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INVITED REVIEW

Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice

¹Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China; Departments of ²Pediatrics and ³Medicine, Georgetown University Medical Center, Washington, District of Columbia; ⁴Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia; ⁵Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, District of Columbia

	ABSTRACT

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Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones/humoral factors, such as aldosterone, angiotensin, catecholamines, endothelin, oxytocin, prolactin pro-opiomelancortin, reactive oxygen species, renin, and vasopressin. Dopamine receptors are classified into D₁-like (D₁ and D₅) and D₂-like (D₂, D₃, and D₄) subtypes based on their structure and pharmacology. In recent years, mice deficient in one or more of the five dopamine receptor subtypes have been generated, leading to a better understanding of the physiological role of each of the dopamine receptor subtypes. This review summarizes the results from studies of various dopamine receptor mutant mice on the role of individual dopamine receptor subtypes and their interactions with other G protein-coupled receptors in the regulation of blood pressure.

knockout mice; dopamine receptor

Dopamine receptors expressed in mammals belong to the -group of the rhodopsin family of G protein-coupled receptors (GPCRs; class A, family A, or family 1) (55, 177, 186, 215). The five mammalian dopamine receptor subtypes, identified by molecular cloning, differ in their primary structures and have distinct affinities for dopamine receptor agonists and antagonists. The D₁-like receptors, comprising the D₁ and D₅ receptor subtypes, couple to the stimulatory G proteins G_s and G_olf and activate adenylyl cyclases. The D₂-like receptors, comprising the D₂, D₃, and D₄ receptor subtypes, couple to the inhibitory G proteins G_i and G_o and inhibit adenylyl cyclases and modulate ion channels (104, 268).

In general, D₁-like receptors are expressed postsynaptically/postjunctionally, whereas D₂-like receptors can be expressed presynaptically/prejunctionally as well as postsynaptically/postjunctionally (19, 81, 95, 115, 217, 223, 261, 265, 268). Although the dopamine receptor subtypes are expressed in patterns unique to the subtype, they may be coexpressed within individual cells or in distinct cells in the same organ, including those of the kidney, intestines, and blood vessels. This situation often precludes the assignment of one individual receptor subtype to a particular system. Moreover, studies on the distinct functional properties of dopamine receptor subtypes expressed in vivo are limited by the lack of agonists and antagonists with selectivity for the individual receptor subtypes. In recent years, a number of laboratories have used gene targeting, via homologous recombination, to generate mice deficient in one or more of the dopamine receptor subtypes (2, 5, 17, 19, 22, 32, 56, 58, 81, 93, 95, 115, 138, 201, 217, 223, 235, 261).

Several recent studies have shown that in addition to specific intramolecular interactions that could define the activation states of GPCRs, intermolecular interactions may also be important (37). Specifically, GPCRs can regulate the function of other receptors by altering expression and/or via direct protein-protein interactions (187).

A number of direct interactions between dopamine receptors and other GPCRs, as well as between dopamine receptor subtypes, have been described in the central nervous system. In neostriatal slices, D₁ receptor activation affects the trafficking of N-methyl-D-aspartate (NMDA) receptors between subcellular compartments (59). Conversely, NMDA receptor activation alters D₁ receptor subcellular distribution (218). The D₁ receptor and subunits NR₁ and NR₂ of the NMDA receptor physically interact in cell lines and hippocampal neurons, resulting in D₁ receptor regulation of NMDA-elicited currents (77, 131, 181). There is a mutually inhibitory modulation between D₅ and GABA_A receptors that results from a protein-protein interaction between the D₅ receptor and the ₂-subunit of the GABA_A receptor (140). The A₁ adenosine receptor heterodimerizes with D₁ receptors (80), whereas the closely related A_2A adenosine receptor heterodimerizes with D₂ receptors (40, 75, 92). These interactions result in cointernalization, cross-desensitization of signaling activities, and functional antagonism between the receptors. D₂ receptors interact physically through heterooligomerization with somatostatin receptor 5 and create a novel receptor with enhanced functional activity and pharmacological properties different than those of the individual receptors (200) that may explain the synergistic interactions between somatostatin and dopamine in the central nervous system (106).

D₁ and D₂ receptors physically interact forming a heteromeric protein complex and coexpress and colocalize within neurons in the human and rat brain. D₁ and D₂ receptor coactivation generates a novel PLC-mediated calcium signal, indicating that D₁ and D₂ receptors acquire a new cellular function when coactivated in the same cell (132). Recombinant human dopamine D₂ and D₃ receptors form functional heterodimers upon coexpression in COS-7 cells, and D₂ and D₃ receptor coexpression enhances the potency of D₂ receptor agonists in transfected cells (149, 214). Because the ultimate effect of dopamine is the sum of the interactions of the different dopamine receptor subtypes and other GPCRs (which may be dependent on the state of sodium balance), impairment of these interactions may result in defective regulation of sodium transport and hypertension.

This review summarizes the role of the different dopamine receptor subtypes in epithelial ion transport, renal physiology, and blood pressure regulation, taking into account clues obtained from mutant mice. Moreover, we also review the role of each dopamine receptor subtype in the pathogenesis of hypertension.

D₁ Receptors

Localization of the D₁ receptor subtype.
THE KIDNEY. Earlier autoradiographic, radioligand binding, and functional studies using D₁-like receptor agonists and antagonists have shown the presence of D₁-like receptors in the renal cortex (proximal tubules) but not in glomeruli or the medulla in the rat kidney (71, 72, 73, 90, 98, 230). However, glomerular mesangial cells (222) and podocytes (31), in culture, express D₁-like receptors. As aforementioned, these studies are limited because the ligands cannot distinguish D₁ from D₅ receptors.

D₁ receptor mRNA is expressed in the rat renal cortex (proximal and distal tubule, arteriole, and juxtaglomerular apparatus) but not in the glomerulus or medulla (169, 248, 250). Immortalized renal proximal tubule cells from the rat (171), mouse (unpublished observations), opossum (160), human (241), and pig (123) also express D₁ receptors.

Immunohistochemical and electron microscopic studies have revealed D₁ receptors in the cortex and medulla in the rat (9, 170), mouse (5), and human kidney (178), specifically in apical and basolateral membranes of the proximal and distal convoluted tubule, medullary thick ascending limb of Henle, macula densa, and cortical collecting duct. There are more D₁ receptors in the S3 segment than in S1 and S2 segments of the proximal tubule of the rat kidney (unpublished observations). The expression of D₁ receptors in the collecting duct has not been detailed, but dopamine does not stimulate cAMP production in the inner medullary collecting duct (148). The inhibition of vasopressin action by dopamine in this nephron segment has also been attributed to stimulation of ₂-adrenergic receptors (62).

D₁ receptors are observed throughout the renal vasculature, including juxtaglomerular cells in rats (9, 170, 250), but only in large intrarenal arteries in humans (178) (Table 1). In agreement with the latter finding, selective D₁-like receptor stimulation increases plasma renin activity in rats but not in humans (188); the effect in mice is not known. D₁ receptor immunostaining in renal veins has not been described. Consistent with mRNA studies and adenylyl cyclase activation in response to D₁-like receptor agonist (70), D₁ receptors are not expressed in glomeruli in either the rat or human kidney. Immunoblot studies have revealed the presence of several forms of D₁ receptors in the rat and human renal proximal tubule from 50 to 210 kDa (260), consistent with data obtained in brain tissue (109).

Physiology of the D₁ receptor.
RENAL FUNCTION. Endogenous renal dopamine is a major physiological regulator of renal ion transport (104, 268). During conditions of moderate sodium balance, >50% of renal sodium excretion is regulated by D₁-like receptors (104, 268). Stimulation of the D₁-like receptor by exogenous ligands results in an increase in sodium excretion that is in part due to an increase in renal blood flow and a direct inhibition of renal tubular sodium transport (104, 265, 268); the glomerular filtration rate is variably affected (73, 164, 171, 231). In contrast, inhibition of renal D₁-like receptors decreases sodium excretion without affecting renal blood flow or the glomerular filtration rate in sodium-replete states (42, 73, 114).

As indicated above, the D₁-like receptor family is composed of two receptor subtypes: D₁ and D₅. The D₁-like receptor subtype mediating the natriuretic effect of D₁-like receptor is not known because of the lack of specific agonists for each D₁-like receptor subtype. Because cAMP is involved in the inhibition of renal ion transport by D₁-like receptors and the D₁ receptor increases cAMP production to a greater extent than the D₅ receptor in renal proximal tubule cells (206), it is likely that the natriuretic effect of dopamine is due mainly to the D₁ receptor in this nephron segment. This remains to be tested, however. Direct evidence of the involvement of the D₁ receptor in the inhibition of renal sodium transport comes from studies with a chronic selective intrarenal cortical infusion of D₁ receptor antisense oligodeoxynucleotides, which selectively decrease D₁ receptor protein without affecting D₅ receptors (239). In this study, sodium excretion during a normal or high salt intake is decreased by the selective renal cortical inhibition of D₁ receptor expression (239).

D₁-like receptors decrease ion transport in many segments of the nephron (proximal tubule, medullary thick ascending limb of Henle, and cortical collecting duct) by inhibiting the activities of sodium/hydrogen exchanger 3 (NHE3; SLC9A3), sodium-phosphate cotransporter (NaPi-IIa/SLC34A1 and NaPi-IIc/SLC34A3), and Cl^–/HCO₃^– exchanger (SLC26A6) at the apical membrane and electrogenic Na⁺/HCO₃^– cotransporter (NBCe1A; SLC4A4) and Na⁺-K⁺-ATPase at the basolateral membrane (5, 11, 16, 21, 24, 86, 97, 164, 180, 247). In the medullary thick ascending limb of Henle, D₁-like receptors decrease sodium transport (78) by inhibiting Na⁺-K⁺-ATPase activity, but dopamine actually increases sodium-potassium-chloride cotransporter (NKCC2; SLC12A1) activity in this nephron segment (10). We have suggested that D₁-like stimulation of NKCC2 may be important in K⁺ recycling. However, eicosanoids [20-hydroxyeicosatetraenoic acid (20-HETE)] may synergize with D₁-like receptors to inhibit NKCC2 activity. G protein-dependent, cAMP/PKA-dependent, and PKC-independent mechanisms are involved in the D₁-like receptor inhibition of Na⁺/Pi₂, NHE3, Na/HCO₃^– cotransporter, and Cl^–/HCO₃^– exchanger activity, including their translocation out of brush-border membranes (20, 23, 24, 68, 125, 180, 245). In contrast, D₁-like receptors inhibit Na⁺-K⁺-ATPase activity via cAMP/PKA, certain PKC isoforms, and 20-HETE, which internalize its subunits (15, 57, 65, 86, 101, 121, 135, 167, 176, 211). The inhibitory effect of D₁-like receptors on Na⁺-K⁺-ATPase is nephron segment specific: PKA is involved in D₁-like receptor-mediated inhibition in the cortical collecting duct, whereas PKC is involved in the proximal convoluted tubule; eicosanoids are involved in all nephron segments studied (15, 57, 65, 101, 118, 135, 167, 211, 212).

In addition to the direct inhibition of D₁-like receptors on sodium excretion, D₁-like and D₂-like receptors interact to enhance this effect. We have reported that the increase in sodium excretion induced by Z-1046, a dopamine receptor agonist with a rank order potency of D₄ > D₃ > D₂ > D₅ > D₁, is blocked by either D₁-like or D₂-like receptor antagonists (127). D₂-like receptors may potentiate the inhibitory effect of D₁-like receptors on Na⁺-Pi cotransport, NHE3, and Na⁺-K⁺-ATPase activities in renal proximal tubules (see below).

CARDIOVASCULAR FUNCTION. Circulating concentrations of dopamine are too low to stimulate its own receptors (104, 268). Dopamine administered systemically to increase blood pressure exerts its effect via nondopaminergic receptors; β-adrenergic receptors increase cardiac output, whereas -adrenergic receptors increase vascular resistance. D₁ receptors are expressed in the human and rat heart (152, 178, 277). However, D₁-like receptor agonists do not directly affect myocardial contractility (184).

Dopamine, at low concentrations, dilates resistance arteries via D₁-like receptors (87, 104, 268). The vasorelaxant effect of dopamine in the rabbit pulmonary artery has been reported to be both endothelium dependent and independent (251). However, in the mesenteric artery, the vasodilatory effect of the D₁ receptor agonist is endothelium independent (269, 270). The vasorelaxant effect of the D₁ receptor is enhanced by calcium channel blockade with nifedipine, indicating that calcium channels are involved in the vasodilatory effect of D₁ receptors (269, 270). The vasodilatation induced by D₁-like receptors is probably mediated by cAMP; inhibition of Na⁺-K⁺-ATPase activity would cause vasoconstriction. In coronary arteries, cAMP cross activation of cGMP-dependent protein kinase stimulates large-conductance calcium-activated potassium channel activity (244).

INTERACTIONS WITH THE RENIN-ANGIOTENSIN SYSTEM. The D₁ receptor may also regulate renal and cardiovascular function by interacting with other systems, including the renin-angiotensin-aldosterone and sympathetic nervous systems. Angiotensin type 1 (AT₁) receptors stimulate all renal proximal tubular ion-transporting proteins that are inhibited by D₁-like receptors (46, 64, 220). The natriuretic effect of D₁-like receptors is enhanced when angiotensin II production is decreased or when AT₁ receptors are blocked (46). The renal vasoconstrictor effect of angiotensin II can also be antagonized by D₁-like receptor agonists. D₁-like and AT₁ receptors have opposing effects on the generation of second messengers: D₁-like receptors stimulate adenylyl cyclases, whereas AT₁ receptors inhibit them. While both D₁-like and AT₁ receptors stimulate PLC activity, they stimulate different PKC isoforms (18, 63, 88, 256). Dopamine, via the D₁-like receptor, also decreases AT₁ receptor expression and angiotensin II binding sites in renal proximal tubule cells from normotensive Wistar-Kyoto (WKY) rats (49, 267, 274). However, the D₁ receptor can also inhibit AT₁ receptor function by direct physical interactions (267), whereas the D₅ receptor may be responsible for the D₁-like receptor inhibition of AT₁ receptor expression (274) (see below). In contrast, angiotensin type 2 (AT₂) receptors participate in the natriuresis induced by D₁-like receptors (203). There is a negative interaction between D₁-like and adrenergic receptors, similar to the negative interaction between AT₁ and D₁-like receptors in the regulation of renal sodium transport and VSMC contractility. In opossum kidney cells, the dopaminergic inhibition of Na⁺/Pi₂ is potentiated by treatment with -adrenergic receptor antagonists (129). We have preliminary data showing that the increase in proliferation of VMSCs produced by stimulation of ₁-adrenergic receptors is inhibited by stimulation of D₁-like receptors (Li Z, Zeng C, and Jose PA; unpublished observations).

D₁ receptors and hypertension.
IMPAIRED RENAL D₁ RECEPTOR FUNCTION. In rodents with genetic hypertension [spontaneously hypertensive rats (SHRs) and Dahl salt-sensitive rats], D₁-like receptor agonist-mediated diuretic and natriuretic responses are impaired (47, 73, 104, 113, 164, 268). The impaired natriuretic response to exogenous D₁-like agonists is accompanied by an impaired natriuretic effect of endogenous renal dopamine (47, 73, 127). The impaired natriuretic effect of D₁-like receptor agonists has specificity, because the natriuretic effect of cholecystokinin is not impaired in SHRs (127). In hypertensive humans, the ability of D₁-like receptor agonists to inhibit proximal tubular reabsorption is impaired (171); however, the overall natriuretic effect of exogenously administered D₁ receptor agonists may be greater in hypertensive subjects than in normotensive subjects (163, 171). This is due to the fact that the actions of D₁-like receptors on renal hemodynamics and distal renal tubule function (see below) are preserved in hypertension (163, 171).

The decreased ability of D₁-like receptor agonists to inhibit ion transport in rodent genetic hypertension is due to diminished D₁-like receptor inhibition of NHE3 (5), Cl^–/HCO₃^– exchanger (180), Na⁺/HCO₃^– cotransporter (125), and Na⁺-K⁺-ATPase activities (101, 164). The impaired inhibition of ion transport by D₁-like receptors in rodent models of genetic hypertension is due, in part, to impaired production of second messengers (e.g., cAMP, diacylglycerol, eicosanoids) in renal proximal tubules (45, 69, 72, 101, 103, 120, 180) and the thick ascending limb of Henle (164) but not in the cortical collecting duct (174). The impaired ability of D₁-like receptors to stimulate cAMP production in renal proximal tubules in genetic hypertension need not be due to decreased total cellular expression of D₁ receptor (259) but rather to increased serine phosphorylation and decreased expression of D₁ receptors at the plasma membrane (205, 259). The impaired ability of D₁-like receptors to stimulate cAMP production in renal proximal tubules is specific because the ability of parathyroid hormone to stimulate cAMP production or stimulate G proteins is intact (103, 120, 205); β-adrenergic function is also intact, at least in young SHRs (153). There is organ specificity because D₁ receptor action in the brain striatum is also intact (72). The impaired D₁-like receptor function is probably of genetic origin, because it precedes the onset of hypertension and cosegregates with high blood pressure (5, 72, 128, 175).

IMPAIRED ARTERIAL D₁ RECEPTOR FUNCTION. In general, the renal and nonrenal vasodilatory effects of D₁-like receptors in hypertension are not impaired (156, 171). There are, however, reports of an impaired renal vasodilatory effect of D₁-like receptor agonist in humans with essential hypertension (39) and in SHRs (43). Indeed, there is an impaired ability of D₁-like receptors to stimulate adenylyl cyclase in renal arteries of SHRs (43). We have also reported an impaired ability of D₁-like receptor agonists to vasodilate mesenteric arteries of SHRs (269).

D₁ receptor mutant mice. D₁ receptor-null (D₁^–/–) mice were generated by targeted mutagenesis. The targeting construct contained 7.0 kb of 129/Sv-derived D₁ receptor genomic sequence in the pPNT vector (5, 58). Both homozygous and heterozygous mice had greater systolic, diastolic, and mean arterial pressures than wild-type mice. Renal tubules from homozygous D₁ receptor knockout mice have no binding sites for ¹²⁵I-labeled SCH-23982, a D₁-like receptor antagonist, and do not increase cAMP accumulation in response to D₁-like receptor agonist stimulation. The response to parathyroid hormone, however, is intact. These data provide reasonable correlation between defective D₁ receptor/signal transduction and the development of hypertension in mice (5).

Deficiency of the D₁ receptor could be involved in human essential hypertension. The human D₁ gene locus at chromosome 5 at q35.1 is linked to human essential hypertension (124). A polymorphism, A-48G, identified at 248 bp of the 5'-untranslated region, is associated with essential hypertension in Japanese subjects (210) but not in Caucasian subjects (30) and has also been reported to be associated with albuminuria (191). There are no reports of the association of polymorphisms of the coding region of the D₁ receptor and essential hypertension.

D₁ receptors and blood pressure regulation summary. D₁ receptors regulate blood pressure in the long term by decreasing renal sodium transport and may interact directly and negatively to regulate AT₁ receptor function and increase AT₂ receptor expression. While D₁ receptors can also increase renin secretion, this may only be manifest in rats on a low-sodium diet or during hypovolemia (250); a role of D₁ receptors on renin secretion in humans has not been proved. D₁ receptors may also exert antihypertensive effects by preventing oxidative stress (see below). It remains to be proved, however, if D₁^–/– mice are salt sensitive and whether D₁ receptor-mediated ion transport is impaired in the renal proximal tubule of D₁^–/– mice.

D₂ Receptors

Localization of the D₂ receptor subtype.
THE KIDNEY. The D₂ receptor is expressed as D_2short and D_2long (154). It has been suggested that the D_2short receptor functions as the presynaptic receptor, whereas the D_2long receptor functions as the postsynaptic receptor; the D_2short receptor is expressed to a greater extent in presynaptic receptors than in postsynaptic receptors (111, 139). D_2long mRNA is expressed in renal tubules and glomeruli (79). Most of D₂-like receptors in the rat kidney are prejunctional (25). However, D₂ receptor protein has been described in the opossum kidney cell, a proximal tubule cell line that has some distal tubular cell characteristics (159). The expression of D₂ receptors in the intact kidney is not well documented (Table 1).

BLOOD VESSELS. D₂ receptor protein has been described in the heart and coronary artery (44). Dopamine at low and high concentrations constricts isolated porcine pial veins via postsynaptic ₂-adrenoceptors and dopamine D₁ and D₂ receptors (228). However, in the cat and other species, D₁ receptors are vasodilatory; the D₂ receptor agonist LY-141865 is vasodilatory only at high concentrations (61). The reason for this apparent species difference is not readily apparent. As stated above, D₁ receptor-mediated inhibition of Na⁺-K⁺-ATPase, per se, should lead to vasoconstriction because of an increase in intracellular sodium and, subsequently, intracellular calcium by the activation of the sodium/calcium exchanger. The D₂ receptor could cause vasoconstriction by inhibition of cAMP production but could also cause vasodilation by inhibition of norepinephrine release.

Physiological role of the D₂ receptor.
RENAL FUNCTION. D₂ receptors have variable effects on sodium transport that could not be entirely related to the lack of selectivity of D₂ receptor ligands (213). D₂ receptors can affect renal function by regulating dopamine transporter activity (130) and renal dopamine production (179). There are studies showing vasodilatory and natriuretic effects of D₂-like receptors (104, 179, 268). However, in rat renal proximal tubules, bromocriptine, a D₂-like receptor agonist with a 10-fold affinity for D₂ over D₃ receptors, stimulates Na⁺-K⁺-ATPase activity by increasing its -subunit in the plasma membrane (100, 158). Bromocriptine also increases chloride transport in the medullary thick ascending limb of the rat (85). LY-171555, a D₂-like receptor agonist with some selectivity to the D₂ receptor, stimulates Na⁺-K⁺-ATPase activity in murine fibroblasts heterologously expressing D_2Long receptors (249). Interestingly, in sodium-depleted women, dopamine produces an antinatriuretic effect (3). Sulpiride, a D₂-like receptor antagonist with an equal affinity for all D₂-like receptors, impairs the natriuretic effect of dopamine in volume-expanded women (4). Thus, it is possible that the antinatriuretic effect of the D₂ receptor may become manifest during volume depletion, whereas the natriuretic effect becomes manifest during volume-expanded states. Whether this is a direct effect or whether it is due to an interaction with other dopamine receptors (e.g., the D₁ receptor) remains to be determined.

As stated above, D₁ and D₂ receptors can heterodimerize (60) and interact with each other (183, 185). In LTK2 cells transfected with either rat D₁ or D_2Long cDNA, D₁-like receptor stimulation decreases Na⁺-K⁺-ATPase activity, whereas D₂-like receptor stimulation produces the opposite effect; these effects are transduced by increases or decreases in cAMP production, respectively (85, 96). Bromocriptine and LY-171555 inhibit adenylyl cyclase activities; this has been thought to be the mechanism of the D₂ receptor-mediated stimulation of Na⁺-K⁺-ATPase activity (100, 249). Unlike the D₃ receptor, the D₂ receptor can inhibit adenylyl cyclase activity even in the absence of adenylyl cyclase V (199), which is not expressed in the kidney (33). However, in Chinese hamster ovary (CHO) cells heterologously expressing 10 times more D₂ than D₁ receptors, stimulation of either receptor results in a potentiation of arachidonic acid release compared with those cells expressing only one receptor (117, 183). Arachidonic acid cytochrome P-450 products have been shown to inhibit renal sodium transport (12, 101, 209). Thus, D₁-D₂ synergism in the production of cAMP, PLC, and arachidonic acid products might account for the D₂ receptor-mediated natriuretic effect. The D₁ receptor-mediated activation of PKC could lead to a D_2long receptor-mediated sensitization of adenylyl cyclase VI (29). D₁ and D₂ receptors also synergistically interact to increase c-fos (50) and inhibit Na⁺-K⁺-ATPase activity (35). We have speculated that the D₂-like receptor stimulates sodium transport under conditions of "low" sodium intake; in contrast, under conditions of "moderate" sodium excess, D₂-like receptors, in concert with D₁-like receptors, inhibit Na⁺-K⁺-ATPase activity in renal proximal tubules cells and synergistically increase sodium excretion (3, 4, 34, 66, 112).

D₂ RECEPTORS AND ROS. D₂ receptors, like D₁ and D₅ receptors, may also have an antioxidant function. D₂ receptor-null (D₂^–/–) mice, which are hypertensive, have increased urinary excretion of 8-isoprostane, increased NADPH oxidase activity, and increased renal expression of NADPH oxidase subunits Nox1, Nox2, and Nox4 as well as decreased expression of the antioxidant enzyme heme oxygenase-2 in the kidneys. Apocynin, which impairs NADPH oxidase subunit assembly and activity, or hemin, an inducer of heme oxygenase, normalizes blood pressure in D₂^–/– mice (14).

D₂ receptors and hypertension. Abnormalities of D₂-like receptor function have been reported in hypertension. One of the polymorphisms of the D₂ receptor is associated with hypertension (232, 233). This polymorphism is also associated with decreased D₂ receptor expression (165). Transfer of a segment of chromosome 8 containing the D₂ receptor gene from the normotensive Brown-Norway rat onto an SHR background decreases blood pressure (122).

D₂ receptor mutant mice. The D₂ receptor gene was mutated by homologous recombination in embryonic stem cells with a targeting vector to delete all of exon 7 and the 5'-half of exon 8, the region encoding the majority of the putative third intracellular loop, the last two transmembrane domains, and the carboxy terminus. Blastocyst injection was used to generate chimeric mice on a mixed 129/Sv x C57BL/6J background. The original F2 hybrid strain (129/Sv x C57BL/6J) that contained the mutated D₂ receptor allele was backcrossed to wild-type C57BL/6J for five generations and genotyped (138). These mice have normal basic motor skills without tremor, ataxia, or abnormal stance or posture but had decreased initiation of movement. We have reported that systolic and diastolic blood pressures are higher in D₂ homozygous and heterozygous mutant mice than in control (D₂^+/+) mice. D₂^–/– and D₂^+/+ mice have a similar ability to excrete an acute saline load. -Adrenergic blockade decreases blood pressure to a greater extent in D₂^–/– mice than in D₂^+/+ mice. Epinephrine excretion is greater in D₂^–/– mice than in D₂^+/+ mice, and acute adrenalectomy decreases blood pressure to a similar level in D₂^–/– and D₂^+/+ mice. An endothelin type B (ET_B) receptor blocker for both ET_B1 and ET_B2 receptors decreases, whereas a selective ET_B1 blocker increases, blood pressure in D₂^–/– mice but not D₂^+/+ mice. ET_B receptor expression is greater in D₂^–/– mice than in D₂^+/+ mice. We have concluded that the enhanced vascular reactivity in D₂^–/– mice may be caused by increased sympathetic and ET_B receptor activities (138) and increased ROS production (14). We have also found that D₂^–/– mice have increased production of aldosterone and that treatment with a mineralocorticoid receptor blocker ameliorates hypertension in these mice (14).

In another strain of D₂^–/– mice, blood pressure is normal on a normal salt diet but is increased on a high-salt diet with a decrease in renal dopamine production (235). Sympathetic activity is not different between these D₂^–/– mice and their wild-type littermates. However, renal aromatic amino acid decarboxylase activity and dopamine synthesis are reduced in these D₂^–/– mice. Basal urine flow and sodium excretion are lower in D₂^–/– mice than in D_2+/+ mice, but dopamine increases urine volume and sodium excretion in D₂^–/– mice to levels similar to those in D₂^+/+ mice (179). As with the differences in two different strains of D₃^–/– mice, the differences between the two strains of D₂^–/– mice could be related to genetic background.

D₂ receptors and blood pressure regulation summary. D₂ receptors affect renal function by regulating dopamine production, dopamine transporter activity, and sympathetic nerve activity. D₂ receptors, by themselves, increase renal sodium transport, but coactivation of D₁ receptors produces the opposite effect. D₂ receptors regulate blood pressure by influencing sodium transport and by inhibiting ROS production. D₂ receptors may also have anti-inflammatory actions (13).

D₃ Receptors

Localization of D₃ receptors.
THE KIDNEY. Specific radioligand binding of (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), which has a high affinity for both D₂ and D₃ receptors, is reported in cortical tubules and mesangial cells of the rat kidney (26). D₃ receptor mRNA is expressed in glomerular, tubular, and vascular fractions of the rat kidney (79). D₃ receptor protein is expressed in the apical/subapical area but not in the basolateral areas of the rat renal proximal tubule (168) (Table 1). The expression of the D₃ receptor in other nephron segments has not been consistent. Nurnberger et al. (194) could not detect any D₃ receptor protein in the distal tubule, cortical collecting duct, glomeruli, and renal vessels. This is in contrast to the report of O'Connell et al. (172), in which D₃ receptor protein was found not only in the renal proximal tubule but also in the apical membrane of the distal convoluted tubule and cortical collecting duct (intercalated cells); D₃ receptor protein was also observed in glomeruli and renal blood vessels. In mice, D₃ receptor protein, detected by immunocytochemistry, is mainly found in apical vesicles, subjacent to the microvillous brush borders of the S1 segment of the proximal convoluted tubule, the macula densa, cytoplasm of the thick ascending limb of loop of Henle, distal convoluted tubule, and glomeruli, but not in the collecting duct (238). All three studies are in agreement in the absence of specific staining in the medulla. O'Connell et al. (172) could not find D₃ receptors in juxtaglomerular cells but found them expressed in the macula densa of the rat kidney. However, D₃ receptor mRNA and functional D₃ receptors have been described in rat juxtaglomerular cells in primary culture (207). The discrepancy between the findings in the kidney in situ and juxtaglomerular cells in culture suggests that the expression of D₃ receptors is conditional (e.g., culture dependent). Two species of D₃ receptor (45 and 90 kDa) are expressed in renal brush-border membranes (127) and proximal tubule cells (264), as detected by immunoblot studies.

BLOOD VESSELS. D₂-like receptors are located mainly in the intima and adventitia of blood vessels. In the rat renal artery, the D₃ receptor is located at both prejunctional (adventitia) and post-/extrajunctional sites (tunica media) (27). In contrast, in the rat mesenteric artery, we found that the D₃ receptor is expressed in both the tunicae intima and media (270). Rat pulmonary arteries do not express D₃ receptors (196), and, therefore, it is possible that the localization of the D₃ receptor is blood vessel specific.

Physiology of the D₃ receptor.
RENAL FUNCTION. The D₃ receptor agonists 7-OH-DPAT and PD-128907 (134), which have preferential selectivity for D₃ receptors over D₂ and D₄ receptors, decrease renal sodium transport (144). Acute intravenous administration of 7-OH-DPAT in salt-resistant Dahl rats increases the glomerular filtration rate and sodium and water excretion without affecting blood pressure (144). Quinerolane, a D₂-like receptor agonist with 21-fold selectivity for the D₃ receptor over the D₂ receptor, opens K⁺ channels, resulting in hyperpolarization and inhibition of Na⁺-K⁺-ATPase activity (82). PD-128907, a selective D₃ receptor agonist with a 120-fold selectivity over the D₂ receptor, infused directly into the renal artery, dose dependently increases fractional sodium excretion in WKY rats (but not in SHRs) fed a normal salt diet or high-salt diet (263). That D₃ receptors can mediate natriuresis is supported by the decreased ability of D₃ receptor-deficient mice to excrete an acute saline load (17). The renal effects of D₃ receptor activation are mediated by actions on postjunctional glomerular and tubular receptors and presynaptic modulation of norepinephrine release because renal denervation attenuates the effects of 7-OH-DPAT (155).

ARTERIES. Systemic administration of D₃ receptor agonists decreases systemic blood pressure (144, 146). The postjunctional D₃ receptor-mediated vasodilation is more manifest when renal vascular resistance is increased. Our studies in the isolated relaxed mesenteric artery have shown that two different D₃ receptor agonists, PD-128907 and 7-OH-DPAT, have no effects on basal vascular contractility (269, 270). However, when mesenteric artery rings are preconstricted by high-potassium or norepinephrine, both PD-128907 and 7-OH-DPAT induce vasorelaxation. In norepinephrine-preconstricted mesenteric artery rings, a calcium channel blocker increases the vasorelaxant effect of PD-128907, indicating that the vasorelaxant effect of the D₃ receptor is, in part, caused by a decrease in intracellular calcium. The vasodilatory effect of D₃ receptors may also involve small- and/or large-conductance calcium-activated potassium channels (50, 269), a mechanism that also occurs in renal tubules (82). The hyperpolarization caused by a decrease in intracellular potassium probably prevents the vasoconstriction that occurs with inhibition of Na⁺-K⁺-ATPase (82). As with the inhibitory effect of the D₃ receptor on sodium transport, the vasodilatory effect of the D₃ receptor is probably not related to its ability to inhibit adenylyl cyclase activity. Indeed, the D₃ receptor may not inhibit renal cAMP production because this action necessitates the presence of adenylyl cyclase V (199), which is not expressed in the kidney (33). Thus, the D₃ receptor induces a natriuresis and vasodilation via mechanisms that are different from but complement the D₁ receptor, which induces a natriuresis and vasodilation by activation of G_s and/or adenylyl cyclase activity.

D₃ RECEPTOR-MEDIATED ANTIOXIDATIVE EFFECTS. The effect of D₃ receptors on ROS is controversial. One report (67) has shown that the D₃ receptor stimulates PLD activity in human embryonic kidney (HEK)-293 cells heterologously expressing the human D₃ receptor. However, the D₃ receptor has been reported to increase a dopamine autotrophic factor that has an antioxidant action, and, thus, the D₃ receptor may have an antioxidant effect, albeit indirectly (41). The D₃ receptor is expressed in the tunica intima (269, 270), and activation of the D₃ receptor inhibits superoxide production in human brain endothelium cells as measured by a cytochrome c reduction assay (Yang Z, Zeng C, and Jose PA; unpublished observations). The hypertension in D₃ receptor-null (D₃^–/–) mice is not associated with increased production of ROS, but this may be due to increased expression of D₅ receptors in these mice (unpublished data). As discussed above, the D₅ receptor exhibits significant antioxidant activity.

INTERACTIONS WITH THE RENIN-ANGIOTENSIN SYSTEM. D₃^–/– mice have renin-dependent hypertension (17), and renal AT₁ receptor expression (266, 276) is higher in D₃^–/– mice than in their wild-type (D₃^+/+) littermates, supporting the notion discussed earlier that the dopaminergic and renin-angiotensin systems interact to regulate renal function (46, 64, 99, 220, 266). Activation of the D₃ receptor decreases AT₁ receptor expression in renal proximal tubule cells from normotensive rats (266). The D₃ receptor probably also inhibits renin release; plasma renin levels are elevated in D₃^–/– mice (17). Because renal proximal tubule cells can generate angiotensin II (48), a D₃ receptor-mediated decrease in angiotensin II formation could also be responsible for the decrease in AT₁ receptor expression since angiotensin II has been reported to increase AT₁ receptor mRNA in rats (48). However, long-term infusion of angiotensin II in vivo in rats has no effect on AT₁ receptor expression in renal proximal tubules (89). Angiotensin II does not increase AT₁ receptor expression in immortalized renal proximal tubule cells from normotensive rats (264). Therefore, the D₃ receptor, independent of angiotensin II, can regulate AT₁ receptor expression.

D₃ receptors and hypertension. D₃ receptor deficiency may be important in the development of salt-sensitive hypertension. As discussed above, D₃^–/– mice are hypertensive (17, 266, 276). Salt-resistant Dahl rats on a high-sodium diet and chronically treated with a highly selective D₃ receptor antagonist (BSF-135170) have increased blood pressure (146). D₃ Ser9Gly, heterologously expressed in CHO cells, has been reported to impair D₃ receptor-mediated inhibition of cAMP production but acquires the ability to decrease PGE₂ production (91). However, there is no association of D₃ Ser9Gly, or other D₃ receptor gene variants, with hypertension (224), although the chromosome locus of the D₃ receptor gene (3q13.3) has been linked to human essential hypertension (108, 197).

IMPAIRED RENAL D₃ RECEPTOR FUNCTION. Activation of D₃ receptors induces a natriuresis in salt-sensitive Dahl rats on a normal sodium diet but not in hypertensive salt-sensitive Dahl rats on a high-sodium diet. The diminished functional response in the hypertensive salt-sensitive Dahl rats rat is associated with a decreased [³H]7-OH-DPAT binding to renal membrane protein (146). However, the same group (145) did not find a strain-dependent natriuretic effect of 7-OH-DAT in WKY rats and SHRs. The interpretation of this study is confounded by the systemic administration of 7-OH-DPAT; the activation of D₃ receptors outside of the kidney may have obfuscated any differential effect on sodium excretion between WKY rats and SHRs. To overcome any confounding systemic effects of administered ligands, we studied the renal effects of another selective D₃ receptor agonist, PD-128907, infused directly into the renal artery in WKY rats and SHRs fed a high-salt diet. PD-128907 dose dependently increases fractional sodium excretion in WKY rats. No such effect is noted in SHRs (263). The mechanisms causing the impaired D₃ receptor in the kidney in hypertension are not completely known. The stimulatory effect of the D₃ receptor agonist PD-128907 on D₃ receptor expression is no longer evident in renal proximal tubule cells from SHRs (266). It is possible that mechanisms that impair D₁ receptor function in SHRs also impair D₃ receptor, e.g., increased GPCR-related kinase-4 (GRK4) activity (208) or the impaired synergistic interaction between D₁ and D₃ receptors occurs because of an impaired D₁ receptor function, per se. The impaired natriuretic function of D₃ receptors in SHRs may, in part, be related to the aberrant D₃ and AT₁ receptor interaction in renal proximal tubule cells (266). The D₃ receptor decreases AT₁ receptor expression in renal proximal tubule cells from WKY rats, whereas D₃ receptor stimulation increases AT₁ receptor expression in SHRs (266).

IMPAIRED ARTERIAL D₃ RECEPTOR FUNCTION. In isolated mesenteric arterial rings, D₃ agonist-induced vasorelaxation is similar in WKY rats and SHRs except at very high concentrations; this effect is via the D₃ receptor, because it can be blocked by the D₃ receptor antagonist U99194A. There is an additive vasodilatory effect between D₁ and D₃ receptors in WKY rats, which is lost in SHRs (269, 270).

D₁/D₃ RECEPTOR INTERACTIONS. D₁ and D₃ receptors have been shown to colocalize inside and outside the central nervous system (198, 272, 279). In the central nervous system, these receptors are coexpressed in the same neurons, particularly in the nucleus accumbens and caudate-putamen, and elicit opposite effects on target gene expression by regulating ERK activation and c-fos induction (279). D₃^–/– mice have blunted dorsal striatal and extrastriatal c-fos responses to D₁ receptor stimulation, indicating cooperativity between these receptors in the modulation of c-fos responses (116). Moreover, in neocortical neurons, constitutive inactivation of D₃ receptors leads to a decrease in agonist-promoted D₁ receptor activity (216). In neurons of the island of Calleja, basal c-fos expression is maintained by endogenous dopamine acting tonically on D₁ and D₃ receptors, subserving opposite effects on the same cell while having a synergistic effect in the nucleus accumbens (198). These indicate that the two receptor subtypes may affect cells in synergy or in opposition depending on the cell type or signal generated.

In denuded preconstricted mesenteric rings, D₁ receptor stimulation augments the vasodilatory effects of D₃ agonists (270). In the same way, D₃ receptor stimulation augments the vasodilatory effects of the D₁-like agonist fenoldopam (269), supporting a role of cooperative D₁/D₃ interaction in the regulation of blood pressure.

Stimulation of D₁ receptors increases D₃ receptor expression in the medulloblastoma TE671 cell line (133), embryonic thoracic aortic smooth muscle cells (A10) (270), human coronary artery VSMCs, and immortalized renal proximal tubular cells from normotensive WKY rats (269). Conversely, in renal proximal tubular cells from WKY rats, stimulation of D₃ receptors increases D₁ receptor protein expression (269, 275).

D₁ and D₃ receptors coimmunoprecipitate in VSMCs (270) and renal proximal tubular cells from WKY rats (269). The coimmunoprecipitation is increased in renal proximal tubular cells from WKY rats after long-term treatment with the D₁-like agonist fenoldopam (269) as well as after treatment with the D₃ agonist PD-128907. These effects are probably mediated by increased receptor protein expression (272) and indicate a physical interaction between D₁ and D₃ receptors. Furthermore, in renal proximal tubular cells from WKY rats, treatment with a D₃ agonist rapidly and transiently increases the amount of D₁ receptors at the cell surface membrane (272). D₁ receptors can be recruited to the cell surface membrane from the cytosol within minutes after D₁ receptor stimulation (38). The mechanisms for the synergism between D₃ and D₁ receptors may be time related. The D₃ receptor-mediated increase in cell surface membrane expression of D₁ receptors occurs in the short term, whereas the D₃ receptor-mediated increase in total D₁ receptor expression is a long-term effect (272).

The D₁/D₃ receptor interaction is impaired in SHRs. Preconstricted mesenteric artery rings are less sensitive to the vasorelaxant effects of fenoldopam in SHRs than in WKY rats. Pretreatment with the D₃ agonist PD-128907 does not produce any additional vasorelaxant effect in SHR rings as it does in WKY rings (269). There is a lack of responsiveness of SHRs to infusion of the preferential D₂-like agonist Z-1046. SHRs, unlike WKY rats, do not react to the infusion of Z-1046 by increasing glomerular filtration and water and sodium excretion (127). In renal proximal tubular cells from SHRs, the D₁-like agonist fenoldopam decreases rather than increases the expression of D₃ receptor protein, and the D₁-like agonist does not increase the coimmunoprecipitation of D₃ and D₁ receptors (269). Similarly, treatment with a D₃ agonist does not increase the expression of D₁ receptors in renal proximal tubular cells from SHRs and does not affect the coimmunoprecipitation of the two receptors (272). Furthermore, the basal level of cell surface membrane expression of D₁ receptors in renal proximal tubular cells is lower in SHRs than in WKY rats and is decreased further after treatment with a D₃ agonist (272). Taken together, these data indicate that the interaction between D₁ and D₃ receptors is absent or lessened in hypertension, and results in defective inhibition of sodium transport and relaxation of vascular smooth muscles and ultimately in the development and/or maintenance of high blood pressure.

D₃ receptor mutant mice. D₃^–/– mice were generated by targeted mutagenesis. The targeting construct contained 7 kb of 129/sv-derived D₃ receptor genomic sequence in the GKNeo cassette in the antisense orientation at the SalI site in exon 2 (2). Homologous recombination resulted in a mutant allele in which sequences downstream of Arg¹⁴⁸ in the second intracellular loop of the D₃ receptor were replaced by sequences derived from the Neo gene. Despite the similarity of the primary peptide sequences of the three members of the D₂-like receptors, the locomotor phenotype of D₃ mutants does not resemble that of D₂ mutants. D₃^–/– mice develop normally, are fertile, and, at most, show a transient and rapidly habituating locomotor hyperactivity in a novel environment. Heterozygous and homozygous D₃ mutant mice on a mixed C57/BL6 and B129 background (17) as well as those in a congenic C57BL/6 background (238) have higher systolic and diastolic blood pressures than their wild-type (D₃^+/+) littermates. In a report by Staudacher et al. (225), D₃^–/– mice, also in a congenic C57BL/6 background, have blood pressures similar to their D₃^+/+ littermate on a low, normal, or high salt intake. This report has to be interpreted with caution because C57BL/6 mice fed a high-salt diet may or may not have increased blood pressure depending on the source of these mice. Thus, C57BL/6 mice from Jackson Laboratories develop hypertension when fed a high-salt diet (226), whereas those from Taconic (253) do not. Nevertheless, these two strains of D₃^–/– mice cannot increase sodium excretion after an acute or a chronic salt load (17, 225). In our study (17), renal renin activity and AT₁ receptor expression are greater in homozygous mice than in wild-type mice; values for heterozygous mice are intermediate. Blockade of AT₁ receptors decreases systolic blood pressure for a longer duration in mutant mice than in wild-type mice. Thus, disruption of the D₃ receptor increases renal renin production and produces renal sodium retention and renin-dependent hypertension (17).

D₃ receptors and blood pressure regulation summary. D₃ receptors may regulate blood pressure directly by inhibition of renal sodium transport or indirectly by interaction with D₁ receptors or by inhibition of renin secretion and AT₁ receptor expression. These effects are impaired in hypertensive states.

D₄ Receptors

Localization of the D₄ receptor subtype.
THE KIDNEY. D₄ receptor mRNA is expressed in the kidney (151), especially in the cortical and medullary collecting ducts (227). D₄ receptor mRNA has also been reported in rat juxtaglomerular cells in culture (207). D₄ receptor protein expression is highest in the cortical and medullary collecting ducts (227) (luminal > basolateral), followed by the proximal tubule (S1 > S2 > S3; unpublished data) and distal convoluted tubule (195). D₄ receptors are not expressed in the glomerulus or loop of Henle (Table 1).

BLOOD VESSELS. The D₄ receptor is expressed in human aortic and umbilical endothelial cells and modulates von Willebrand factor secretion (262). D₄ receptor protein has been reported to be expressed in the adventitia and adventitia-media border of pulmonary (196) as well as pial and mesenteric arteries (8). D₄ receptors may be expressed pre- and postjunctionally (8). In the renal artery, D₄ receptor protein is observed perivascularly in the adventitia and adventitia-media border, especially in the afferent and efferent arterioles. D₄ receptor immunostaining disappears in the blood vessel (but not in the tubule) after renal denervation, indicating that vascular D₄ receptors are prejunctional, whereas tubular D₄ receptors are postjunctional (195). D₄ receptors are expressed in the atria but not ventricles of rats and humans (193). In contrast, the right and left ventricles of the guinea pig express D₄ receptors. The D₄ receptor agonist PD-168077 exerts a negative chronotropic and inotropic effect associated with a decrease in cAMP production in the isolated guinea pig heart preparation (83). However, D₄ receptors normally have minimal effects on the rat cardiovascular system (184).

Physiology of the D₄ receptor.
RENAL FUNCTION. D₄ receptors antagonize vasopressin- and aldosterone-dependent water and sodium reabsorption in the cortical collecting duct (137, 202). In the rabbit cortical collecting duct, the D₄ receptor-mediated decrease in sodium transport is exerted mainly at the basolateral membrane despite a greater expression of D₄ receptors in luminal membranes (202). However, renal cortical and medullary Na⁺-K⁺-ATPase activities are similar in D₄ receptor-null (D₄^–/–) and control (D₄^+/+) mice. D₄^–/– mice also do not have an impaired ability to excrete an acute saline load. It is possible that high blood pressure in D₄^–/– mice, which elicits a pressure natriuresis, obfuscates any deficit in the renal handling of sodium in D₄^–/– mice (32).

D₄ RECEPTORS AND ROS. D₄ receptors may not have inhibitory effects on the production of ROS (28).

D₄ receptors and hypertension. A locus near the D₄ receptor gene (11p15.5) has been linked to hypertension. The most intensively studied D₄ receptor polymorphism is a 48-bp repeat located in exon 3 of the D₄ receptor gene. This variant codes for a 16-amino acid sequence located in the third intracellular loop of D₄ receptor protein, a region that is thought to interact with G proteins and influence intracellular levels of cAMP (236). The number of repeats at the D₄ site varies from 2 to 10, but in Caucasian subjects the 4- and 7-repeat lengths are the most common. In this population, the long variant of the D₄ gene is associated with a 3.0-mmHg higher systolic blood pressure and 2.0-mmHg higher diastolic blood pressure (219).

D₄ receptor protein is increased in the renal cortex of SHRs relative to WKY rats, but D₄ protein in the inner medulla is similar in those two rat strains (221). The effects of D₄ agonists and antagonists on cardiovascular and renal function in genetically hypertensive rats have not been reported.

D₄ receptor mutant mice. A 129SvEv mouse genomic library was screened with a human D4.4 receptor probe. Positive phages were mapped and partially sequenced. The CsCl banded targeting vector was linearized (NotI) , electroporated into 2 x 10⁷ 129/Ola Hsd E14TG2A embryonic stem cells, and maintained under double selection. The original F₂ hybrid strain (129/Sv x C57BL/6) carrying a mutant form of the dopamine D₄ receptor was backcrossed to C57BL/6J mice. We have reported that in conscious or pentobarbital-anesthetized mice, systolic and diastolic blood pressures are elevated in D₄^–/– mice compared with D₄^+/+ littermates. Juxtaglomerular cells in culture also express D₄ receptors (207), but D₄^–/– mice do not have altered circulating or renal renin levels (32). The protein expression of the AT₁ receptor is increased in homogenates of the kidney and brain of D₄^–/– mice relative to D₄^+/+ mice, although AT₁ receptor expression in the heart is similar in the two strains. Bolus intravenous injection of the AT₁ receptor antagonist losartan initially decreases mean arterial pressure to a similar degree in D₄^–/– and D₄^+/+ littermates. However, the hypotensive effect of losartan dissipates after 10 min in D₄^+/+ mice, whereas the effect persists for >45 min in D₄^–/– mice. The absence of the D₄ receptor increases blood pressure, possibly via increased AT₁ receptor expression (32).

D₄ receptors and blood pressure regulation summary. D₄ receptors may serve to antagonize vasopressin and aldosterone effects during conditions of normal salt intake. A role of D₄ receptors in cardiovascular and renal physiology remains to be determined. However, disruption of the D₄ receptor results in increased blood pressure that may be related to the activation of AT₁ receptors in the brain. D₄ receptors may negatively regulate the expression of AT₁ receptors involved in the central regulation of blood pressure. However, areas in the brain where D₄ receptors interact with AT₁ receptors remain to be described. AT₁ receptors are also increased in the kidneys of D₄^–/– mice, but these mice do not have an impaired ability to excrete an acute sodium load. It is possible that D₄^–/– mice may not be able to excrete a chronic sodium load, but that remains to be determined.

D₅ Receptors

The D₅ receptor has generated significant interest because of its relatively high affinity for dopamine compared with the other dopamine receptors (229). Moreover, the D₅ receptor can be activated in the absence or presence of low concentrations of endogenous agonist. The physiological role of the D₅ receptor in the regulation of renal and cardiovascular function has been difficult to determine with certainty. This is due, in large part, to the fact that the D₁ and D₅ receptors are pharmacologically indistinguishable. As mentioned above, the lack of selective ligands has made it virtually impossible to selectively activate or block D₁ or D₅ receptors in vivo. Genetic approaches to this problem have been employed by investigators who used gene silencing techniques to inhibit D₁ or D₅ receptor expression and generate D₁ or D₅ receptor-deficient mice (5, 58, 93, 95, 223).

Localization of the D₅ receptor subtype.
THE KIDNEY. In rats and mice, the D₅ receptor is expressed in the proximal (S3 > S1 = S2) (unpublished observations) and distal convoluted tubules, cortical collecting duct, medullary ascending limb of Henle, and arterioles, but not in the glomeruli, juxtaglomerular cells, or macula densa (7, 9, 252, 254, 255, 280) (Table 1). The thick ascending limb of Henle and cortical collecting duct may also preferentially express the D₅ receptor over the D₁ receptor (7, 255). The opossum kidney also expresses the D₅ receptor, but its expression is lost in an opossum kidney cell line (160). Immortalized rat and human proximal tubule cells express D₅ receptors; the molecular sizes are similar to those described for the D₁ receptor (259, 274).

BLOOD VESSELS. The D₅ receptor is expressed in VSMCs outside the kidney, e.g., the coronary artery (7, 162). The vascular distribution of the D₁ receptor is similar to the D₅ receptor. As with the D₁ receptor, the D₅ receptor is expressed in pulmonary, mesenteric, and pial arteries (8, 192). In the pulmonary artery, D₅ receptor immunostaining has been reported in the tunica intima and media of extrapulmonary branches and tunica media of large-sized (but not medium or small sized) intrapulmonary branches, similar to those described for the D₁ receptor (196).

Physiology of the D₅ receptor.
RENAL FUNCTION. As indicated above, D₁-like receptors induce a diuresis and natriuresis in WKY rats (104, 268). Due to the lack of selective D₁ and D₅ receptor agonists or antagonists, the relative contribution of D₁ and D₅ receptors to the natriuretic effect caused by D₁-like receptor stimulation is not known. We have presumed that both D₁ and D₅ receptors are involved because both receptors increase cAMP production and cAMP mediates the D₁-like receptor-mediated inhibition of ion transport (206). As indicated earlier, the D₁ receptor increases cAMP production to a greater extent than the D₅ receptor in renal proximal tubule cells (206); therefore, it is possible that the natriuretic effect of dopamine is mainly due to the D₁ receptor. As also indicated above, the effect of a high-salt diet on blood pressure in D₁^–/– mice has not been determined. However, in D₅ receptor-null (D₅^–/–) mice, a high-salt diet further increases blood pressure, suggesting that the renal D₅ receptor plays an important role in the control of blood pressure by regulating renal salt transport (see below). However, the nephron segments in which the D₅ receptor regulates ion transport remain to be determined. Because D₅ receptor expression may be greater than D₁ receptor expression in distal nephron segments (255), the D₁-like receptor regulating sodium excretion in those nephron segments may be the D₅ receptor.

D₅ RECEPTOR-MEDIATED ANTIOXIDATIVE EFFECTS. Dopamine has contrasting, concentration-dependent effects on ROS production. High concentrations of dopamine and D₁-like receptors agonists (2–300 µM) increase the generation of ROS (36, 147, 173, 237, 242). Excessive stimulation of D₂-like receptors (e.g., D₂ and D₃) can also increase ROS production (246). However, D₁-like and D₂-like receptors act as antioxidants at physiologically relevant concentrations of dopamine and low concentrations of their respective agonists (51, 105, 204). It should also be noted that renal tubules do not normally synthesize dopamine at the high concentrations shown to induce oxidative stress (240).

Low concentrations of dopamine, acting on D₁ and D₅ receptors, decrease ROS in human lymphocytes (51), brain cortical cells (166), and renal VSMCs (258). Increased oxidative stress enhances vascular VSMC contractility and proliferation (190). The activation of both D₁ and D₅ receptors inhibits oxidative stress in VSMCs stimulated by PDGF-BB (258). We have reported that the D₅ receptor inhibits the production of ROS by inhibition of PLD and NADPH oxidase expression and activity in HEK-293 cells heterologously expressing the human D₅ receptor (252, 253). NADPH oxidase protein expression and activity in the kidney and brain are higher in D₅^–/– mice than in control (D₅^+/+) mice. Apocynin, a drug that impairs the assembly and activity of NADPH oxidase subunits, normalizes blood pressure and NADPH oxidase activity and subunit expression in D₅^–/– mice. In addition, the D₅ receptor increases the expression and activity of antioxidant enzymes. For example, in the same HEK-293 cells heterologously expressing the human D₅ receptor, D₅ receptor stimulation increases the activity and expression of heme oxygenase-1. Heme oxygenase-1 protein expression and activity in the kidney are lower in D₅^–/– mice than in D₅^+/+ mice. Furthermore, hemin, a heme oxygenase inducer, normalizes blood pressure and renal heme oxygenase activity in D₅^–/– mice (143). Thus, the ability of the D₅ receptor to decrease ROS production may explain, in part, its antihypertensive action.

D₅ RECEPTORS AND PROLIFERATION OF VSMC. Proliferation of VSMCs is believed to play a key role in hypertension. Vasodilator hormones such as natriuretic peptides and β-adrenergic receptor agonists have been shown to act as antigrowth factors (1, 157). As aforementioned, D₁-like receptors have also been shown to inhibit the proliferative effect of some hormones, such as PDGF-BB (258). This inhibition is reversed by a D₁-like receptor antagonist and by D₁ or D₅ receptor antisense oligonucleotides, indicating that both D₁ and D₅ receptors have an antiproliferative effect in VSMCs. Vascular D₁-like receptor agonists inhibit the proliferation of VSMCs, possibly through PKA activation and suppression of PLD, PKC, and MAPK activity (257). Inhibition of PLD and PKC is probably mediated by the D₅ receptor (102, 243, 252). D₁ receptors can stimulate PLC (69) and, therefore, PKC activity (63, 88, 101, 118, 167, 212, 256, 257), which can in turn increase D₁ receptor function. In contrast, D₅ receptors inhibit PKC activation (243); PKC can also inhibit D₅ function (107).

D₅ receptors and hypertension. D₅ receptor gene locus (chromosome 4p15.1–16.1) is linked to essential hypertension (6); the human D₅ receptor gene has polymorphisms that code for receptors with abnormal coupling to adenylyl cyclase (52).

D₅ receptor mutant mice. D₅^–/– mice were generated by injecting into C57BL/6 mouse blastocysts 129/SV embryonic stem cells containing the targeting construct generated by ligating the neomycin resistance gene in reverse orientation at the unique SfiI site in the second intracellular loop of the D₅ receptor. D₅^–/– mice are viable and develop normally (93, 94). Disruption of the D₅ receptor gene is not associated with an altered expression of the other dopamine receptors, including the D₁ receptor (93, 94).

Hollon et al. (93) reported that D₅^–/– mice (>F6) are hypertensive, with an elevated epinephrine-to-norepinephrine ratio and a greater reduction in mean arterial pressure after adrenalectomy or treatment with an -adrenergic blocker compared with D₅^+/+ mice. This study indicates that the hypertension is caused by increased sympathetic activity. However, because the percentage decrease in systolic blood pressure after adrenalectomy is similar in both D₅^–/– and D₅^+/+ mice, the hypertension in D₅^–/– mice is ascribed to central nervous system mechanisms (93, 273).

D₅ receptors, present in the prefrontal cortex, project to several brain areas involved with cardiovascular regulation. Sympathetic responses from the prefrontal cortex, transmitted to the lateral hypothalamic area, stimulate non-NMDA glutamate receptors in the ventrolateral medulla (41, 150, 278). A centrally, but not peripherally, acting non-NMDA glutamatergic antagonist decreases blood pressure in D₅^–/– mice, suggesting that the increased blood pressure in D₅^–/– mice may be caused by the activation of a sympathetic/non-NMDA glutamatergic axis (93). V₁ vasopressin and oxytocin antagonists that cross the blood-brain barrier also decrease blood pressure in D₅^–/– mice but not in D₅^+/+ mice. Interestingly, the hypotensive effect of the oxytocin antagonist occurs only 24 h after its administration and negates any further reduction in blood pressure by vasopressin or glutamatergic blockade. These results are consistent with the observation that oxytocin sensitizes V₁ vasopressin receptors and further suggest that the decrease in blood pressure in D₅^–/– mice engendered by these various antagonists occurs via a central nervous system pathway involving glutaminergic, oxytocin, vasopressin, and adrenergic receptors (Fig. 1) (93, 273).

View larger version (15K): [in this window] [in a new window]   Fig. 1. D2 and D5 receptors affect blood pressure by inhibition of the central sympathetic nervous system. D5 receptors are present in the prefrontal cortex, which projects to several brain areas involved with cardiovascular regulation, including the lateral hypothalamic area and ventrolateral medulla. D5 and D2 receptors affect blood pressure by decreasing the central sympathetic nervous system, although the detailed mechanisms remain to be determined. The dotted lines indicate inhibitory effects, whereas the solid lines indicate stimulatory effects.

D₅ receptors and blood pressure regulation summary. D₅ receptors, being constitutively active, may play a greater role than D₁ receptors in the basal regulation of blood pressure. The D₅ receptor may acutely regulate blood pressure by inhibition of the central adrenergic nervous system, via the NMDA-oxytocin-V₁ receptor-adrenergic axis (Fig. 1). Long-term regulation of blood pressure may involve sodium transport and AT₁ receptors and ROS; D₅^–/– mice are salt sensitive. Because D₅ receptors are more numerous than D₁ receptors in more distal nephron segments, the D₅ receptor-mediated regulation of sodium transport may be exerted in the distal nephron.

Overall Summary

Dopamine regulates blood pressure by renal and nonrenal mechanisms, some of which are specific to the five dopamine receptor subtypes (104, 268). All dopamine receptor subtypes participate in the regulation of sodium balance, individually and by interacting with each other to increase sodium excretion under conditions of moderate sodium balance. All dopamine receptors, except the D₄ receptor, have antioxidant functions. A deficiency in dopamine production and/or a dysfunction in dopamine receptors contribute to various forms of hypertension in both humans and animal models.

D₁^–/– mice have greater systolic, diastolic, and mean arterial pressure and do not increase cAMP production in response to D₁-like receptor agonist stimulation (5). D₅^–/– mice develop hypertension via increased central sympathetic activity through activation of glutaminergic, oxytocin, vasopressin, and adrenergic receptors (93). Besides these central nervous system mechanisms, renal AT₁ receptors and ROS are also involved (252, 253, 265, 274).

D₄^–/– mice have increased blood pressure, in part by increased AT₁ receptor activity in the brain and kidney (32). The increased blood pressure of D₂^–/– mice seems to be related to impaired renal dopamine production, impaired ability to excrete a chronic salt load, increased sympathetic activity, and increased ET_B receptor expression in VSMCs (138, 179, 235). The increased blood pressure in D₃^–/– mice may be related to the activation of the renin-angiotensin-aldosterone system and a decreased ability to excrete a chronic sodium load (5, 225). Some discrepancies in the characteristics of different strains of D₂^–/– and D₃^–/– mice could be related to differences in genetic background. C57BL/6 mice may or may not increase their blood pressures in response to sodium intake depending on their genetic background (226, 253).

Finally, it seems that under conditions of salt depletion, dopamine, via D₂ receptors, induces sodium retention, probably by stimulating sodium transport. In addition, the stimulatory effect of D₁ receptors on the renin-angiotensin system may become manifest. During states of moderate sodium excess, dopamine receptors, individually or by interacting with each other, increase sodium excretion (Fig. 2). The inhibitory effect of D₃ receptors also becomes manifest. Therefore, dopamine receptors may increase or decrease sodium transport to maintain sodium balance and blood pressure. Abnormalities in dopamine receptor subtypes, per se or caused by constitutively active variants of GRK4, result in hypertension. A major limitation of the studies in dopamine receptor subtype-null mice is the fact that the mutations are neither tissue specific nor inducible knockout mice. Studies in mice with inducible and tissue-specific deletion of dopamine receptor subtype genes are needed to decipher the exact role and mechanism(s) by which dopamine receptor subtypes regulate renal function and blood pressure.

View larger version (21K): [in this window] [in a new window]   Fig. 2. Dopamine receptors and cardiovascular function. Each of the dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. The major dopamine receptor that regulates blood pressure may be the D1 receptor, which synergies with the D3 receptor to regulate sodium transport in the kidney and intestines directly or indirectly by the inhibitory effect of D1 and D3 receptors on angiotensin II (ANG II) type 1 (AT1) receptor expression and/or interactions during conditions of modest sodium excess. D4 receptors help in this process. Furthermore, D3 receptors can inhibit renin secretion; D2 receptors aid in the excretion of sodium by decreasing aldosterone secretion and by inhibiting the vasconstrictor effect of endothelin type B (ETB) receptors. D2 and D5 receptors negatively regulate the sympathetic nervous system. UNaV, urinary excretion of sodium.

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	FOOTNOTES

 

Address for reprint requests and other correspondence: C. Zeng, Dept. of Cardiology, Daping Hospital, The Third Military Medical Univ., Chongqing City 400042, People's Republic of China (e-mail: cyzeng1{at}hotmail.com)

	REFERENCES

TOP ABSTRACT GRANTS REFERENCES

 

1. Abell TJ, Richard AM, Ikram H, Espiner EA, Yandle Y. Atrial natriuretic factor inhibits proliferation of vascular smooth muscle cells stimulated by platelet-derived growth factor. Biochem Biophys Res Commun 160: 1392–1396, 1989.[CrossRef][Web of Science][Medline]
2. Accili D, Fishburn CS, Drago J, Steiner H, Lachowicz JE, Park BH, Gauda EB, Lee EJ, Cool MH, Sibley DR, Gerfen CR, Westphal H, Fuchs S. A targeted mutation of the D₃ dopamine receptor gene is associated with hyperactivity in mice. Proc Natl Acad Sci USA 93: 1945–1949, 1996.[Abstract/Free Full Text]
3. Agnoli GC, Borgatti R, Cacciari M, Garutti C, Ikonomu E, Lenzi P. Antagonistic effects of sulpiride–racemic and enantiomers–on renal response to low-dose dopamine infusion in normal women. Nephron 51: 491–498, 1989.[Web of Science][Medline]
4. Agnoli GC, Cacciari M, Garutti C, Ikonomu E, Lenzi P, Marchetti G. Effects of extracellular fluid volume changes on renal response to low-dose dopamine infusion in normal women. Clin Physiol 7: 465–479, 1987.[Web of Science][Medline]
5. Albrecht FE, Drago J, Felder RA, Printz MP, Eisner GM, Robillard JE, Sibley DR, Westphal HJ, Jose PA. Role of the D1A dopamine receptor in the pathogenesis of genetic hypertension. J Clin Invest 97: 2283–2288, 1996.[Web of Science][Medline]
6. Allayee H, de Bruin TW, Michelle Dominguez K, Cheng LS, Ipp E, Cantor RM, Krass KL, Keulen ET, Aouizerat BE, Lusis AJ, Rotter JI. Genome scan for blood pressure in Dutch dyslipidemic families reveals linkage to a locus on chromosome 4p. Hypertension 38: 773–778, 2001.[Abstract/Free Full Text]
7. Amenta F. Light microscope autoradiography of peripheral dopamine receptor subtypes. Clin Exp Hypertens 19: 27–41, 1997.[CrossRef][Web of Science][Medline]
8. Amenta F, Barili P, Bronzetti E, Felici L, Mignini F, Ricci A. Localization of dopamine receptor subtypes in systemic arteries. Clin Exp Hypertens 22: 277–288, 2000.[CrossRef][Web of Science][Medline]
9. Amenta F, Barili P, Bronzetti E, Ricci A. Dopamine D₁-like receptor subtypes in the rat kidney: a microanatomical study. Clin Exp Hypertens 21: 17–23, 1999.[CrossRef][Web of Science][Medline]
10. Aoki Y, Albrecht FE, Bergman KR, Jose PA. Stimulation of Na⁺-K⁺-2Cl-cotransport in rat medullary thick ascending limb by dopamine. Am J Physiol Regul Integr Comp Physiol 271: R1561–R1567, 1996.[Abstract/Free Full Text]
11. Aperia A, Bertorello A, Seri I. Dopamine causes inhibition of Na⁺-K⁺-ATPase activity in rat proximal convoluted tubule segments. Am J Physiol Renal Fluid Electrolyte Physiol 252: F39–F45, 1987.[Abstract/Free Full Text]
12. Aperia A, Eklof AC, Holtback U, Nowicki S, Sundelof M, Greengard P. The renal dopamine system. Adv Pharmacol 42: 870–873, 1998.[Medline]
13. Armando I, Wang X, Pascua AM, Villar VM, Luo Y, Jones JE, Asico L, Escano C, Jose PA. Regulation of Renal NADPH Oxidase and Inflammation by Dopamine D₂ Receptors. Orlando, FL: American Heart Association Scientific Sessions, November 2007.
14. Armando I, Wang X, Villar VA, Jones JE, Asico LD, Escano C, Jose PA. Reactive oxygen species-dependent hypertension in dopamine D₂ receptor-deficient mice. Hypertension 49: 672–678, 2007.[Abstract/Free Full Text]
15. Asghar M, Hussain T, Lokhandwala MF. Activation of dopamine D₁-like receptor causes phosphorylation of alpha₁-subunit of Na⁺,K⁺-ATPase in rat renal proximal tubules. Eur J Pharmacol 411: 61–66, 2001.[CrossRef][Web of Science][Medline]
16. Asghar M, Hussain T, Lokhandwala MF. Overexpression of PKC-βI and - contributes to higher PKC activity in the proximal tubules of old Fischer 344 rats. Am J Physiol Renal Physiol 285: F1100–F1107, 2003.[Abstract/Free Full Text]
17. Asico LD, Ladines C, Fuchs S, Accili D, Carey RM, Semeraro C, Pocchiari F, Felder RA, Eisner GM, Jose PA. Disruption of the dopamine D₃ receptor gene produces renin-dependent hypertension. J Clin Invest 102: 493–498, 1998.[Web of Science][Medline]
18. Assuncao-Miranda I, Guilherme AL, Reis-Silva C, Costa-Sarmento G, Oliveira MM, Vieyra A. Protein kinase C-mediated inhibition of renal Ca²⁺ ATPase by physiological concentrations of angiotensin II is reversed by AT₁- and AT₂-receptor antagonists. Regul Pept 127: 151–157, 2005.[CrossRef][Web of Science][Medline]
19. Azdad K, Piet R, Poulain DA, Oliet SH. Dopamine D₄ receptor-mediated presynaptic inhibition of GABAergic transmission in the rat supraoptic nucleus. J Neurophysiol 90: 559–565, 2003.[Abstract/Free Full Text]
20. Bacic D, Capuano P, Baum M, Zhang J, Stange G, Biber J, Kaissling B, Moe OW, Wagner CA, Murer H. Activation of dopamine D₁-like receptors induces acute internalization of the renal Na⁺/phosphate cotransporter NaPi-IIa in mouse kidney and OK cells. Am J Physiol Renal Physiol 288: F740–F747, 2005.[Abstract/Free Full Text]
21. Bacic D, Kaissling B, McLeroy P, Zou L, Baum M, Moe OW. Dopamine acutely decreases apical membrane Na/H exchanger NHE3 protein in mouse renal proximal tubule. Kidney Int 64: 2133–2141, 2003.[CrossRef][Web of Science][Medline]
22. Baik JH, Picetti R, Saiardi A, Thiriet G, Dierich A, Depaulis A, Le Meur M, Borrelli E. Parkinsonian-like locomotor impairment in mice lacking dopamine D₂ receptors. Nature 377: 424–428, 1995.[CrossRef][Medline]
23. Baines AD, Drangova R. Does dopamine use several signal pathways to inhibit Na-Pi transport in OK cells? J Am Soc Nephrol 9: 1604–1612, 1998.[Abstract]
24. Banday AA, Hussain T, Lokhandwala MF. Renal dopamine D₁ receptor dysfunction is acquired and not inherited in obese Zucker rats. Am J Physiol Renal Physiol 287: F109–F116, 2004.[Abstract/Free Full Text]
25. Barili P, Fringuelli C, Baldoni E, Mignini F, Zaccheo D, Amenta F. Dopamine D₂-like receptors in the kidney of spontaneously hypertensive rats: a radioligand binding assay and light microscope autoradiography study. J Auton Pharmacol 18: 89–97, 1998.[CrossRef][Web of Science][Medline]
26. Barili P, Ricci A, Baldoni E, Mignini F, Amenta F. Pharmacological characterizsation and autoradiographic localisation of a putative dopamine D₃ receptor in the rat kidney. Eur J Pharmacol 338: 89–95, 1997.[CrossRef][Web of Science][Medline]
27. Barili P, Sabbatini M, Soares-da-Silva P, Amenta F. The peripheral dopaminergic system: morphological analysis, functional and clinical applications. Ital J Anat Embryol 107: 145–167, 2002.[Medline]
28. Bastianetto S, Danik M, Mennicken F, Williams S, Quirion R. Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation. BMC Neurosci 7: 28, 2006.[CrossRef][Medline]
29. Beazely MA, Watts VJ. Activation of a novel PKC isoform synergistically enhances D2L dopamine receptor-mediated sensitization of adenylate cyclase type 6. Cell Signal 17: 647–653, 2005.[CrossRef][Web of Science][Medline]
30. Beige J, Bellmann A, Sharma AM, Gessner R. Ethnic origin determines the impact of genetic variants in dopamine receptor gene (DRD1) concerning essential hypertension. Am J Hypertens 17: 1184–1187, 2004.[CrossRef][Web of Science][Medline]
31. Bek M, Fischer KG, Greiber S, Hupfer C, Mundel P, Pavenstadt H. Dopamine depolarizes podocytes via a D₁-like receptor. Nephrol Dial Transplant 14: 581–587, 1999.[Abstract/Free Full Text]
32. Bek MJ, Wang X, Asico LD, Jones JE, Zheng S, Li X, Eisner GM, Grandy DK, Carey RM, Soares-da-Silva P, Jose PA. Angiotensin-II type 1 receptor-mediated hypertension in D₄ dopamine receptor-deficient mice. Hypertension 47: 288–295, 2006.[Abstract/Free Full Text]
33. Bek MJ, Zheng S, Xu J, Yamaguchi I, Asico LD, Sun XG, Jose PA. Differential expression of adenylyl cyclases in the rat nephron. Kidney Int 60: 890–899, 2001.[CrossRef][Web of Science][Medline]
34. Bertorello A, Aperia A. Inhibition of proximal tubule Na⁺-K⁺-ATPase activity requires simultaneous activation of DA1 and DA2 receptors. Am J Physiol Renal Fluid Electrolyte Physiol 259: F924–F928, 1990.[Abstract/Free Full Text]
35. Bertorello AM, Hopfield JF, Aperia A, Greengard P. Inhibition by dopamine of (Na⁺-K⁺)ATPase activity in neostriatal neurons through D₁ and D₂ dopamine receptor synergism. Nature 347: 386–388, 1990.[CrossRef][Medline]
36. Bianchi P, Seguelas MH, Parini A, Cambon C. Activation of pro-apoptotic cascade by dopamine in renal epithelial cells is fully dependent on hydrogen peroxide generation by monoamine oxidases. J Am Soc Nephrol 14: 855–862, 2003.[Abstract/Free Full Text]
37. Bouvier M. Oligomerization of G-protein-coupled transmitter receptors. Nat Rev Neurosci 2: 274–286, 2001.[CrossRef][Web of Science][Medline]
38. Brismar H, Asghar M, Carey RM, Greengard P, Aperia A. Dopamine-induced recruitment of dopamine D₁ receptors to the plasma membrane. Proc Natl Acad Sci USA 95: 5573–5578, 1998.[Abstract/Free Full Text]
39. Bughi S, Horton R, Antonipillai I, Manoogian C, Ehrlich L, Nadler J. Comparison of dopamine and fenoldopam effects on renal blood flow and prostacyclin excretion in normal and essential hypertensive subjects. J Clin Endocrinol Metab 69: 1116–1121, 1989.[Abstract/Free Full Text]
40. Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg SR, Neve K, Fuxe K, Agnati LF, Woods AS, Ferré S, Lluis C, Bouvier M, Franco R. Adenosine A2A-dopamine D₂ receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem 278: 46741–46749, 2003.[Abstract/Free Full Text]
41. Carvey PM, McGuire SO, Ling ZD. Neuroprotective effects of D₃ dopamine receptor agonists. Parkinsonism Relat Disord 7: 213–223, 2001.[CrossRef][Web of Science][Medline]
42. Carey RM, Siragy HM, Ragsdale NV, Howell NL, Felder RA, Peach MJ, Chevalier RL. Dopamine-1 and dopamine-2 mechanisms in the control of renal function. Am J Hypertens 3: 59S–63S, 1990.[Medline]
43. Chatziantoniou C, Ruan X, Arendshorst WJ. Interactions of cAMP-mediated vasodilators with angiotensin II in rat kidney during hypertension. Am J Physiol Renal Fluid Electrolyte Physiol 265: F845–F852, 1993.[Abstract/Free Full Text]
44. Cavallotti C, Nuti F, Bruzzone P, Mancone M. Age-related changes in dopamine D₂ receptors in rat heart and coronary vessels. Clin Exp Pharmacol Physiol 29: 412–418, 2002.[CrossRef][Web of Science][Medline]
45. Chen C, Beach RE, Lokhandwala MF. Dopamine fails to inhibit renal tubular sodium pump in hypertensive rats. Hypertension 21: 364–372, 1993.[Abstract/Free Full Text]
46. Chen C, Lokhandwala MF. Potentiation by enalaprilat of fenoldopam-evoked natriuresis is due to blockade of intrarenal production of angiotensin-II in rats. Naunyn Schmiedebergs Arch Pharmacol 352: 194–200, 1995.[Web of Science][Medline]
47. Chen CJ, Lokhandwala MF. An impairment of renal tubular DA-1 receptor function as the causative factor for diminished natriuresis to volume expansion in spontaneously hypertensive rats. Clin Exp Hypertens 14: 615–628, 1992.[CrossRef][Web of Science]
48. Cheng HF, Becker BN, Burns KD, Harris RC. Angiotensin II upregulates type-1 angiotensin II receptors in renal proximal tubule. J Clin Invest 95: 2012–2019, 1995.[Web of Science][Medline]
49. Cheng HF, Becker BN, Harris RC. Dopamine decreases expression of type-1 angiotensin II receptors in renal proximal tubule. J Clin Invest 97: 2745–2752, 1996.[Web of Science][Medline]
50. Cho DI, Quan W, Oak MH, Choi HJ, Lee KY, Kim KM. Functional interaction between dopamine receptor subtypes for the regulation of c-fos expression. Biochem Biophys Res Commun 357: 1113–1138, 2007.[CrossRef][Web of Science][Medline]
51. Cosentino M, Rasini E, Colombo C, Marino F, Blandini F, Ferrari M, Samuele A, Lecchini S, Nappi G, Frigo G. Dopaminergic modulation of oxidative stress and apoptosis in human peripheral blood lymphocytes: evidence for a D₁-like receptor-dependent protective effect. Free Radic Biol Med 36: 1233–12340, 2004.[CrossRef][Web of Science][Medline]
52. Cravchik A, Gejman PV. Functional analysis of the human D₅ dopamine receptor missense and nonsense variants: differences in dopamine binding affinities. Pharmacogenetics 9: 199–206, 1999.[Web of Science][Medline]
53. Crowley SD, Gurley SB, Herrera MJ, Ruiz P, Griffiths R, Kumar AP, Kim HS, Smithies O, Le TH, Coffman TM. Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci USA 103: 17985–17990, 2006.[Abstract/Free Full Text]
54. DiBona GF. Sympathetic nervous system and the kidney in hypertension. Curr Opin Nephrol Hypertens 11: 197–200, 2002.[CrossRef][Web of Science][Medline]
55. Dickson ME, Sigmund CD. Genetic basis of hypertension: revisiting angiotensinogen. Hypertension 48: 14–20, 2006.[Free Full Text]
56. Dickinson SD, Sabeti J, Larson GA, Giardina K, Rubinstein M, Kelly MA, Grandy DK, Low MJ, Gerhardt GA, Zahniser NR. Dopamine D₂ receptor-deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum. J Neurochem 72: 148–156, 1999.[CrossRef][Web of Science][Medline]
57. Done SC, Leibiger IB, Efendiev R, Katz AI, Leibiger B, Berggren PO, Pedemonte CH, Bertorello AM. Tyrosine 537 within the Na⁺,K⁺-ATPase alpha-subunit is essential for AP-2 binding and clathrin-dependent endocytosis. J Biol Chem 277: 17108–17111, 2002.[Abstract/Free Full Text]
58. Drago J, Gerfen CR, Lachowicz JE, Steiner H, Hollon TR, Love PE, Ooi GT, Grinberg A, Lee EJ, Huang SP, Bartlett PF, Jose PA, Sibley DR, Westphal H. Altered striatal function in a mutant mouse lacking D_1A dopamine receptors. Proc Natl Acad Sci USA 91: 12564–12568, 1994.[Abstract/Free Full Text]
59. Dunah AW, Standaert DG. Dopamine D₁ receptor-dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane. J Neurosci 21: 5546–5558, 2001.[Abstract/Free Full Text]
60. Dziedzicka-Wasylewska M, Faron-Gorecka A, Andrecka J, Polit A, Kusmider M, Wasylewski Z. Fluorescence studies reveal heterodimerization of dopamine D₁ and D₂ receptors in the plasma membrane. Biochemistry 45: 8751–8759, 2006.[CrossRef][Web of Science][Medline]
61. Edvinsson L, McCulloch J, Sharkey J. Vasomotor responses of cerebral arterioles in situ to putative dopamine receptor agonists. Br J Pharmacol 85: 403–410, 1985.[Web of Science][Medline]
62. Edwards RM, Brooks DP. Dopamine inhibits vasopressin action in the rat inner medullary collecting duct via ₂-adrenoceptors. J Pharmacol Exp Ther 298: 1001–1006, 2001.[Abstract/Free Full Text]
63. Efendiev R, Bertorello AM, Pedemonte CH. PKC-beta and PKC-zeta mediate opposing effects on proximal tubule Na⁺,K⁺-ATPase activity. FEBS Lett 456: 45–48, 1999.[CrossRef][Web of Science][Medline]
64. Efendiev R, Budu CE, Cinelli AR, Bertorello AM, Pedemonte CH. Intracellular Na⁺ regulates dopamine and angiotensin II receptors availability at the plasma membrane and their cellular responses in renal epithelia. J Biol Chem 278: 28719–28726, 2003.[Abstract/Free Full Text]
65. Efendiev R, Cinelli AR, Leibiger IB, Bertorello AM, Pedemonte CH. FRET analysis reveals a critical conformational change within the Na,K-ATPase alpha1 subunit N-terminus during GPCR-dependent endocytosis. FEBS Lett 580: 5067–5070, 2006.[CrossRef][Web of Science][Medline]
66. Eklof AC. The natriuretic response to a dopamine DA1 agonist requires endogenous activation of dopamine DA2 receptors. Acta Physiol Scand 160: 311–314, 1997.[CrossRef][Web of Science][Medline]
67. Everett PB, Senogles SE. D₃ dopamine receptor activates phospholipase D through a pertussis toxin-insensitive pathway. Neurosci Lett 371: 34–39, 2004.[CrossRef][Web of Science][Medline]
68. Felder CC, Campbell T, Albrecht F, Jose PA. Dopamine inhibits Na⁺-H⁺ exchanger activity in renal BBMV by stimulation of adenylate cyclase. Am J Physiol Renal Fluid Electrolyte Physiol 259: F297–F303, 1990.[Abstract/Free Full Text]
69. Felder CC, Jose PA, Axelrod J. The dopamine-1 agonist, SKF 82526, stimulates phospholipase-C activity independent of adenylate cyclase. J Pharmacol Exp Ther 248: 171–175, 1989.[Abstract/Free Full Text]
70. Felder RA, Blecher M, Eisner GM, Jose PA. Cortical tubular and glomerular dopamine receptors in the rat kidney. Am J Physiol Renal Fluid Electrolyte Physiol 246: F557–F568, 1984.[Abstract/Free Full Text]
71. Felder RA, Jose PA. Dopamine1 receptors in rat kidneys identified with ¹²⁵I-Sch 23982. Am J Physiol Renal Fluid Electrolyte Physiol 255: F970–F976, 1988.[Abstract/Free Full Text]
72. Felder RA, Kinoshita S, Ohbu K, Mouradian MM, Sibley DR, Monsma FJ Jr, Minowa T, Minowa MT, Canessa LM, Jose PA. Organ specificity of the dopamine1 receptor/adenylyl cyclase coupling defect in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 264: R726–R732, 1993.[Abstract/Free Full Text]
73. Felder RA, Seikaly MG, Cody P, Eisner GM, Jose PA. Attenuated renal response to dopaminergic drugs in spontaneously hypertensive rats. Hypertension 15: 560–569, 1990.[Abstract/Free Full Text]
74. Felder RA, Wang X, Gildea J, Bengra C, Sasaki M, Zeng C, Jones JE, Zheng W, Asico LD, Jose PA. Human renal angiotensin type 1 receptor regulation by the D₁ dopamine receptor (Abstract). Hypertension 42: 438A, 2003.
75. Ferré S, Ciruela F, Canals M, Marcellino D, Burgueno J, Casadó V, Hillion J, Torvinen M, Fanelli F, de Benedetti P, Goldberg SR, Bouvier M, Fuxe K, Agnati LF, Lluis C, Franco R, Woods A. Adenosine A2A-dopamine D₂ receptor-receptor heteromers. Targets for neuro-psychiatric disorders. Parkinsonism Relat Disord 10: 265–271, 2004.[CrossRef][Web of Science][Medline]
76. Fink GD. Hypothesis: the systemic circulation as a regulated free-market economy. A new approach for understanding the long-term control of blood pressure. Clin Exp Pharmacol Physiol 32: 377–383, 2005.[CrossRef][Web of Science][Medline]
77. Fiorentini C, Gardoni F, Spano P, Di Luca M, Missale C. Regulation of dopamine D₁ receptor trafficking and desensitization by oligomerization with glutamate N-methyl-D-aspartate receptors. J Biol Chem 278: 20196–20202, 2003.[Abstract/Free Full Text]
78. Fryckstedt J, Meister B, Aperia A. Control of electrolyte transport in the kidney through a dopamine- and cAMP-regulated phosphoprotein, DARPP-32. J Auton Pharmacol 12: 183–189, 1992.[Web of Science][Medline]
79. Gao DQ, Canessa LM, Mouradian MM, Jose PA. Expression of the D₂ subfamily of dopamine receptor genes in kidney. Am J Physiol Renal Fluid Electrolyte Physiol 266: F646–F650, 1994.[Abstract/Free Full Text]
80. Gines S, Hillion J, Torvinen M, Le Crom S, Casado V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M, Agnati LF, Verniera P, Lluis C, Ferre S, Fuxe K, Franco R. Dopamine and adenosine A1 receptors form functionally interacting heterotrimeric complexes. Proc Natl Acad Sci USA 97: 8606–8611, 2000.[Abstract/Free Full Text]
81. Glickstein SB, Schmauss C. Dopamine receptor functions: lessons from knockout mice [corrected]. Pharmacol Ther 91: 63–83, 2001.[CrossRef][Web of Science][Medline]
82. Gomes P, Soares-Da-Silva P. D₂-like receptor-mediated inhibition of Na⁺-K⁺-ATPase activity is dependent on the opening of K⁺ channels. Am J Physiol Renal Physiol 283: F114–F123, 2002.[Abstract/Free Full Text]
83. Gomez Mde J, Rousseau G, Nadeau R, Berra R, Flores G, Suarez J. Functional and autoradiographic characterization of dopamine D₂-like receptors in the guinea pig heart. Can J Physiol Pharmacol 80: 578–587, 2002.[CrossRef][Web of Science][Medline]
84. Granger JP, Schnackenberg CG. Renal mechanisms of angiotensin II-induced hypertension. Semin Nephrol 20: 417–425, 2000.[Web of Science][Medline]
85. Grider J, Kilpatrick E, Ott C, Jackson B. Effect of dopamine on NaCl transport in the medullary thick ascending limb of the rat. Eur J Pharmacol 342: 281–284, 1998.[CrossRef][Web of Science][Medline]
86. Grider JS, Ott CE, Jackson BA. Dopamine D₁ receptor-dependent inhibition of NaCl transport in the rat thick ascending limb: mechanism of action. Eur J Pharmacol 473: 185–190, 2003.[CrossRef][Web of Science][Medline]
87. Hall JE. The kidney, hypertension, and obesity. Hypertension 41: 625–633, 2003.[Abstract/Free Full Text]
88. Han JY, Heo JS, Lee YJ, Lee JH, Taub M, Han HJ. Dopamine stimulates ⁴⁵Ca²⁺ uptake through cAMP, PLC/PKC, and MAPKs in renal proximal tubule cells. J Cell Physiol 211: 486–494, 2007.[CrossRef][Web of Science][Medline]
89. Harrison-Bernard LM, Zhuo J, Kobori H, Ohishi M, Navar LG. Intrarenal AT₁ receptor and ACE binding in ANG II-induced hypertensive rats. Am J Physiol Renal Physiol 282: F19–F25, 2002.[Abstract/Free Full Text]
90. Hedge SS, Ricci A, Amenta F, Lokhandwala MF. Evidence from functional and autoradiographic studies for the presence of tubular dopamine-1 receptors and their involvement in the renal effects of fenoldopam. J Pharmacol Exp Ther 251: 1237–1245, 1989.[Abstract/Free Full Text]
91. Hellstrand M, Danielsen EA, Steen VM, Ekman A, Eriksson E, Nilsson CL. The ser9gly SNP in the dopamine D₃ receptor causes a shift from cAMP related to PGE2 related signal transduction mechanisms in transfected CHO cells. J Med Genet 41: 867–871, 2004.[Free Full Text]
92. Hillion J, Canals M, Torvinen M, Casado V, Scott R, Terasmaa A, Hansson A, Watson S, Olah ME, Mallol J. Coaggregation, cointernalization and codesensitization of adenosine A2A receptors and dopamine D₂ receptors. J Biol Chem 277: 18091–18097, 2002.[Abstract/Free Full Text]
93. Hollon TR, Bek MJ, Lachowicz JE, Ariano MA, Mezey E, Ramachandran R, Wersinger SR, Soares-da-Silva P, Liu ZF, Grinberg A, Drago J, Young WS 3rd, Westphal H, Jose PA, Sibley DR. Mice lacking D₅ dopamine receptors have increased sympathetic tone and are hypertensive. J Neurosci 22: 10801–10810, 2002.[Abstract/Free Full Text]
94. Holmes A, Hollon TR, Gleason TC, Liu Z, Dreiling J, Sibley DR, Crawley JN. Behavioral characterization of dopamine D₅ receptor null mutant mice. Behav Neurosci 115: 1129–1144, 2001.[CrossRef][Web of Science][Medline]
95. Holmes A, Lachowicz JE, Sibley DR. Phenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes. Neuropharmacology 47: 1117–1134, 2004.[Web of Science][Medline]
96. Horiuchi A, Takeyasu K, Mouradian MM, Jose PA, Felder RA. D1A dopamine receptor stimulation inhibits Na⁺-K⁺ ATPase activity through protein kinase A. Mol Pharmacol 43: 281–285, 1993.[Abstract]
97. Hu MC, Fan L, Crowder LA, Karim-Jimenez Z, Murer H, Moe OW. Dopamine acutely stimulates Na⁺/H⁺ exchanger (NHE3) endocytosis via clathrin-coated vesicles: dependence on protein kinase A-mediated NHE3 phosphorylation. J Biol Chem 276: 26906–26915, 2001.[Abstract/Free Full Text]
98. Huo T, Healy DP. Autoradiographic localization of dopamine DA₁ receptors in rat kidney with [³H]Sch 23390. Am J Physiol Renal Fluid Electrolyte Physiol 257: F414–F423, 1989.[Abstract/Free Full Text]
99. Hussain T, Abdul-Wahab R, Kotak DK, Lokhandwala MF. Bromocriptine regulates angiotensin II response on sodium pump in proximal tubules. Hypertension 32: 1054–1059, 1998.[Abstract/Free Full Text]
100. Hussain T, Abdul-Wahab R, Lokhandwala MF. Bromocriptine stimulates Na⁺, K⁺-ATPase in renal proximal tubules via the cAMP pathway. Eur J Pharmacol 321: 259–263, 1997.[CrossRef][Web of Science][Medline]
101. Hussain T, Lokhandwala MF. Altered arachidonic acid metabolism contributes to the failure of dopamine to inhibit Na⁺,K⁺-ATPase in kidney of spontaneously hypertensive rats. Clin Exp Hypertens 18: 963–974, 1996.[CrossRef][Web of Science][Medline]
102. Hussain T, Lokhandwala MF. Dopamine-1 receptor G-protein coupling and the involvement of phospholipase A2 in dopamine-1 receptor mediated cellular signaling mechanisms in the proximal tubules of SHR. Clin Exp Hypertens 19: 131–140, 1997.[CrossRef][Web of Science][Medline]
103. Hussain T, Lokhandwala MF. Renal dopamine D_1A receptor coupling with G_S and G_q/11 proteins in spontaneously hypertensive rats. Am J Physiol Renal Physiol 272: F339–F346, 1997.[Abstract/Free Full Text]
104. Hussain T, Lokhandwala MF. Renal dopamine receptors and hypertension. Exp Biol Med (Maywood) 228: 134–142, 2003.[Abstract/Free Full Text]
105. Ishige K, Chen Q, Sagara Y, Schubert D. The activation of dopamine D₄ receptors inhibits oxidative stress-induced nerve cell death. J Neurosci 21: 6069–6076, 2001.[Abstract/Free Full Text]
106. Izquierdo-Claros RM, Boyano-Adanez MC, Larsson C, Gustavsson L, Arilla E. Acute effects of D₁- and D₂-receptor agonist and antagonist drugs on somatostatin binding, inhibition of adenylyl cyclase activity and accumulation of inositol 1,4,5-trisphosphate in the rat striatum. Brain Res Mol Brain Res 47: 99–107, 1997.[Medline]
107. Jackson A, Sedaghat K, Minerds K, James C, Tiberi M. Opposing effects of phorbol-12-myristate-13-acetate, an activator of protein kinase C, on the signaling of structurally related human dopamine D₁ and D₅ receptors. J Neurochem 95: 1387–1400, 2005.[CrossRef][Web of Science][Medline]
108. James K, Weitzel LR, Engelman CD, Zerbe G, Norris JM; Framingham Heart Study. Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study. BMC Genet 4, Suppl 1: S83, 2003.[CrossRef][Medline]
109. Jarvie KR, Booth G, Brown EM, Niznik HB. Glycoprotein nature of dopamine D₁ receptors in the brain and parathyroid gland. Mol Pharmacol 36: 566–574, 1989.[Abstract]
110. Jin XH, Zhang JZ, Zhao YJ, Zhao RR. Localization of dopamine1A receptor mRNA in different vascular beds in rat: a nonradioactive in situ hybridization study. Methods Find Exp Clin Pharmacol 19: 657–663, 1997.[Web of Science][Medline]
111. Jomphe C, Tiberi M, Trudeau LE. Expression of D₂ receptor isoforms in cultured neurons reveals equipotent autoreceptor function. Neuropharmacology 50: 595–605, 2006.[CrossRef][Web of Science][Medline]
112. Jose PA, Asico LD, Eisner GM, Pocchiari F, Semeraro C, Felder RA. Effects of costimulation of dopamine D₁- and D₂-like receptors on renal function. Am J Physiol Regul Integr Comp Physiol 275: R986–R994, 1998.[Abstract/Free Full Text]
113. Jose PA, Eisner GM, Drago J, Carey RM, Felder RA. Dopamine receptor signaling defects in spontaneous hypertension. Am J Hypertens 9: 400–405, 1996.[CrossRef][Web of Science][Medline]
114. Jose PA, Eisner GM, Felder RA. Regulation of blood pressure by dopamine receptors. Nephron Physiol 95: 19–27, 2003.[CrossRef]
115. Joseph JD, Wang YM, Miles PR, Budygin EA, Picetti R, Gainetdinov RR, Caron MG, Wightman RM. Dopamine autoreceptor regulation of release and uptake in mouse brain slices in the absence of D₃ receptors. Neuroscience 112: 39–49, 2002.[CrossRef][Web of Science][Medline]
116. Jung MY, Schmauss C. Decreased c-fos responses to dopamine D₁ receptor agonist stimulation in mice deficient for D₃ receptors. J Biol Chem 274: 29406–29412, 1999.[Abstract/Free Full Text]
117. Kanterman RY, Mahan LC, Briley EM, Monsma FJ Jr, Sibley DR, Axelrod J, Felder CC. Transfected D2 dopamine receptors mediate the potentiation of arachidonic acid release in Chinese hamster ovary cells. Mol Pharmacol 39: 364–369, 1991.[Abstract]
118. Khundmiri SJ, Lederer E. PTH and DA regulate Na-K ATPase through divergent pathways. Am J Physiol Renal Physiol 282: F512–F522, 2002.[Abstract/Free Full Text]
119. Kim MO, Koh PO, Kim JH, Kim JS, Kang SS, Cho GJ, Kim K, Choi WS. Localization of dopamine D₁ and D₂ receptor mRNAs in the rat systemic and pulmonary vasculatures. Mol Cell 9: 417–421, 1999.[Medline]
120. Kinoshita S, Sidhu A, Felder RA. Defective dopamine-1 receptor adenylate cyclase coupling in the proximal convoluted tubule from the spontaneously hypertensive rat. J Clin Invest 84: 1849–1856, 1989.[Web of Science][Medline]
121. Kirchheimer C, Mendez CF, Acquier A, Nowicki S. Role of 20-HETE in D₁/D₂ dopamine receptor synergism resulting in the inhibition of Na⁺-K⁺-ATPase activity in the proximal tubule. Am J Physiol Renal Physiol 292: F1435–F1442, 2007.[Abstract/Free Full Text]
122. Kren V, Pravenec M, Lu S, Krenova D, Wang JM, Wang N, Merriouns T, Wong A, St Lezin E, Lau D, Szpirer C, Szpirer J, Kurtz TW. Genetic isolation of a region of chromosome 8 that exerts major effects on blood pressure and cardiac mass in the spontaneously hypertensive rat. J Clin Invest 99: 577–581, 1997.[Web of Science][Medline]
123. Kruse MS, Adachi S, Scott L, Holtback U, Greengard P, Aperia A, Brismar H. Recruitment of renal dopamine 1 receptors requires an intact microtubulin network. Pflügers Arch 445: 534–539, 2003.[Web of Science][Medline]
124. Krushkal J, Xiong M, Ferrell R, Sing CF, Turner ST, Boerwinkle E. Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation. Hum Mol Genet 7: 1379–1383, 1998.[Abstract/Free Full Text]
125. Kunimi M, Seki G, Hara C, Taniguchi S, Uwatoko S, Goto A, Kimura S, Fujita T. Dopamine inhibits renal Na⁺:HCO₃^– cotransporter in rabbits and normotensive rats but not in spontaneously hypertensive rats. Kidney Int 57: 534–543, 2000.[CrossRef][Web of Science][Medline]
126. Kuzhikandathil EV, Oxford GS. Dominant-negative mutants identify a role for GIRK channels in D₃ dopamine receptor-mediated regulation of spontaneous secretory activity. J Gen Physiol 115: 697–706, 2000.[Abstract/Free Full Text]
127. Ladines CA, Zeng C, Asico LD, Sun X, Pocchiari F, Semeraro C, Pisegna J, Wank S, Yamaguchi I, Eisner GM, Jose PA. Impaired renal D₁-like and D₂-like dopamine receptor interaction in the spontaneously hypertensive rat. Am J Physiol Regul Integr Comp Physiol 281: R1071–R1078, 2001.[Abstract/Free Full Text]
128. Lao YS, Hendley ED, Felder RA, Jose PA. Elevated renal cortical calmodulin-dependent protein kinase activity and blood pressure. Clin Exp Hypertens 24: 289–300, 2002.[CrossRef][Web of Science][Medline]
129. Lederer ED, Sohi SS, McLeish KR. Dopamine regulates phosphate uptake by opossum kidney cells through multiple counter-regulatory receptors. J Am Soc Nephrol 9: 975–985, 1998.[Abstract]
130. Lee FJ, Pei L, Moszczynska A, Vukusic B, Fletcher PJ, Liu F. Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D₂ receptor. EMBO J 26: 2127–2136, 2007.[CrossRef][Web of Science][Medline]
131. Lee FJ, Xue S, Pei L, Vukusic B, Chery N, Wang Y, Wang YT, Niznik HB, Yu XM, Liu F. Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D₁ receptor. Cell 111: 219–230, 2002.[CrossRef][Web of Science][Medline]
132. Lee SP, So CH, Rashid AJ, Varghese GV, Cheng RC, Lanca AJ, O'Dowd BF, George SR. Dopamine D₁ and D₂ receptor co-activation generates a novel phospholipase C-mediated calcium signal. J Biol Chem 279: 35671–35678, 2004.[Abstract/Free Full Text]
133. Levavi-Sivan B, Park BH, Fuchs S, Fishburn CS. Human D₃ dopamine receptor in the medulloblastoma TE671 cell line: cross-talk between D₁ and D₃ receptors. FEBS Lett 439: 138–142, 1998.[CrossRef][Web of Science][Medline]
134. Levesque D. Aminotetralin drugs and D₃ receptor functions. What may partially selective D₃ receptor ligands tell us about dopamine D₃ receptor functions? Biochem Pharmacol 52: 511–518, 1996.[CrossRef][Web of Science][Medline]
135. Li D, Aperia A, Celsi G, da Cruz e Silva EF, Greengard P, Meister B. Protein phosphatase-1 in the kidney: evidence for a role in the regulation of medullary Na⁺-K⁺-ATPase. Am J Physiol Renal Fluid Electrolyte Physiol 269: F673–F680, 1995.[Abstract/Free Full Text]
136. Li H, Yu P, Jose PA. Role of AT₁ receptor ubiquitination in the D₅ dopamine receptor-mediated AT₁ receptor degradation (Abstract). FASEB J 20: A1285, 2006.[Free Full Text]
137. Li L, Schafer JA. Dopamine inhibits vasopressin-dependent cAMP production in the rat cortical collecting duct. Am J Physiol Renal Physiol 275: F62–F67, 1998.[Abstract/Free Full Text]
138. Li XX, Bek M, Asico LD, Yang Z, Grandy DK, Goldstein DS, Rubinstein M, Eisner GM, Jose PA. Adrenergic and endothelin B receptor-dependent hypertension in dopamine receptor type-2 knockout mice. Hypertension 38: 303–308, 2001.[Abstract/Free Full Text]
139. Lindgren N, Usiello A, Goiny M, Haycock J, Erbs E, Greengard P, Hokfelt T, Borrelli E, Fisone G. Distinct roles of dopamine D_2L and D_2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites. Proc Natl Acad Sci USA 100: 4305–4309, 2003.[Abstract/Free Full Text]
140. Liu F, Wan Q, Pristupa ZB, Yu XM, Wang YT, Nisnik HB. Direct protein-protein coupling enables cross-talk between dopamine D₅ and -aminobutyric acid A receptors. Nature 403: 274–280, 2000.[CrossRef][Medline]
141. Lin JC, Tsao WL, Wang Y. Cardiovascular effects of NMDA in the RVLM of spontaneously hypertensive rats. Brain Res Bull 37: 289–294, 1995.[CrossRef][Web of Science][Medline]
142. Lotharius J, O'Malley KL. The Parkinsonism-inducing drug 1-methyl-4- phenylpyridinium triggers intracellular dopamine oxidation. A novel mechanism of toxicity. J Biol Chem 275: 38581–38588, 2000.[Abstract/Free Full Text]
143. Lu Q, Asico LD, Jones JE, Bai R, Li H, Maines MD, Jose PA. Impaired heme oxygenase activity, increased reactive oxygen species, and high blood pressure in D₅ dopamine receptor deficient mice (Abstract). J Am Soc Nephrol 16: 163A, 2005.[CrossRef]
144. Luippold G, Kuster E, Joos TO, Muhlbauer B. Dopamine D₃ receptor activation modulates renal function in anesthetized rats. Naunyn Schmiedebergs Arch Pharmacol 358: 690–693, 1998.[CrossRef][Web of Science][Medline]
145. Luippold G, Piesch C, Osswald H, Muhlbauer B. Dopamine D₃ receptor mRNA and renal response to D₃ receptor activation in spontaneously hypertensive rats. Hypertens Res 26: 855–861, 2003.[CrossRef][Web of Science][Medline]
146. Luippold G, Zimmermann C, Mai M, Kloor D, Starck D, Gross G, Muhlbauer B. Dopamine D₃ receptors and salt-dependent hypertension. J Am Soc Nephrol 12: 2272–2279, 2001.[Abstract/Free Full Text]
147. Luo Y, Roth GS. The roles of dopamine oxidative stress and dopamine receptor signaling in aging and age-related neurodegeneration. Antioxid Redox Signal 2: 449–460, 2000.[CrossRef][Medline]
148. Maeda Y, Terada Y, Nonoguchi H, Knepper MA. Hormone and autacoid regulation of cAMP production in rat IMCD subsegments. Am J Physiol Renal Fluid Electrolyte Physiol 263: F319–F327, 1992.[Abstract/Free Full Text]
149. Maggio R, Scarselli M, Novi F, Millan MJ, Corsini GU. Potent activation of dopamine D₃/D₂ heterodimers by the antiparkinsonian agents, S32504, pramipexole and ropinirole. J Neurochem 87: 631–641, 2003.[CrossRef][Web of Science][Medline]
150. Maiorov DN, Krenz NR, Krassioukov AV, Weaver LC. Role of spinal NMDA and AMPA receptors in episodic hypertension in conscious spinal rats. Am J Physiol Heart Circ Physiol 273: H1266–H1274, 1997.[Abstract/Free Full Text]
151. Matsumoto M, Hidaka K, Tada S, Tasaki Y, Yamaguchi T. Full-length cDNA cloning and distribution of human dopamine D₄ receptor. Mol Brain Res 29: 157–162, 1995.[Medline]
152. Matsumoto T, Ozono R, Sasaki N, Oshima T, Matsuura H, Kajiyama G, Carey RM, Kambe M. Type 1A dopamine receptor expression in the heart is not altered in spontaneously hypertensive rats. Am J Hypertens 13: 673–677, 2000.[CrossRef][Web of Science][Medline]
153. Michel MC, Siepmann F, Buscher R, Philipp T, Brodde OE. Ontogenesis of sympathetic responsiveness in spontaneously hypertensive rats. I. Renal alpha 1-, alpha 2-, and beta-adrenergic receptors and their signaling. Hypertension 22: 169–177, 1993.[Abstract/Free Full Text]
154. Monsma FJ Jr, McVittie LD, Gerfen CR, Mahan LC, Sibley DR. Multiple D₂ dopamine receptors produced by alternative RNA splicing. Nature 342: 926–929, 1989.[CrossRef][Medline]
155. Muhlbauer B, Kuster E, Luippold G. Dopamine D₃ receptors in the rat kidney: role in physiology and pathophysiology. Acta Physiol Scand 168: 219–223, 2000.[CrossRef][Web of Science][Medline]
156. Murphy MB, Murray C, Shorten GD. Fenoldopam: a selective peripheral dopamine-receptor agonist for the treatment of severe hypertension. N Engl J Med 345: 1548–1557, 2001.[Free Full Text]
157. Nakaki T, Nakayama M, Yamamoto S, Kato R. Alpha 1-adrenergic stimulation and beta 2-adrenergic inhibition of DNA synthesis in vascular smooth muscle cells. Mol Pharmacol 37: 30–36, 1989.[Web of Science]
158. Narkar VA, Hussain T, Lokhandwala MF. Activation of D₂-like receptors causes recruitment of tyrosine-phosphorylated NKA 1-subunits in kidney. Am J Physiol Renal Physiol 283: F1290–F1295, 2002.[Abstract/Free Full Text]
159. Narkar VA, Hussain T, Pedemonte C, Lokhandwala MF. Dopamine D₂ receptor activation causes mitogenesis via p44/42 mitogen-activated protein kinase in opossum kidney cells. J Am Soc Nephrol 12: 1844–1852, 2001.[Abstract/Free Full Text]
160. Nash SR, Godinot N, Caron MG. Cloning and characterization of the opossum kidney cell D₁ dopamine receptor: expression of identical D1A and D1B dopamine receptor mRNAs in opossum kidney and brain. Mol Pharmacol 44: 918–925, 1993.[Abstract]
161. Nasjletti A. The role of eicosanoids in angiotensin-dependent hypertension. Hypertension 31: 194–200, 1998.[Abstract/Free Full Text]
162. Natarajan AR, Han G, White R, Jose PA. The human D₅ dopamine receptor mediates big KCa channel activity in human coronary artery smooth muscle cells (Abstract). Hypertension 48: e80, 2006.[CrossRef]
163. Nielsen CB, Pedersen EB. Abnormal distal tubular sodium reabsorption during dopamine infusion in patients with essential hypertension evaluated by the lithium clearance methods. Clin Nephrol 47: 304–309, 1997.[Web of Science][Medline]
164. Nishi A, Eklöf AC, Bertorello AM, Aperia A. Dopamine regulation of renal Na⁺,K⁺-ATPase activity is lacking in Dahl salt-sensitive rats. Hypertension 21: 767–771, 1993.[Abstract/Free Full Text]
165. Noble EO, Blum K, RitchieT, Montgomery A, Sheridan PJ. Allelic association of the D₂ dopamine receptor gene with the receptor-binding characteristics in alcoholism. Arch Gen Psychiatry 48: 648–654, 1991.[Abstract/Free Full Text]
166. Noh JS, Gwag BJ. Attenuation of oxidative neuronal necrosis by a dopamine D₁ agonist in mouse cortical cell cultures. Exp Neurol 146: 604–608, 1997.[CrossRef][Web of Science][Medline]
167. Nowicki S, Kruse MS, Brismar H, Aperia A. Dopamine-induced translocation of protein kinase C isoforms visualized in renal epithelial cells. Am J Physiol Cell Physiol 279: C1812–C1818, 2000.[Abstract/Free Full Text]
168. Nurnberger A, Rabiger M, Mack A, Diaz J, Sokoloff P, Muhlbauer B, Luippold G. Subapical localization of the dopamine D₃ receptor in proximal tubules of the rat kidney. J Histochem Cytochem 52: 1647–1655, 2004.[Abstract/Free Full Text]
169. O'Connell DP, Aherne AM, Lane E, Felder RA, Carey RM. Detection of dopamine receptor D1A subtype-specific mRNA in rat kidney by in situ amplification. Am J Physiol Renal Physiol 274: F232–F241, 1998.[Abstract/Free Full Text]
170. O'Connell DP, Botkin SJ, Ramos SI, Sibley DR, Ariano MA, Felder RA, Carey RM. Localization of dopamine D_1A receptor protein in rat kidneys. Am J Physiol Renal Fluid Electrolyte Physiol 268: F1185–F1197, 1995.[Abstract/Free Full Text]
171. O'Connell DP, Ragsdale NV, Boyd DG, Felder RA, Carey RM. Differential human renal tubular responses to dopamine type 1 receptor stimulation are determined by blood pressure status. Hypertension 29: 115–122, 1997.[Abstract/Free Full Text]
172. O'Connell DP, Vaughan CJ, Aherne AM, Botkin SJ, Wang ZQ, Felder RA, Carey RM. Expression of the dopamine D₃ receptor protein in the rat kidney. Hypertension 32: 886–895, 1998.[Abstract/Free Full Text]
173. Offen D, Ziv I, Sternin H, Melamed E, Hochman A. Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson's disease. Exp Neurol 141: 32–39, 1996.[CrossRef][Web of Science][Medline]
174. Ohbu K, Felder RA. Nephron specificity of dopamine receptor-adenylyl cyclase defect in spontaneous hypertension. Am J Physiol Renal Fluid Electrolyte Physiol 264: F274–F279, 1993.[Abstract/Free Full Text]
175. Ohbu K, Hendley ED, Yamaguchi I, Felder RA. Renal dopamine-1 receptors in hypertensive inbred rat strains with and without hyperactivity. Hypertension 21: 485–490, 1993.[Abstract/Free Full Text]
176. Ominato Satoh MT, Katz AI. Regulation of Na-KATPase activity in the proximal tubule: role of the protein kinase C pathway and of eicosanoids. J Membr Biol 152: 235–243, 1996.[CrossRef][Web of Science][Medline]
177. Osborn JW, Jacob F, Guzman P. A neural set point for the long-term control of arterial pressure: beyond the arterial baroreceptor reflex. Am J Physiol Regul Integr Comp Physiol 288: R846–R855, 2005.[Abstract/Free Full Text]
178. Ozono R, O'Connell DP, Wang ZQ, Moore AF, Sanada H, Felder RA, Carey RM. Localization of the dopamine D₁ receptor protein in the human heart and kidney. Hypertension 30: 725–729, 1997.[Abstract/Free Full Text]
179. Ozono R, Ueda A, Oishi Y, Yano A, Kambe M, Katsuki M, Oshima T. Dopamine D₂ receptor modulates sodium handling via local production of dopamine in the kidney. J Cardiovasc Pharmacol 42: S75–S79, 2003.[Web of Science][Medline]
180. Pedrosa R, Jose PA, Soares-Da-Silva P. Defective D₁-like receptor-mediated inhibition of Cl^–/HCO₃^– exchanger in immortalized SHR proximal tubular epithelial cells. Am J Physiol Renal Physiol 286: F1120–F1126, 2004.[Abstract/Free Full Text]
181. Pei L, Lee FJ, Moszczynska A, Vukusic B, Liu F. Regulation of dopamine D₁ receptor function by physical interaction with the NMDA receptors. J Neurosci 24: 1149–1158, 2004.[Abstract/Free Full Text]
182. Pettersson-Fernholm KJ, Forsblom CM, Perola M, Fagerudd JA, Groop PH; FinnDiane Study Group. Dopamine D₃ receptor gene polymorphisms, blood pressure and nephropathy in type 1 diabetic patients. Nephrol Dial Transplant 19: 1432–1436, 2004.[Abstract/Free Full Text]
183. Piomelli D, Pilon C, Giros B, Sokoloff P, Martres MP, Schwartz JC. Dopamine activation of the arachidonic acid cascade as a basis for D₁/D₂ receptor synergism. Nature 353: 164–167, 1991.[CrossRef][Medline]
184. Polakowski JS, Segreti JA, Cox BF, Hsieh GC, Kolasa T, Moreland RB, Brioni JD. Effects of selective dopamine receptor subtype agonists on cardiac contractility and regional haemodynamics in rats. Clin Exp Pharmacol Physiol 31: 837–841, 2004.[CrossRef][Web of Science][Medline]
185. Pollack A. Coactivation of D₁ and D₂ dopamine receptors: in marriage, a case of his, hers, and theirs. Sci STKE: pe50, 2004.
186. Premont RT, Gainetdinov RR. Physiological roles of G protein-coupled receptor kinases and arrestins. Annu Rev Physiol 69: 511–534, 2007.[CrossRef][Web of Science][Medline]
187. Prinster SC, Hague C, Hall RA. Heterodimerization of G-protein-coupled receptors: specificity and functional significance. Pharmacol Rev 57: 289–298, 2005.[Abstract/Free Full Text]
188. Ragsdale NV, Lynch M, Chevalier RL, Felder RA, Peach MJ, Carey RM. Selective peripheral dopamine-1 receptor stimulation: differential responses to sodium loading and depletion in humans. Hypertension 15: 914–921, 1990.[Abstract/Free Full Text]
189. Raizada MK, Der Sarkissian S. Potential of gene therapy strategy for the treatment of hypertension. Hypertension 47: 6–9, 2006.[Free Full Text]
190. Rao GN, Berk BC. Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. Circ Res 70: 593–599, 1992.[Abstract/Free Full Text]
191. Rao F, Wessel J, Wen G, Zhang L, Rana BK, Kennedy BP, Greenwood TA, Salem RM, Chen Y, Khandrika S, Hamilton BA, Smith DW, Holstein-Rathlou NH, Ziegler MG, Schork NJ, O'Connor DT. Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism. Hypertension 49: 1015–1031, 2007.[Abstract/Free Full Text]
192. Ricci A, Amenta F, Bronzetti E, Felici L, Hussain T, Lokhandwala MF. Age-related changes of dopamine receptor protein immunoreactivity in the rat mesenteric vascular tree. Mech Ageing Dev 123: 537–546, 2002.[CrossRef][Web of Science][Medline]
193. Ricci A, Bronzetti E, Fedele F, Ferrante F, Zaccheo D, Amenta F. Pharmacological characterization and autoradiographic localization of a putative dopamine D₄ receptor in the heart. J Auton Pharmacol 18: 115–121, 1998.[CrossRef][Web of Science][Medline]
194. Ricci A, Collier WL, Amenta F. Pharmacological characterization and autoradiographic localization of dopamine receptors in the portal vein. J Auton Pharmacol 14: 61–68, 1994.[CrossRef][Web of Science][Medline]
195. Ricci A, Marchal-Victorion S, Bronzetti E, Parini A, Amenta F, Tayebati SK. Dopamine D₄ receptor expression in rat kidney: evidence for pre- and postjunctional localization. Histochem Cytochem 50: 1091–1096, 2002.[Abstract/Free Full Text]
196. Ricci A, Mignini F, Tomassoni D, Amenta F. Dopamine receptor subtypes in the human pulmonary arterial tree. Auton Autacoid Pharmacol 26: 361–369, 2006.[CrossRef][Medline]
197. Rice T, Rankinen T, Province MA, Chagnon YC, Perusse L, Borecki IB, Bouchard C, Rao DC. Genome-wide linkage analysis of systolic and diastolic blood pressure: the Quebec Family Study. Circulation 102: 1956–1963, 2000.[Abstract/Free Full Text]
198. Ridray S, Griffon N, Mignon V, Souil E, Carboni S, Diaz J, Schwartz JC, Sokoloff P. Coexpression of dopamine D₁ and D₃ receptors in islands of Calleja and shell of nucleus accumbens of the rat: opposite and synergistic functional interactions. Eur J Neurosci 10: 1676–1686, 1998.[CrossRef][Web of Science][Medline]
199. Robinson SW, Caron MG. Selective inhibition of adenylyl cyclase type V by the dopamine D₃ receptor. Mol Pharmacol 52: 508–514, 1997.[Abstract/Free Full Text]
200. Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC, Patel YC. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288: 154–157, 2000.[Abstract/Free Full Text]
201. Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G, Fang Y, Larson JL, McDougall JA, Chester JA, Saez C, Pugsley TA, Gershanik O, Low MJ, Grandy DK. Mice lacking dopamine D₄ receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90: 991–1001, 1997.[CrossRef][Web of Science][Medline]
202. Saito O, Ando Y, Kusano E, Asano Y. Functional characterization of basolateral and luminal dopamine receptors in rabbit CCD. Am J Physiol Renal Physiol 281: F114–F122, 2001.[Abstract/Free Full Text]
203. Salomone LJ, Howell NL, McGrath HE, Kemp BA, Keller SR, Gildea JJ, Felder RA, Carey RM. Intrarenal dopamine D₁-like receptor stimulation induces natriuresis via an angiotensin type-2 receptor mechanism. Hypertension 49: 155–161, 2007.[Abstract/Free Full Text]
204. Sam EE, Verbeke N. Free radical scavenging properties of apomorphine enantiomers and dopamine: possible implication in their mechanism of action in Parkinsonism. J Neural Transm 10: 115–127, 1995.[CrossRef][Web of Science]
205. Sanada H, Jose PA, Hazen-Martin D, Yu PY, Xu J, Bruns DE, Phipps J, Carey RM, Felder RA. Dopamine-1 receptor coupling defect in renal proximal tubule cells in hypertension. Hypertension 33: 1036–1042, 1999.[Abstract/Free Full Text]
206. Sanada H, Xu J, Watanabe H, Jose PA, Felder RA. Differential expression and regulation of dopamine-1 (D-1) and dopamine-5 (D-5) receptor function in human kidney (Abstract). Am J Hypertens 13: 156A, 2000.
207. Sanada H, Yao L, Jose PA, Carey RM, Felder RA. Dopamine D₃ receptors in rat juxtaglomerular cells. Clin Exp Hypertens 19: 93–105, 1997.[CrossRef][Web of Science][Medline]
208. Sanada H, Yatabe J, Midorikawa S, Katoh T, Hashimoto S, Watanabe T, Xu J, Luo Y, Wang X, Zeng C, Armando I, Felder RA, Jose PA. Amelioration of genetic hypertension by suppression of renal G protein-coupled receptor kinase type 4 expression. Hypertension 47: 1131–1139, 2006.[Abstract/Free Full Text]
209. Sarkis A, Lopez B, Roman RJ. Role of 20-hydroxyeicosatetraenoic acid and epoxy-eicosatrienoic acids in hypertension. Curr Opin Nephrol Hypertens 13: 205–214, 2004.[Web of Science][Medline]
210. Sato M, Soma M, Nakayama T, Kanmatsuse K. Dopamine D₁ receptor gene polymorphism is associated with essential hypertension. Hypertension 36: 183–186, 2000.[Abstract/Free Full Text]
211. Satoh T, Cohen HT, Katz AI. Intracellular signaling in the regulation of renal Na-K-ATPase. I. Role of cyclic AMP and phospholipase A2. J Clin Invest 89: 1496–1500, 1992.[Web of Science][Medline]
212. Satoh T, Cohen HT, Katz AI. Different mechanisms of renal Na-K-ATPase regulation by protein kinases in proximal and distal nephron. Am J Physiol Renal Fluid Electrolyte Physiol 265: F399–F405, 1993.[Abstract/Free Full Text]
213. Sautel F, Griffon N, Levesque D, Pilon C, Schwartz JC, Sokoloff P. A functional test identifies dopamine agonists selective for D₃ versus D₂ receptors. Neuroreport 6: 329–332, 1995.[Web of Science][Medline]
214. Scarselli M, Novi F, Schallmach E, Lin R, Baragli A, Colzi A, Griffon N, Corsini GU, Sokoloff P, Levenson R, Vogel Z, Maggio R. D₂/D₃ dopamine receptor heterodimers exhibit unique functional properties. J Biol Chem 276: 30308–30314, 2001.[Abstract/Free Full Text]
215. Schioth HB, Fredriksson R. The GRAFS classification system of G-protein coupled receptors in comparative perspective. Gen Comp Endocrinol 142: 94–101, 2005.[CrossRef][Web of Science][Medline]
216. Schmauss C. A single dose of methamphetamine leads to a long term reversal of the blunted dopamine D₁ receptor-mediated neocortical c-fos responses in mice deficient for D₂ and D₃ receptors. J Biol Chem 275: 38944–38948, 2000.[Abstract/Free Full Text]
217. Schmitz Y, Schmauss C, Sulzer D. Altered dopamine release and uptake kinetics in mice lacking D₂ receptors. J Neurosci 22: 8002–8009, 2002.[Abstract/Free Full Text]
218. Scott L, Kruse MS, Forssberg H, Brismar H, Greengard P, Aperia A. Selective up-regulation of dopamine D₁ receptors in dendritic spines by NMDA receptor activation. Proc Natl Acad Sci USA 99: 1661–1664, 2002.[Abstract/Free Full Text]
219. Sen S, Nesse R, Sheng L, Stoltenberg SF, Gleiberman L, Burmeister M, Weder AB. Association between a dopamine-4 receptor polymorphism and blood pressure. Am J Hypertens 18: 1206–1210, 2005.[CrossRef][Web of Science][Medline]
220. Sheikh-Hamad D, Wang YP, Jo OD, Yanagawa N. Dopamine antagonizes the actions of angiotensin II in renal brush-border membrane. Am J Physiol Renal Fluid Electrolyte Physiol 264: F737–F743, 1993.[Abstract/Free Full Text]
221. Shin Y, Kumar U, Patel Y, Patel SC, Sidhu A. Differential expression of D₂-like dopamine receptors in the kidney of the spontaneously hypertensive rat. J Hypertens 21: 199–207, 2003.[CrossRef][Web of Science][Medline]
222. Shultz PJ, Sedor JR, Abboud HE. Dopaminergic stimulation of cAMP accumulation in cultured rat mesangial cells. Am J Physiol Heart Circ Physiol 253: H358–H364, 1987.[Abstract/Free Full Text]
223. Sibley DR. New insights into dopaminergic receptor function using antisense and genetically altered animals. Annu Rev Pharmacol Toxicol 39: 313–341, 1999.[CrossRef][Web of Science][Medline]
224. Soma M, Nakayama K, Rahmutula D, Uwabo J, Sato M, Kunimoto M, Aoi N, Kosuge K, Kanmatsuse K. Ser9Gly polymorphism in the dopamine D₃ receptor gene is not associated with essential hypertension in the Japanese. Med Sci Monit 8: CR1–CR4, 2002.[Medline]
225. Staudacher T, Pech B, Tappe M, Gross G, Muhlbauer B, Luippold G. Arterial blood pressure and renal sodium excretion in dopamine D₃ receptor knockout mice. Hypertens Res 30: 93–101, 2007.[CrossRef][Web of Science][Medline]
226. Sugiyama F, Churchill GA, Higgins DC, Johns C, Makaritsis KP, Gavras H, Paigen B. Concordance of murine quantitative trait loci for salt-induced hypertension with rat and human loci. Genomics 71: 70–77, 2001.[CrossRef][Web of Science][Medline]
227. Sun D, Wilborn TW, Schafer JA. Dopamine D₄ receptor isoform mRNA and protein are expressed in the rat cortical collecting duct. Am J Physiol Renal Physiol 275: F742–F751, 1998.[Abstract/Free Full Text]
228. Sun MH, Ishine T, Lee TJ. Dopamine constricts porcine pial veins. Eur J Pharmacol 334: 165–167, 1997.[CrossRef][Web of Science][Medline]
229. Sunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HH, Niznik HB. Cloning of the gene for a human dopamine D₅ receptor with higher affinity for dopamine than D₁. Nature 350: 614–619, 1991.[CrossRef][Medline]
230. Takemoto F, Satoh T, Cohen HT, Katz AI. Localization of dopamine-1 receptors along the microdissected rat nephron. Pflügers Arch 419: 243–248, 1991.[CrossRef][Web of Science][Medline]
231. Teirstein PS, Price MJ, Mathur VS, Madyoon H, Sawhney N, Baim DS. Differential effects between intravenous and targeted renal delivery of fenoldopam on renal function and blood pressure in patients undergoing cardiac catheterization. Am J Cardiol 97: 1076–1081, 2006.[CrossRef][Web of Science][Medline]
232. Thomas GN, Critchley JA, Tomlinson B, Cockram CS, Chan JC. Relationships between the taqI polymorphism of the dopamine D₂ receptor and blood pressure in hyperglycaemic and normoglycaemic Chinese subjects. Clin Endocrinol (Oxf) 55: 605–611, 2001.[CrossRef][Medline]
233. Thomas GN, Tomlinson B, Critchley JA. Modulation of blood pressure and obesity with the dopamine D₂ receptor gene TaqI polymorphism. Hypertension 36: 177–182, 2000.[Abstract/Free Full Text]
234. Touyz RM. Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II. Exp Physiol 90: 449–455, 2005.[Abstract/Free Full Text]
235. Ueda A, Ozono R, Oshima T, Yano A, Kambe M, Teranishi Y, Katsuki M, Chayama K. Disruption of the type 2 dopamine receptor gene causes a sodium-dependent increase in blood pressure in mice. Am J Hypertens 16: 853–858, 2003.[CrossRef][Web of Science][Medline]
236. Van Tol HHM, Wu CM, Guan HC, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V. Multiple dopamine D₄ receptor variants in the human population. Nature 358: 149–152, 1992.[CrossRef][Medline]
237. Wang H, Joseph JA. Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med 27: 612–616, 1999.[CrossRef][Web of Science][Medline]
238. Wang X, Armando I, Asico LD, Jones JE, Escano CS, Jose PA. Hypertension in dopamine receptor D₃ deficient mice is associated with increased Na transporters in kidney (Abstract). J Am Soc Nephrol 16: 350A, 2005.
239. Wang ZQ, Felder RA, Carey RM. Selective inhibition of the renal dopamine subtype D_1A receptor induces antinatriuresis in conscious rats. Hypertension 33: 504–510, 1999.[Abstract/Free Full Text]
240. Wang ZQ, Siragy HM, Felder RA, Carey RM. Intrarenal dopamine production and distribution in the rat. Physiological control of sodium excretion. Hypertension 29: 228–234, 1997.[Abstract/Free Full Text]
241. Watanabe H, Xu J, Bengra C, Jose PA, Felder RA. Desensitization of human renal D₁ dopamine receptors by G protein-coupled receptor kinase 4. Kidney Int 62: 790–798, 2002.[CrossRef][Web of Science][Medline]
242. Wersinger C, Chen J, Sidhu A. Bimodal induction of dopamine-mediated striatal neurotoxicity is mediated through both activation of D₁ dopamine receptors and autoxidation. Mol Cell Neurosci 25: 124–137, 2004.[CrossRef][Web of Science][Medline]
243. White BH, Kimura K, Sidhu A. Inhibition of hormonally induced inositol trisphosphate production in transfected GH4C1 cells: a novel role for the D₅ subtype of the dopamine receptor. Neuroendocrinology 69: 209–216, 1999.[CrossRef][Web of Science][Medline]
244. White RE, Kryman JP, El-Mowafy AM, Han G, Carrier GO. cAMP-dependent vasodilators cross-activate the cGMP-dependent protein kinase to stimulate BK_Ca channel activity in coronary artery smooth muscle cells. Circ Res 86: 897–905, 2000.[Abstract/Free Full Text]
245. Wiederkehr MR, Di Sole F, Collazo R, Quinones H, Fan L, Murer H, Helmle-Kolb C, Moe OW. Characterization of acute inhibition of Na/H exchanger NHE-3 by dopamine in opossum kidney cells. Kidney Int 59: 197–209, 2001.[Web of Science][Medline]
246. Xia XG, Schmidt N, Teismann P, Ferger B, Schulz JB. Dopamine mediates striatal malonate toxicity via dopamine transporter-dependent generation of reactive oxygen species and D₂ but not D₁ receptor activation. J Neurochem 79: 63–70, 2001.[CrossRef][Web of Science][Medline]
247. Xu J, Li XX, Albrecht FE, Hopfer U, Carey RM, Jose PA. D₁ receptor, G_s, and Na⁺/H⁺ exchanger interactions in the kidney in hypertension. Hypertension 36: 395–399, 2000.[Abstract/Free Full Text]
248. Yamaguchi I, Jose PA, Mouradian MM, Canessa LM, Monsma FJ Jr, Sibley DR, Takeyasu K, Felder RA. Expression of dopamine D_1A receptor gene in proximal tubule of rat kidneys. Am J Physiol Renal Fluid Electrolyte Physiol 264: F280–F285, 1993.[Abstract/Free Full Text]
249. Yamaguchi I, Walk SF, Jose PA, Felder RA. Dopamine D2L receptors stimulate Na⁺/K⁺ ATPase activity in murine LTK2 cells. Mol Pharmacol 49: 373–378, 1996.[Abstract]
250. Yamaguchi I, Yao L, Sanada H, Ozono R, Mouradian MM, Jose PA, Carey RM, Felder RA. Dopamine D1A receptors and renin release in rat juxtaglomerular cells. Hypertension 29: 962–968, 1997.[Abstract/Free Full Text]
251. Yamauchi M, Kobayashi Y, Shimoura K, Hattori K, Nakase A. Endothelium-dependent and -independent relaxation by dopamine in the rabbit pulmonary artery. Clin Exp Pharmacol Physiol 19: 401–410, 1992.[Web of Science][Medline]
252. Yang Z, Asico LD, Yu P, Wang Z, Jones JE, Bai RK, Sibley DR, Felder RA, Jose PA. D₅ dopamine receptor regulation of phospholipase D. Am J Physiol Heart Circ Physiol 288: H55–H61, 2005.[Abstract/Free Full Text]
253. Yang Z, Asico LD, Yu P, Wang Z, Jones JE, Escano CS, Wang X, Quinn MT, Sibley DR, Romero GG, Felder RA, Jose PA. D₅ dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure. Am J Physiol Regul Integr Comp Physiol 290: R96–R104, 2006.[Abstract/Free Full Text]
254. Yao L, Ruan X, Arendshorst WJ, Jose PA. Dopamine receptor subtype (D1A and D1B) expression in rat renal microvessels (Abstract). Pediatr Res 37: 374A, 1995.
255. Yao LP, Huque E, Baraniuk J, Carey RM, Felder RA, Jose PA. Dopamine receptor subtype expression (D1A and D1B) in rat nephron segments (Abstract). J Investig Med 44: 305A, 1996.
256. Yao LP, Li XX, Yu PY, Xu J, Asico LD, Jose PA. Dopamine D₁ receptor and protein kinase C isoforms in spontaneously hypertensive rats. Hypertension 32: 1049–1053, 1998.[Abstract/Free Full Text]
257. Yasunari K, Kohno M, Hasuma T, Horio T, Kano H, Yokokawa K, Minami M, Yoshikawa J. Dopamine as a novel antimigration and antiproliferative factor of vascular smooth muscle cells through dopamine D₁-like receptors. Arterioscler Thromb Vasc Biol 17: 3164–3173, 1997.[Abstract/Free Full Text]
258. Yasunari K, Kohno M, Kano H, Minami M, Yoshikawa J. Dopamine as a novel antioxidative agent for rat vascular smooth muscle cells through dopamine D₁-like receptors. Circulation 101: 2302–2308, 2000.[Abstract/Free Full Text]
259. Yu P, Asico LD, Luo Y, Andrews P, Eisner GM, Hopfer U, Felder RA, Jose PA. D₁ dopamine receptor hyperphosphorylation in renal proximal tubules in hypertension. Kidney Int 70: 1072–1079, 2006.[CrossRef][Web of Science][Medline]
260. Yu P, Yang Z, Jones JE, Wang Z, Owens SA, Mueller SC, Felder RA, Jose PA. D₁ dopamine receptor signaling involves caveolin-2 in HEK-293 cells. Kidney Int 66: 2167–2180, 2004.[CrossRef][Web of Science][Medline]
261. Zapata A, Shippenberg TS. Lack of functional D₂ receptors prevents the effects of the D₃-preferring agonist (+)-PD 128907 on dialysate dopamine levels. Neuropharmacology 48: 43–50, 2005.[CrossRef][Web of Science][Medline]
262. Zarei S, Frieden M, Rubi B, Villemin P, Gauthier BR, Maechler P, Vischer UM. Dopamine modulates von Willebrand factor secretion in endothelial cells via D₂-D₄ receptors. J Thromb Haemost 4: 1588–1595, 2006.[CrossRef][Web of Science][Medline]
263. Zeng C, Asico LD, Zheng S, Hopfer U, Eisner GM, Felder RA, Jose PA. Role of G12- and G13-protein subunit linkage of D₃ dopamine receptors in the impaired natriuretic effect of D₃ dopamine receptors in SHRs (Abstract). Am J Hypertens 17: 96A, 2004.[CrossRef]
264. Zeng C, Asico LD, Wang X, Hopfer U, Eisner GM, Felder RA, Jose PA. Angiotensin II regulation of AT₁ and D₃ dopamine receptors in renal proximal tubule cells of spontaneously hypertensive rats. Hypertension 41: 724–729, 2003.[Abstract/Free Full Text]
265. Zeng C, Felder RA, Jose PA. A new approach for treatment of hypertension: modifying D₁ dopamine receptor function. Cardiovasc Hematol Agents Med Chem 4: 369–377, 2006.[Medline]
266. Zeng C, Liu Y, Wang Z, He D, Huang L, Yu P, Zheng S, Jones JE, Asico LD, Hopfer U, Eisner GM, Felder RA, Jose PA. Activation of D₃ dopamine receptor decreases AT₁ angiotensin receptor expression in rat renal proximal tubule cells. Circ Res 99: 494–500, 2006.[Abstract/Free Full Text]
267. Zeng C, Luo Y, Asico LD, Hopfer U, Eisner GM, Felder RA, Jose PA. Perturbation of D₁ dopamine and AT₁ receptor interaction in spontaneously hypertensive rats. Hypertension 42: 787–792, 2003.[Abstract/Free Full Text]
268. Zeng C, Sanada H, Watanabe H, Eisner GM, Felder RA, Jose PA. Functional genomics of the dopaminergic system in hypertension. Physiol Genomics 19: 233–246, 2004.[Abstract/Free Full Text]
269. Zeng C, Wang D, Asico LD, Welch WJ, Wilcox CS, Hopfer U, Eisner GM, Felder RA, Jose PA. Aberrant D₁ and D₃ dopamine receptor transregulation in hypertension. Hypertension 43: 654–660, 2004.[Abstract/Free Full Text]
270. Zeng C, Wang D, Yang Z, Wang Z, Asico LD, Wilcox CS, Eisner GM, Welch WJ, Felder RA, Jose PA. Dopamine D₁ receptor augmentation of D₃ receptor action in rat aortic or mesenteric vascular smooth muscles. Hypertension 43: 673–679, 2004.[Abstract/Free Full Text]
271. Zeng C, Wang Z, Hopfer U, Asico LD, Eisner GM, Felder RA, Jose PA. Rat strain effects of AT₁ receptor activation on D₁ dopamine receptors in immortalized renal proximal tubule cells. Hypertension 46: 799–805, 2005.[Abstract/Free Full Text]
272. Zeng C, Wang Z, Li H, Yu P, Zheng S, Wu L, Asico LD, Hopfer U, Eisner GM, Felder RA, Jose PA. D₃ dopamine receptor directly interacts with D₁ dopamine receptor in immortalized renal proximal tubule cells. Hypertension 47: 573–579, 2006.[Abstract/Free Full Text]
273. Zeng C, Yang Z, Asico LD, Jose PA. Regulation of blood pressure by D₅ dopamine receptors. Cardiovasc Hematol Agents Med Chem 5: 241–248, 2007.[Medline]
274. Zeng C, Yang Z, Wang Z, Jones J, Wang X, Altea J, Mangrum AJ, Hopfer U, Sibley DR, Eisner GM, Felder RA, Jose PA. Interaction of AT₁ and D₅ dopamine receptors in renal proximal tubule cells. Hypertension 45: 804–810, 2005.[Abstract/Free Full Text]
275. Zeng C, Yu P, Asico LD, Hopfer U, Eisner GM, Jose PA. D₃ dopamine receptor upregulates and directly interacts with the D₁ dopamine receptor in renal proximal tubule cells (Abstract). Am J Hypertens 15: 11A, 2002.
276. Zeng CY, Yang ZW, Wu LJ, Asico LD, Felder RA, Jose PA. Hypertension in D₃ dopamine receptor deficient mice. Zhonghua Xin Xue Guan Bing Za Zhi 33: 1132–1136, 2005.[Medline]
277. Zhang H, Qiao Z, Zhao Y, Zhao R. Transcription of dopamine D1A receptor mRNAs in rat heart. Methods Find Exp Clin Pharmacol 18: 183–187, 1996.[Web of Science][Medline]
278. Zhang J, Abdel-Rahman AA. The hypotensive action of rilmenidine is dependent on functional N-methyl-D-aspartate receptor in the rostral ventrolateral medulla of conscious spontaneously hypertensive rats. J Pharmacol Exp Ther 303: 204–210, 2002.[Abstract/Free Full Text]
279. Zhang L, Lou D, Jiao H, Zhang D, Wang X, Xia Y, Zhang J, Xu M. Cocaine-induced intracellular signaling and gene expression are oppositely regulated by the dopamine D₁ and D₃ receptors. J Neurosci 24: 3344–3354, 2004.[Abstract/Free Full Text]
280. Zheng S, Yu P, Zeng C, Wang Z, Yang Z, Andrews PM, Felder RA, Jose PA. G₁₂- and G₁₃-protein subunit linkage of D₅ dopamine receptors in the nephron. Hypertension 41: 604–610, 2003.[Abstract/Free Full Text]

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