al.,1986; Thomas et al., 1988).

7.3.4. D3 receptor. The renin-angiotensin system hasbeen implicated in the pathogenesis of essential hyperten-sion. Patients with essential hypertension have beengrouped into those with low, normal, or high levels ofplasma renin activity (Sealy et al., 1996). Why there is thisvariability in plasma renin activity is not known. Except forangiotensinogen, there are no mutations of any of the genesdirectly involved in angiotensin II production (renin, con-verting enzyme) or angiotensin receptors that are linked tothe high blood pressure in essential hypertension (Lifton,1996). The mechanism by which the mutation of the an-giotensinogen gene produces hypertension is not known.There is also no animal model of high-renin hypertensionthat does not involve structural damage to the kidney (re-nal artery stenosis) or the production of transgenic animalsexpressing increased copies of angiotensinogen or renin.Although the adult SHR is generally considered a form ofnormal- or low-renin class of hypertension, basal renin re-lease is actually increased during the developmental phaseof hypertension in this genetic model (Henrich and Levi,1991). A D1-like receptor (specifically, the D1 receptor inthe rat) is involved in the stimulation of renin release (An-tonipillai et al., 1989; Kurtz et al., 1988; Yamaguchi et al.,1997) and angiotensinogen gene expression (Wang et al.,1996); thus, an abnormality of a D1-like receptor may be in-volved in the pathogenesis of low-renin essential hyperten-sion. In contrast, D2-like receptors have been shown to in-hibit renin release (Jeffrey et al., 1988; MacDonald et al.,1988; Worth et al., 1986). The D2-like receptor that nega-

tively regulates renin secretion may be the D3 receptor be-cause it is expressed in juxtaglomerular cells, but the D2Long

receptor is not (Sanada et al., 1997b). Quinpirole, a D2-likeagonist with preference for the D3 and D4 receptor over theD2 receptor, decreases AC activity, a mechanism involvedin the stimulation of renin secretion (Sanada et al., 1997b).Z1046, a dopamine agonist with preference for the D3 andD4 receptors over the D2, D1, and D5 receptors, inhibitsrenin secretion (Jose et al., 1997). Mutant mice lackingfunctional D3 receptors have higher renal renin levels andblood pressures than do wild-type mice. Moreover, the AT1

antagonist losartan normalizes systolic blood pressure inhomozygous mice, but only transiently decreases it in wild-type mice. Renal nerve activity is not increased in D3 mu-tant mice because renal norepinephrine content is notgreater in homozygous mice than in heterozygous or wild-type mice. Thus, disruption of the D3 receptor increases sys-tolic blood pressure and produces diastolic hypertension bya mechanism that is due in part to a failure to suppress therenin-angiotensin system. A decreased ability to excrete asodium load may also contribute, at least in the homozygousmice (Asico et al., 1997). The relation, if any, of the in-crease in D3 receptors in patients with essential hyperten-sion and the “D3 receptor knockout studies” remains to bedetermined (Ricci et al., 1997).

8. CONCLUSIONS

All the mammalian dopamine receptors, initially clonedfrom the brain, have been found to be expressed outside theCNS in such sites as the adrenal gland, blood vessels, ca-rotid body, intestines, heart, parathyroid gland, and thekidney and urinary tract. Dopamine receptor subtypes aredifferentially expressed along the nephron, where they reg-ulate renal hemodynamics and electrolyte and water trans-port, as well as renin secretion. Exogenous dopamine, atlow doses, selectively occupies its receptors to decrease vas-cular resistance and increase renal blood flow, with variableeffects on glomerular filtration rate. Additional renal effectsinclude an increase in solute and water excretion caused byhemodynamic and tubular mechanisms. The ability of renalproximal tubules to produce dopamine and the presence ofreceptors in these tubules suggest that dopamine can act inan autocrine or paracrine fashion. Endogenous renaldopamine increases solute and water excretion by effects atseveral nephron segments (proximal tubule, mTAL, CCD).The magnitude of the inhibitory effect of dopamine oneach nephron segment is modest, but the multiple sites ofaction along the nephron result in impressive increases inexcretory rate. The renal effects of dopamine are most ap-parent under conditions of solute (e.g., sodium, phosphate)or protein load.

D1-like receptors, probably of the D1 subtype, vasodilatethe kidney, inhibit sodium transport in proximal tubules,and increase renin secretion. D1-like receptors also decreasesodium transport in the mTAL and in the CCD. Presynap-tic D2-like receptors are also vasodilatory. Postsynaptic


D2-like receptors, by themselves, stimulate renal proximalsodium transport and inhibit the action of vasopressin atthe CCD. However, in concert with D1-like receptors,postsynaptic D2-like receptors may act synergistically to in-hibit sodium transport in the renal proximal tubule and inthe CCD. The ability of postsynaptic D2-like receptors,probably of the D3 subtype, to inhibit renin release maycounteract the stimulatory effect of D1-like receptors andcontribute to their synergistic action to increase sodium ex-cretion in sodium-replete states.

Abnormalities of dopamine function may be importantin the pathogenesis of hypertension in animal models of es-sential hypertension and human essential hypertension.Defective regulation of the D1 receptor in the kidney maybe an important cause of salt-sensitive low-renin hyperten-sion, whereas defective regulation of the D3 receptor maybe a cause of high-renin essential hypertension. The exactmolecular mechanisms by which these defects produce hy-pertension remain to be deciphered.

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Renal Dopamine Receptors in Health and Hypertension

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