EBM Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hussain, T.
Right arrow Articles by Lokhandwala, M. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hussain, T.
Right arrow Articles by Lokhandwala, M. F.
Experimental Biology and Medicine 228:134-142 (2003)
© 2003 Society for Experimental Biology and Medicine

MINIREVIEW

Renal Dopamine Receptors and Hypertension

Tahir Hussain and Mustafa F. Lokhandwala1

Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas 77204


   Abstract
Top
 Abstract
Physiologic Role of Dopamine...
 Dopamine Receptor-Linked...
 Dopamine and Dopamine Receptors...
 Concluding Remarks
 References
 
Dopamine has been recognized as an important modulator of central as well as peripheral physiologic functions in both humans and animals. Dopamine receptors have been identified in a number of organs and tissues, which include several regions within the central nervous system, sympathetic ganglia and postganglionic nerve terminals, various vascular beds, the heart, the gastrointestinal tract, and the kidney. The peripheral dopamine receptors influence cardiovascular and renal function by decreasing afterload and vascular resistance and promoting sodium excretion. Within the kidney, dopamine receptors are present along the nephron, with highest density on proximal tubule epithelial cells. It has been reported that there is a defective dopamine receptor, especially D1 receptor function, in the proximal tubule of various animal models of hypertension as well as in humans with essential hypertension. Recent reports have revealed the site of and the molecular mechanisms responsible for the defect in D1 receptors in hypertension. Moreover, recent studies have also demonstrated that the disruption of various dopamine receptor subtypes and their function produces hypertension in rodents. In this review, we present evidence that dopamine and dopamine receptors play an important role in regulating renal sodium excretion and that defective renal dopamine production and/or dopamine receptor function may contribute to the development of various forms of hypertension.

Key Words: natriuresis • proximal tubule • sodium transport • dopamine receptor • phosphorylation


   Physiologic Role of Dopamine and Dopamine Receptors in the Kidney
Top
 Abstract
 Physiologic Role of Dopamine...
Dopamine Receptor-Linked...
 Dopamine and Dopamine Receptors...
 Concluding Remarks
 References
 
Dopamine and Dopamine Receptor in the Kidney.
Dopamine produces its biologic effects through five genetically distinct dopamine receptor subtypes: D1, D2, D3, D4, and D5 (1). These receptors are categorized into two groups known as D1-like (D1 and D5, whose rat homologs are D1A and D1B) and D2-like (D2, D3, and D4) dopamine receptors based on their ability to stimulate and inhibit adenylyl cyclase, respectively (Fig. 1Go). Of the cloned dopamine receptors, D1A, D1B, D2, and D3 have been identified in the kidney (1–5). The D1-like receptors are present on the smooth muscle of blood vessels of most major organs, the juxtaglomerular apparatus, and on renal tubules (4–8). The D2-like receptor exists on the glomeruli, postganglionic sympathetic nerve terminals, zona glomerulosa cells of the renal cortex, and renal tubules (4–8).



View larger version (18K):
[in this window]
[in a new window]
  		Figure 1. Dopamine receptor subtypes and their second messengers; (+), stimulation; (-), inhibition.

 
The source of the dopamine that activates tubular dopamine receptors is believed to be nonneuronal. The tubular cells contain abundant dopa decarboxylase, which is necessary for synthesis of dopamine (9). The substrate L-dopa is filtered freely from the glomerulus and is actively transported into tubular cells, where L-dopa is converted to dopamine by the decarboxylation process (10, 11). Once dopamine is synthesized, it is transported out of the cells where it can interact with dopamine receptors (Fig. 2Go).



View larger version (37K):
[in this window]
[in a new window]
  		Figure 2. Hypothetical scheme of dopamine synthesis and D1-like receptor signaling pathway that causes inhibition of sodium transporters in proximal tubles of rat kidney. L-AADC, L-aromatic amino acid decarboxylase; AC, adenylyl cyclase; PLC, phospholipase C; PKA, protein kinase A; PKC, protein kinase C; PIP2, phosphatidylinositol bisphosphate; IP3, inositol trisphosphate; L-DOPA, L-dihydroxyphenylalanine; DAG, diacylglycerol.

 
Physiologic Role of Peripheral Dopamine Receptors.
Since the discovery in 1964 that dopamine produces natriuresis and diuresis (12), a tremendous amount of progress has been made in understanding dopamine-mediated effects on renal and cardiovascular function. Selective D1-like receptor agonists cause hypotension, reduce afterload, increase blood flow to certain organs, and promote urinary sodium and water excretion. Selective D2-like receptor agonists produce hypotension, bradycardia, a decrease in afterload, and vasodilation in certain vascular beds (13, 14). The vasodilation and subsequent hypotension caused by D1-like receptor agonists such as fenoldopam result from activation of D1 receptors located on various vascular beds (13, 14). On the other hand, compounds such as bromocriptine, a D2-like receptor agonist, cause vasodilation by activating prejunctional D2-like receptors located on postganglionic sympathetic nerve terminals and causing inhibition of norepinephrine release (13, 14). Therefore, the magnitude of vasodilation and subsequent hypotension seen with D2-like receptor agonists is dependent on existing sympathetic vasoconstrictor tone.

At higher doses dopamine also activates ß-adrenoceptors and {alpha}-adrenoceptors (15). Studies from our laboratory and others have shown that the natriuretic and diuretic response elicited by D1-like receptor agonists involves changes in intrarenal hemodymanics (increase in renal blood flow and glomerular filtration rates) as well as a direct tubular action (12, 16). At lower doses it is the direct action on renal tubules that accounts for the natriuresis and diuresis caused by selective D1-like receptor agonists (8, 13, 16, 17).

A positive correlation has been reported among sodium intake, renal dopamine production, and urinary sodium excretion both in experimental animals and humans (18, 19). Several studies have shown a role for dopamine in the regulation of sodium excretion during acute volume expansion as well as during acute increase in sodium intake (20–25). The increased sodium excretion seen in animals placed on high sodium intake is accompanied by an increase in urinary dopamine excretion (24) and a decrease in Na,K-ATPase activity in the proximal tubules (26). These effects of dopamine can be blocked by D1-like receptor antagonists (21, 22, 25, 26), suggesting a role for D1-like receptors in maintaining body sodium homeostasis during increases in sodium intake.


   Dopamine Receptor-Linked Cellular Signaling Pathways
Top
 Abstract
 Physiologic Role of Dopamine...
 Dopamine Receptor-Linked...
Dopamine and Dopamine Receptors...
 Concluding Remarks
 References
 
Dopamine Receptor-Mediated Regulation of Sodium Transporters.
Role of D1-like Receptors.
The Na,H-exchanger and the Na,K-ATPase provide a primary mechanism for the regulation of sodium ansport across the proximal tubules in the kidney (Fig. 2Go). These two sodium transporters have been identified as final effector proteins for the action of dopamine (27–31). Numerous studies in isolated tubular preparations have shown that dopamine produces inhibition in the activities of Na,H-exchanger and Na,K-ATPase, a mechanism by which dopamine reduces tubular sodium reabsorption and thereby increases sodium excretion. Both the D1-like and the D2-like receptors are coexpressed in proximal tubules and other parts of the nephron (2–6, 8). It is the activation of D1-like receptors that causes inhibition in Na,K-ATPase and Na,H-exchanger activity in proximal tubules and in other parts of the nephron such as medullary thick ascending limb (mTAL) and cortical collecting duct (CCD) (28–30). Similar results were reported in fibroblast LTK cells transfected with D1A receptor, where the D1-like agonist fenoldopam caused inhibition of the Na,K-ATPase activity (32). These results are consistent with the observation that the activation of D1-like receptors promotes sodium excretion (16, 17, 25). Other studies have shown that simultaneous activation of both dopamine receptors, D1-like and D2-like, is required to promote natriuresis and to inhibit Na,K-ATPase activity in proximal tubules (33).

Role of D2-like Receptors.
Unlike the D1-like receptor, the role of D2-like receptor in the kidney is not yet well defined. However, there are reports suggesting that the activation of D2-like receptors produces antidiuresis and antinatriuresis (34, 35). Consistent with this observation, the activation of D2-like receptors has been reported to cause stimulation of the Na,K-ATPase activity in rat renal proximal tubules as well as in LTK-murine cells transfected with the D2Long receptor cDNA (36, 37). Recently, we have found that D2-like receptors are linked to the stimulation of MAP kinase in rat renal proximal tubules and opossum kidney (OK) cells (37). Furthermore, we observed that the activation of MAP kinase by D2-like agonists might be a signaling mechanism responsible for the stimulation of Na,K-ATPase activity as well as mitogenesis, seen in the proximal tubule and OK cells (38). In a recent report, the activation of D2-like receptors in OK cells is shown to inhibit the Na,K-ATPase activity and to hyperpolarize the epithelial cells, actions associated with the opening of K+ channels (39). This observation adds to the complicity of the D2-like receptor signaling and function in the kidney.

Dopamine Receptors and G Proteins.
Dopamine receptors belong to the super-family of G-protein-coupled receptors. The D1-like receptors are coupled with Gs and Gq protein (40, 41). The D2-like receptors are linked to the pertussis toxin-sensitive proteins, likely with Gi in the proximal tubule (36, 37).

Dopamine Receptors and Adenylyl Cyclase/Protein Kinase A.
A correlation between dopamine infusion and urinary cAMP excretion has initially implicated a role for adenylyl cyclase as one of the second messengers involved in dopamine-mediated cellular effects (Figs. 2 and 3GoGo) (42). Later, dopamine was shown to inhibit the Na,H-exchanger via cAMP-dependent as well as cAMP-independent mechanisms in the brush border membrane vesicle preparations (28, 40, 43, 44). Dopamine-mediated increase in cAMP leads to activation of protein kinase A, which, in turn, causes phosphorylation of the Na,H-exchanger and subsequent inhibition of its activity (28, 45, 46). There are also reports implicating the role of the cAMP/PKA pathway in dopamine-mediated inhibition of the Na,K-ATPase activity in proximal tubules (32, 33) and in other parts of the nephron, such as mTAL and CCD (31). Dopamine-related phosphoprotein-32 (DARPP-32), which is present in large quantities in mTAL (47), has also been reported to play a role in dopamine-mediated inhibition of Na,K-ATPase activity in this segment of the nephron (48).



View larger version (21K):
[in this window]
[in a new window]
  		Figure 3. Hypothetical scheme of dopamine D2-like receptor signaling that causes stimulation of the MEK1/2–p44/42 MAPK pathway leading to the stimulation of the Na,K-ATPase activity and the mitogenic response in proximal tubules of the kidney.

 
The stimulation of D2-like receptors causes a decrease in cAMP via the Gi proteins. Studies from our laboratories have shown that a decrease in cAMP is the first biochemical signal that leads to a cascade of events ultimately resulting in the stimulation of Na,K-ATPase (36).

Dopamine D1-like Receptors and Phospholipase C/Protein Kinase C.
Numerous studies have provided evidence for the role of the phospholipase C (PLC) and protein kinase C (PKC) in dopamine-mediated inhibition of the Na,K-ATPase activity in the proximal tubule (Fig. 2Go) (49–54). Inhibitors of PLC and PKC have been shown to block the inhibitory effects of dopamine and D1-like agonists on the phosphorylation and activity of Na,K-ATPase (49, 53, 54). Further studies have suggested that the activation of the D1-like receptors stimulates PLC by regulating the expression and the activity of PLCß1 and PLC{gamma}1 isoforms in the kidney cortex (55). Dopamine and D1-like agonists also stimulate the PKC activity in proximal tubules (56, 57). Further studies suggest that it is the PKC{delta} and especially PKC{zeta} isoforms regulated by D1 receptors that may be involved in dopamine-mediated inhibition of Na,K-ATPase activity (53, 58). The stimulation of these isoforms of PKC might be causing phosphorylation and, as a result, inhibition of the Na,K-ATPase activity (57, 59). The role of phosphatidyl inositide 3-kinase (PI3-kinase) is also demonstrated by PKC-mediated inhibition of the Na,K-ATPase activity in proximal tubular cells (59). Stimulation of PI3-kinase via activation of D2 and D3 receptors has also been reported (60, 61). Additionally, stimulation of PI3-kinase has also been associated with the stimulation of Na,K-ATPase activity (62), and the inhibition of Na,K-ATPase activity is the cause of the increase in PI3-kinase (63).

Dopamine D1-like Receptors and Phospholipase A2.
The role of PLA2 has also been suggested in dopamine-mediated inhibition of Na,K-ATPase in the renal proximal tubule (64, 65). It is likely that D1-like receptor-mediated activation of PKC stimulates PLA2, which in turn releases arachidonic acid from membrane lipids. Arachidonic acid is further metabolized by cytochrome P450 to produce various metabolites, including 20-hydroxyeicosatetraenoic acid (20-HETE), which utilizes PKC to inhibit the Na,K-ATPase activity (66). In mTAL and CCD, the PLA2 pathway interacts with PKA to inhibit Na,K-ATPase activity (31). In regard to the role of these signaling pathways, a recent study reported sequential activation of PKC/PLA2 and PKA/PLA2 pathways in the inhibition of Na,K-ATPase by dopamine (67). Early inhibition of Na,K-ATPase activity by dopamine involves the activation of PKC/PLA2 pathways, whereas the late inhibition involves activation of PKA/PLA2 pathways (67).

Although dopamine receptor-mediated regulation of sodium-transporting proteins is present throughout the nephron length, dopamine receptors located at the proximal tubule and CCD (compared to other segments of the nephron) seem to play an important role in the natriuretic response to exogenously administered or endogenously produced dopamine (26, 68). It is likely that the proximal portion of the nephron is of greater importance because it is the site of major fluid and sodium reabsorption, and it is this site at which dopamine receptor-mediated signaling is selectively defective and unable to regulate Na,K-ATPase and Na,H-exchanger activity in various forms of hypertension in humans and animal models; this is discussed below.

Dopamine D2-like Receptors and Tyrosine Kinase.
Dopamine D2-like receptor activation causes stimulation of Na,K-ATPase activity (Fig. 3Go) (36, 37). Recent studies from our laboratory designed to investigate the cellular signaling mechanism for this response have revealed the involvement of a tyrosine kinase pathway. Inhibitors of tyrosine kinase as well as MAP kinase blocked the stimulatory effect of bromocriptine on Na,K-ATPase activity in renal proximal tubules. Also, bromocriptine increased phosphorylation of p44/42 MAPK in proximal tubules, suggesting that D2-like receptor activation causes stimulation of Na,K-ATPase via a tyrosine kinase-p44/42 MAPK pathway in renal proximal tubules (69). Whereas D2-like receptors activate the p44/42 MAPK pathway and promote mitogenesis, D1-like receptors activate the p38 MAPK pathway, which is involved in apoptosis (70).


   Dopamine and Dopamine Receptors in Hypertension
Top
 Abstract
 Physiologic Role of Dopamine...
 Dopamine Receptor-Linked...
 Dopamine and Dopamine Receptors...
Concluding Remarks
 References
 
Dopamine Deficiency in Human Hypertension.
Deficiency in renal dopamine synthesis and/or secretion has been reported in various forms of human hypertension. Urinary dopamine excretion is lower in salt-sensitive hypertensive patients than in normal subjects or non-salt-sensitive patients on high sodium intake (71). Suppressed dopaminergic activity has also been shown in the prehypertensive stage of primary hypertension (72, 73). Reduced dopaminergic activity has also been observed in young normotensive subjects with an apparent family history of hypertension before any evidence of hypertension emerged (73, 74). The exact mechanism for the renal dopaminergic deficiency in the human primary hypertension is not known. However, a defect in L-dopa-decarboxylase, the enzyme that catalyzes the conversion of L-dopa to dopamine, has been reported in a subject with a family history of hypertension (73–76). Other studies have shown a decrease in both the renal tubular uptake of L-dopa and the conversion of L-dopa to dopamine in a subgroup of salt-sensitive hypertensive patients (77). Because the suppression of renal dopaminergic activity has been observed in young normotensives with a family history of hypertension before any manifestation of the disease, it has been suggested that renal dopaminergic deficiency may contribute to the development of hypertension (78).

Defective Dopamine Receptors in Human Hypertension.
Recently, a defective D1-like dopamine receptor (more specifically D1A subtype) has been reported in primary cells cultured from hypertensive human proximal tubules (79). The D1-like receptor agonist stimulated adenylyl cyclase activity in normotensive cells but was unable to stimulate the enzyme activity in hypertensive proximal tubule cells. Further studies suggest that the defect was receptor specific because adenylyl cyclase stimulation by parathyroid hormone was found to be similar in the cells from both normotensive and hypertensive subjects (79). Furthermore, the D1-like receptor or adenylyl cyclase defect in human cells was suggested to be similar to the defects found in proximal tubules from animal models of genetic hypertension. The detailed molecular mechanism of the defect is discussed below. Interestingly, despite a defective D1A receptor in the proximal tubule, an exogenous dopamine infusion in essential hypertensive patients caused a natriuretic response (80). This suggested that the dopamine receptors located on the distal part of the nephron are up-regulated (81) and therefore offset the defective dopamine receptor function at the level of the proximal tubule. A recent study suggested that D1 receptor gene polymorphism is associated with essential hypertension (82). In a group of essential hypertensive and normotensive patients, polymerase chain reaction was used to amplify the A-48G polymeric site in the D1 receptor gene, and restriction analysis of the polymerase chain reaction product was used to score A and G alleles. This analysis showed that essential hypertensive patients possessing the G allele had a higher diastolic pressure than those lacking the G allele, suggesting that such a polyphosphism in the D1 receptor gene may account for the higher diastolic blood pressure of essential hypertensive patients (82).

In another study reported by Felder et al. (83), they measured G protein-coupled receptor kinase 4 gene variants (GRK4{gamma}A142V) in the renal proximal tubular cells obtained from essential hypertensive patients. They found that single-nucleotide polymorphism of GRK4{gamma}, resulting in increased GRK activity, caused serine phosphorylation and subsequent uncoupling of the D1 receptor from its G protein–effector enzyme complex in renal proximal tubule (83). Moreover, expressing GRK4{gamma}A142V produced hypertension and impaired diuretic and natriuretic effects of D1-like agonist stimulation. These results led the authors to suggest a novel mechanism for the D1-receptor-coupling defect in the kidney that may explain the inability of the kidney to properly excrete sodium in genetic hypertension (83).

Defective Dopamine Receptor in Hypertensive Animal Models.
There are several lines of evidence suggesting a defective dopaminergic system in the kidneys of Dahl salt-sensitive and spontaneously hypertensive rats (SHR). Similar to human hypertension, Dahl salt-sensitive rats produce less kidney dopamine and have a poor natriuretic and diuretic response in the event of sodium load (84–86). In addition to the dopamine production deficiency, defective D1-like receptor function has been reported in proximal tubules of Dahl salt-sensitive rats. The defect in D1-like receptors results in a loss of the ability of dopamine to regulate adenylyl cyclase activity (87, 88) and Na,K-ATPase activity in proximal tubules of salt-sensitive rats (89, 90). The SHR, as a model, has been extensively used to elucidate the mechanisms of the defective D1-like receptor function in proximal tubules. Dopamine production in SHR is normal or even increased (91, 92), but dopamine and D1-like receptor agonist-mediated natriuretic and diuretic responses are diminished compared to normotensive control Wistar Kyoto (WKY) rats (93, 94). In 1989, Kinoshita et al. (95) reported that despite equal numbers of D1-like receptors and intact G protein-adenylyl cyclase complexes, dopamine and D1-like agonists stimulated adenylyl cyclase activity in proximal tubules of SHR to a lesser extent than in normotensive WKY rats. This suggested that the defect resided in the coupling of the receptor with adenylyl cyclase and that the G proteins and adenylyl cyclase were not themselves defective. The defect was specific to D1-like receptor because parathyroid hormone stimulated adenylyl cyclase equally in SHR and WKY rats (95). Also, it has been reported that D1 receptors in the proximal tubule membrane from SHR were resistant to activation by the agonist, and this was most likely a result of the inability of the receptor to associate with Gs{alpha} (41, 96).

In another study, the coupling of D1 receptor to Gs{alpha} and to Na,H-exchanger (NHE3) was examined in brush border membranes obtained from SHR and WKY rats (97). It was found that the inhibitory effect of D1 receptor agonist on NHE activity in SHR was less than that seen in WKY rats and that GTP{gamma}S enhanced the inhibitory effect of a D1 receptor agonist on NHE activity in WKY but not in SHR, suggesting an uncoupling of D1 receptor from Gs{alpha}/NHE3 in SHR (97). It is also reported that the defect in D1-like receptor/adenylyl cyclase was organ (only in the kidney) and nephron segment (only in the proximal tubule) specific (98, 99). The major consequence of the decrease in the ability of dopamine to stimulate adenylyl cyclase in SHR is the subsequent failure to inhibit Na,H-exchanger in the hypertensive animals (100, 101). The decreased inhibitory effect of D1-receptor stimulation on Na,H-exchanger in SHR precedes the development of hypertension (101). These results led the authors to speculate that D1-like receptor genes or genes that regulate their function probably participate in raising the blood pressure in genetic hypertension (101). The stimulation of PLC and PKC by dopamine and D1-like agonist was also reduced in SHR, suggesting a defect in the coupling of D1-like receptor with Gq/11 proteins (102, 103). As a result of the defective coupling of D1-like receptor with G proteins and subsequent decreased stimulation of the associated second-messenger systems (adenylyl cyclase–PKA, PLC–PKC), dopamine and D1-like agonist failed to inhibit Na,H-exchanger and Na,K-ATPase activities in proximal tubules (49, 100, 101). The failure of dopamine and D1-like agonist to inhibit sodium transporters provides a mechanism responsible for the diminished natriuresis and diuresis in SHR in response to dopamine as well as the inability of SHR to excrete sodium in response to volume expansion (93, 94). The impaired D1-like receptor inhibition of Na,H-exchanger activity in the SHR preceded the establishment of hypertension (104).

Further studies in SHR revealed that they had lost high-affinity binding to the agonist (105, 106), and as a result, D1-like receptors were unable to interact with G proteins in response to the agonist (41, 96). Limited sequencing of the D1AmRNA (equivalent to the third cytoplasmic loop of cloned D1A receptor, which is believed to be the G protein-interacting domain) revealed no mutation in the protein in SHR (99). However, there are a number of studies that provide a sequence of events suggesting a molecular basis for the defect in the D1A receptor (a D1-like receptor). The titration of the sulfhydryl groups present on D1A receptors revealed that sulfhydryl groups may be buried inside the receptor protein (107), which may be the result of posttranslational modifications or conformational changes in the receptor protein. In a recent study, Felder et al. (83) reported a greater agonist-independent phosphorylation of D1A receptor caused by the higher constitutive activity of GRK4. Furthermore, the greater phosphorylation of D1A receptor may also be contributed to by the decreased ability of the D1A receptor agonist (fenoldopam) to increase the dephosphorylating enzyme, protein phosphatase 2A, activity in the proximal tubule membrane of SHR (108).

Hypertension in Dopamine Receptor Knockout Animals.
Compelling evidence showing a relationship between defective D1A receptors or signaling system and hypertension comes from two sets of experiments: one on cross-breeds of normotensive and hypertensive rats and the second on mice lacking functional D1A receptors (109). In the F2 generation from female WKY rats and male SHR crosses, the defective D1-like receptor function (inability of dopamine to inhibit Na,H-exchanger) in the proximal tubules cosegregated with the increased systolic blood pressure (>160 mmHg) and decreased ability to excrete sodium in response to a D1-like agonist infused into the renal arteries of the rats. The activation of D1-like receptors inhibited the Na,H-exchanger in rats of the same F2 generation with systolic blood pressure <140 mmHg (109).

In another set of experiments, mutant mice were generated that were lacking functional D1A receptors. Compared to the control mice, both homozygous and heterozygous mice had greater systolic, diastolic, and mean arterial pressure. Renal tubules from homozygous mice had no binding sites for [125I]SCH23982, a D1-like ligand, and showed no stimulation of cAMP by dopamine (109). This provides a reasonable correlation between defective D1A receptor/signal transduction and the development of hypertension in mice. In addition to the observation made with D1A receptors, the disruption of D3 receptors has also recently been shown to cause renin-dependent hypertension (110). However, the mechanism of hypertension caused by disruption of D3 receptors is different from that caused by D1A receptors. The renal renin activity was much greater in mice lacking D3 receptors (both homozygous and heterozygous) than in a wild-type control group. A single bolus dose of losartan, an angiotensin II AT1 receptor antagonist, causes a decrease in systolic blood pressure in the homozygous mice to a greater extent and for a longer time than in the wild-type mice. During acute volume expansion, blood pressure was unchanged, GFRs were similar, and urine flow increased to a similar extent in the wild-type and the mutant mice (both homozygous and heterozygous). However, the increase in sodium excretion was attenuated in homozygous mice compared to the control (110). There is evidence that shows that a physiologic and biochemical interaction exists between dopamine and angiotensin II receptors in the kidney (111–113). Intrarenally produced angiotensin has been shown to counteract fenoldopam-induced sodium excretion (111).

Also, it has been shown that both D1-like and D2-like receptor agonists cause a decrease in AT1 receptor binding sites in proximal tubular preparations (112–114). Although the AT1 receptor binding sites have not been measured in the D3 mutant mice, it is possible that the absence of D3 receptors might have caused an increase in AT1 receptors in the proximal tubules along with the higher renin production. Recently, effects of D2 receptor disruption has also been reported (115). The disruption of D2 receptors caused higher systolic and diastolic blood pressure in mutant mice. Further study revealed that hypertension in D2 receptor mutant mice resulted from an increase in {alpha}-adrenergic and endothelin B (ETB) receptor activities, which produces vasoconstriction (115).


   Concluding Remarks
Top
 Abstract
 Physiologic Role of Dopamine...
 Dopamine Receptor-Linked...
 Dopamine and Dopamine Receptors...
 Concluding Remarks
References
 
There is clear evidence that dopamine is an important modulator of cardiovascular and renal function. A deficiency in dopamine production and/or a dysfunction in dopamine receptor contributes to various forms of hypertension in both humans and animal models. Recently, a study (83) revealed the molecular nature and the cause of the defect in D1 receptor protein in proximal tubular cells of animals and hypertensive patients. This study further demonstrated that the defect in D1 receptors might be corrected, in the proximal tubule cells obtained from hypertensive patients, by removing the cause of defect, namely, in vitro treatment of the cells with antisense GRK4 oligonucleotides (83). However, it is yet to be determined whether correction of the dopamine receptor, especially D1 receptor, function would lead to a reduction in blood pressure in humans and experimental models of hypertension.


   Footnotes
 
1 To whom requests for reprints should be addressed at College of Pharmacy, University of Houston, Houston TX 77204. E-mail: Mlokhandwala{at}uh.edu Back


   References
Top
 Abstract
 Physiologic Role of Dopamine...
 Dopamine Receptor-Linked...
 Dopamine and Dopamine Receptors...
 Concluding Remarks
 References
 

  1. Sibley DR, Monsma FJ Jr. Molecular biology of dopamine receptors. Trends Pharmacol Sci 13:61–69, 1992.[Medline]
  2. Yamaguchi I, Jose PA, Mouradian MM, Canessa LM, Monsma FJ Jr, Sibley DR, Takeyasu K, Felder RA. Expression of dopamine D1A receptor gene in proximal convoluted tubule of rat kidneys. Am J Physiol 264:F280–F285, 1993.[Abstract/Free Full Text]
  3. Nash SR, Godinot N, Caron MG. Cloning and characterization of the opossum kidney cell D1 dopamine receptor: expression of D1A and D1B receptor mRNAs in opossum kidney and brain. Mol Pharmacol 44:918–925, 1993.[Abstract]
  4. Felder CC, McKelvey AM, Gitler MS, Eisner GM, Jose PA. Dopamine receptor subtypes in renal brush border and basolateral membrane. Kidney Int 36:183–193, 1989.[Medline]
  5. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature Lond 347:146–151, 1990.[Medline]
  6. Felder RA, Blecher M, Eisner GM, Jose PA. Cortical tubular and glomerular dopamine receptors in the rat kidney. Am J Physiol 246:F557–F568, 1984.
  7. Missale C, Pizzi M, Memo M, Picotti GB, Carruba MO. Postsynaptic D1 and D2 dopamine receptors are present in rabbit renal and mesenteric arteries. Neurosci Lett 61:207–211, 1985.[Medline]
  8. Lokhandwala MF, Amenta F. Anatomical distribution and function of dopamine receptors in the kidney. FASEB J 5:3023–3030, 1991.[Abstract]
  9. Goldstein M, Fuxe K, Hokfelt T. Characterization and tissue localization of catecholamine synthesizing enzymes. Pharmacol Rev 24:293–308, 1972.[Abstract]
  10. Baines AD, Chan W. Production of urine free dopamine from DOPA: a micropuncture study. Life Sci 26:253–259, 1980.[Medline]
  11. Zimlichman R, Levinson PP, Kelly G, Stull R, Keiser HR, Goldstein DS. Derivation of urinary dopamine from plasma dopa. Clin Sci 75:515–520, 1988.[Medline]
  12. McDonald RH, Goldberg LI, McNay JL, Tuttle EP. Effect of dopamine in man: augmentation of sodium excretion, glomerular filtration rate and renal plasma flow. J Clin Invest 43:1116–1124, 1964.
  13. Jose PA, Raymond JR, Bates MD, Aperia A, Felder RA, Carey RM. The renal dopamine receptors. J Am Soc Nephrol 2:1265–1278, 1992.[Abstract]
  14. Lokhandwala MF, Chen CJ. Peripheral dopamine receptors. In: Niznik HB, Ed. Dopamine Receptors and Transporters. New York: Marcel Dekker, pp89–102, 1994.
  15. vanVeldhuisen DK, Gribes ARJ, deGraeff PA, Lie KI. Effects of dopaminergic agents on cardiac and renal function in normal man and in patients with congestive heart failure. Int J Cardiol 37:293–300, 1992.[Medline]
  16. Hegde SS, Ricci A, Amenta F, Lokhandwala MF. Evidence from functional and autoradiographic studies for the presence of tubular dopamine-1 receptor and their involvement in the renal effects of fenoldopam. J Pharmacol Exp Ther 251:1237–1245, 1989.[Abstract/Free Full Text]
  17. Beheray S, Kansra V, Hussain T, Lokhandwala MF. Diminished natriuretic response to dopamine in old rats is due to an impaired D1-like receptor-signaling pathway. Kidney Intl 58:712–720, 2000.[Medline]
  18. Ball SG, Oates HS, Lee MR. Urinary dopamine in man and rat: Effect of inorganic salts on dopamine excretion. Clin Sci Mol Med 55:167–173, 1978.[Medline]
  19. Romero-Vecchione E, Vasquez J, Lema G, Guerrero H, Rosa F, Bermudez M. Low urinary dopamine excretion associated to low sodium excretion in normotensive Piaroa Amazonian ethnia compared to urban subjects. Invest Clin 36:61–71, 1995.[Medline]
  20. Chen CJ, Lokhandwala MF. Role of renal dopamine in the natriuretic response to different degrees of volume expansion in rats. Clin Exp Hypertens 13:1117–1126, 1991.
  21. Hegde SS, Jadhav AL, Lokhandwala MF. Role of kidney dopamine in the natriuretic response to volume expansion in rats. Hypertension 13:828–834, 1989.[Abstract/Free Full Text]
  22. Akpaffiong MJ, Redfern PM, Woodward B. Factors affecting the release and excretion of dopamine in the rats. J Pharm Pharmacol 32:839–843, 1980.[Medline]
  23. Oates NS, Ball SG, Perkins CM, Lee MR. Plasma and urine dopamine in man given sodium chloride in the diet. Clin Sci 56:261–264, 1979.[Medline]
  24. Vyas SJ, Jadhav AL, Eichberg J, Lokhandwala MF. Dopamine receptor-mediated activation of phospholipase C is associated with natriuresis during high salt intake. Am J Physiol 262:F494–F498, 1992.[Abstract/Free Full Text]
  25. Pelayo JC, Fildes RD, Eisner GM, Jose PA. Effects of dopamine blockade on renal sodium excretion. Am J Physiol 245:F247–F253, 1983.
  26. Bertorello A, Hokfelt T, Goldstein M, Aperia A. Proximal tubule Na,K-ATPase activity is inhibited during high salt diet: evidence for DA-mediated effect. Am J Physiol 254:F795–F801, 1988.[Abstract/Free Full Text]
  27. Gesek FA, Schoolwerth AC. Hormonal interaction with the proximal Na,H-exchanger. Am J Physiol 258:F514–F521, 1990.[Abstract/Free Full Text]
  28. 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 259:F297–F303, 1990.[Abstract/Free Full Text]
  29. Chen CJ, Lokhandwala MF. Inhibition of Na,K-ATPase in renal proximal tubule by dopamine involves DA-1 receptor activation. Naunyn-Schmiedebergs Arch Pharmacol 347:289–295, 1993.[Medline]
  30. Satoh T, Cohen HT, Katz AI. Different mechanisms of renal Na,K-ATPase regulation by protein kinases in the proximal and distal nephron. Am J Physiol 265:F399–F405, 1993.[Abstract/Free Full Text]
  31. Bertorello A, Katz AI. Short-term regulation of renal Na,K-ATPase activity: physiological relevance and cellular mechanisms. Am J Physiol 265:F743–F755, 1993.[Abstract/Free Full Text]
  32. 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]
  33. Bertorello A, Aperia A. Inhibition of proximal tubule Na,K-ATPase activity requires simultaneous activation of DA1 and DA2 receptors. Am J Physiol 259:F924–F928, 1990.[Abstract/Free Full Text]
  34. Siragy HM, Felder RA, Howell NL, Chevalier RL, Peach MJ, Carey RM. Evidence that dopamine-2 mechanisms control renal function. Am J Physiol 259:F793–F800, 1990.[Abstract/Free Full Text]
  35. Siragy HM, Felder RA, Peach MJ, Carey RM. Intrarenal DA2 dopamine receptor stimulation in the conscious dog. Am J Physiol 262:F932–F938, 1992.[Abstract/Free Full Text]
  36. Hussain T, Abdul-Wahab R, Lokhandwala MF. Bromocriptine stimulates Na,K ATPase in renal proximal tubules via cAMP pathway. Eur J Pharmacol 321:259–263, 1997.[Medline]
  37. Yamaguchi I, Walk SF, Jose PA, Felder RA. Dopamine D2L receptors stimulate Na,K-ATPase activity in murine LTK-cells. Mol Pharmacol 46:373–378, 1996.
  38. Narkar V, Hussain T, Pedemonte C, Lokhandwala MF. Evidence for expression of dopamine D2 and D4 receptors in opossum kidney cells and the role of D2 receptors in mitogenesis. J Am Soc Nephrol 11:A2342, 2000.
  39. 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 283:F114–F123, 2002.[Abstract/Free Full Text]
  40. Albrecht FE, Xu J, Moe OW, Hopfer U, Sigmonds WF, Orlowski J, Jose PA. Regulation of NHE by G protein subunits in renal brush border membranes. Am J Physiol 278:R1064–R1073, 2000.[Abstract/Free Full Text]
  41. Hussain T, Lokhandwala MF. Renal dopamine-1 receptor coupling with Gs and Gq/11 proteins in spontaneously hypertensive rats. Am J Physiol 272:F339–F346, 1997.[Abstract/Free Full Text]
  42. Vlanchoyannis J, Weismuller G, Schoeppe W. Effects of dopamine on kidney function and on the adenylyl cyclase phosphodiesterase system in man. Eur J Clin Invest 6:131–137, 1976.[Medline]
  43. Felder CC, Albrecht F, Eisner GM, Jose PA. The signal transducers for the dopamine-1 regulated sodium transport in renal cortical brush border membrane vesicles. Am J Hypertens 3:47S–50S, 1990.[Medline]
  44. Felder CC, Albrecht FE, Campbell T, Eisner GM, Jose PA. cAMP-independent, G protein-linked inhibition of Na/H-exchange in renal brush border by D1 dopamine agonist. Am J Physiol 264:F1032– F1037, 1993.[Abstract/Free Full Text]
  45. Beheray S, Hussain T, Lokhandwala MF. Dopamine inhibits Na,H-exchanger via D1-like receptor-mediated stimulation of protein kinase A in renal proximal tubules. Clin Exp Hypertens 22:635–644, 2000.
  46. 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]
  47. Aperia A, Hokfelt T, Meister B, Bertorello A, Fryckstedt J, Holtback U, Seri I. The significance of L-amino acid and DARRP-32 in the kidney. Am J Hypertens 3:11S–13S, 1990.[Medline]
  48. Aperia A, Fryckstedt J, Svensson L, Hemmings HC Jr, Nairn AC, Greengard P. Phosphorylated Mr 32,000 dopamine- and cAMP-regulated phosphoprotein inhibits Na,K-ATPase activity in renal tubule cells. Proc Natl Acad Sci USA 88:2798–2801, 1991.[Abstract/Free Full Text]
  49. Chen CJ, Beach RE, Lokhandwala MF. Dopamine fails to inhibit renal tubular sodium pump in hypertensive rats. Hypertension 21:364–372, 1993.[Abstract/Free Full Text]
  50. Felder CC, Jose PA, Axelrod J. The dopamine-1 agonist, SKF 82526, stimulates phospholipase C activity independent of adenylate cyclase. J Pharmacol Exp Ther 248:171–175, 1989.[Abstract/Free Full Text]
  51. Felder CC, Blecher M, Jose PA. Dopamine-1 mediated stimulation of phospholipase C activity in rat renal cortical membranes. J Biol Chem 264:8739–8745, 1989.[Abstract/Free Full Text]
  52. Vyas SJ, Eichberg J, Lokhandwala MF. Characterization of receptors involved in dopamine induced activation of phospholipase C in rat renal cortex. J Pharmacol Exp Ther 260:134–139, 1992.[Abstract/Free Full Text]
  53. Efendiev R, Bertorello AM, Pedemonte CH. PKC-ß and PKC-{zeta} mediate opposing effects on proximal tubule Na,K-ATPase activity. FEBS Lett 456:45–48, 1999.[Medline]
  54. Asghar M, Hussain T, Lokhandwala MF. Activation of dopamine D1-like receptor causes phosphorylation of a1-subunit of Na,K-ATPase in renal proximal tubules. Eur J Pharmacol 411:61–66, 2000.
  55. Yu PY, Asico LD, Eisner GM, Jose PA. Differential regulation of renal phospholipase C by catecholamines. J Clin Invest 95:304–308, 1995.
  56. Kansra V, Chen CJ, Lokhandwala MF. Dopamine causes stimulation of protein kinase C in rat renal proximal tubules by activating dopamine D1 receptors. Eur J Pharmacol 289:391–394, 1995.[Medline]
  57. Asghar M, Kansra V, Hussain T, Lokhandwala MF. Hyperphosphorylation of Na-pump contributes to defective dopamine receptors in old rats. J Am Soc Nephrol 12:226–232, 2000.[Abstract/Free Full Text]
  58. 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]
  59. Chibalin AV, Ogimoto G, Pedemonte CH, Pressley TA, Katz AI, Feraille E, Berggren PO, Bertorello AM. Dopamine-induced endocytosis of Na,K-ATPase in initiated by phosphorylation of ser-18 in the rat a-subunit and is responsible for decreased activity in epithelial cells. J Biol Chem 274:1920–1927, 1999.[Abstract/Free Full Text]
  60. Welsh GI, Hall DA, Warnes A, Strange PG, Proud CG. Activation of microtubule-associated protein kinase (Erk) and p70 S6 kinase by D2 dopamine receptors. J Neurochem 70:2139–2146, 1998.[Medline]
  61. Cussac D, Newman-Tancredi A, Pasteau V, Millan MJ. Human dopamine D3 receptors mediate mitogen-activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase c-dependent mechanism. Mol Pharmacol 56:1025–1030, 1999.[Abstract/Free Full Text]
  62. Sweeney S, Niu W, Canfield VA, Levenson R, Klip A. Insulin increases plasma membrane content and reduces phosphorylation of Na+-K+ pump {alpha}1-subunit in HEK-293 cells. Am J Physiol 281:C1797–C1803, 2001.[Abstract/Free Full Text]
  63. Zhou X, Jiang G, Zhao A, Bondeva T, Hirszel P, Balla T. Inhibition of Na,K-ATPase activates PI3 kinase and inhibits apoptosis in LLC-PK1 cells. Biochem Biophys Res Commun 285:46–51, 2001.[Medline]
  64. Satoh T, Cohen HT, Katz AI. Different mechanisms of renal Na,K-ATPase regulation by protein kinases in the proximal and distal nephron. Am J Physiol 265:F399–F405, 1993.
  65. 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.
  66. Nowicki S, Cheng XJ, Ohtomo Y, Aperia A. Regulation of renal Na,K-ATPase (NKA) activity by 20-hydroxyeicosatetraenoic acid (20-HETE) is mediated by protein kinase C. J Clin Invest 99:1224–1230, 1997.[Medline]
  67. Khundmiri SJ, Lederer E. PTH and DA regulate Na-K ATPase through divergent pathways. Am J Physiol 282:F512–F552, 2002.[Abstract/Free Full Text]
  68. Seri I, Kone BC, Gullans SR, Aperia A, Brenner BM, Ballermann BJ. Influence of Na intake on dopamine-induced inhibition of renal cortical Na,K-ATPase. Am J Physiol 258:F52–F60, 1990.[Abstract/Free Full Text]
  69. Narkar VA, Hussain T, Lokhandwala MF. Role of tyrosine kinase and P44/42 MAPK in D2-like receptor-mediated stimulation of Na,K-ATPase. Am J Physiol 282:F697–F702, 2002.[Abstract/Free Full Text]
  70. Zhen X, Uryu K, Wang HY, Friedman E. D1 dopamine receptor agonists mediate activation of p38 mitogen-activated protein kinase and c-Jun amino-terminal kinase by a protein kinase A-dependent mechanism in SK-N-MC human neuroblastoma cells. Mol Pharmacol 54:453–458, 1998.[Abstract/Free Full Text]
  71. Shikuma R, Yoshimura M, Kambra S, Yamazaki H, Takashina R, Takahashi H, Takeda K, Ijichi H. Dopaminergic modulation of salt-sensitivity in patients with essential hypertension. Life Sci 38:915–921, 1986.[Medline]
  72. Iimura O, Shimamoto K. Suppressed dopaminergic activity and water-sodium handling in kidneys at the prehypertensive stage of essential hypertension. J Auton Pharmacol 10(Suppl 1): 73S–77S, 1990.
  73. Iimura O, Shimamoto K, Ura N. Dopaminergic activity and water-sodium handling in the kidneys of essential hypertensive subjects: Is renal dopaminergic activity suppressed at the prehypertensive stage? J Cardiovasc Pharmacol 16:56S–58S, 1990.
  74. Iimura O. The role of renal dopaminergic activity in the pathophysiology of essential hypertension. Jap Heart J 37:815–828, 1996.
  75. Kuchel O, Shigetomi S. Defective dopamine generation from dihydroxyphenyl-alanine in stable essential hypertensive patients. Hypertension 19:634–638, 1992.[Abstract/Free Full Text]
  76. Clark BA, Rosa RM, Epstein FH, Young JB, Landsberg L. Altered dopaminergic responses in hypertension. Hypertension 19:589–594, 1992.[Abstract/Free Full Text]
  77. Gill JR, Grossman E, Goldstein DS. High urinary dopa and low urinary dopamine to dopa ratio in salt-sensitive hypertension. Hypertension 18:614–621, 1991.[Abstract/Free Full Text]
  78. Shimamoto K, Ura N, Nishimura M, Iimura O. Renal kallikrein-kinin, prostaglandin E2 and dopamine systems in young normotensive subjects with a family history of essential hypertension. Am J Med Sci 307:S70–S74, 1994.
  79. Sanada H, Jose PA, Hazen-Martin D, Yu PY, Bruns D, Phipps J, Carey RM, Felder R. Dopamine-1 receptor coupling defect in renal proximal tubule cells in hypertension. Hypertension 33:1036–1042, 1999.[Abstract/Free Full Text]
  80. Andrejak M, Hary L. Enhanced dopamine renal responsiveness in patients with hypertension. Clin Pharmacol Ther 40:610–614, 1986.[Medline]
  81. O'Connell DP, Ragsdale NV, Boyd DG, Felder RA, Carey RM. Differential human tubular responses to dopamine type 1 receptor stimulation are determined by blood pressure status. Hypertension 29:115–122, 1997.[Abstract/Free Full Text]
  82. 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]
  83. Felder RA, Sanada H, Xu J, Yu PY, Wang Z, Watanabe H, Asico LD, Wang W, Zheng S, Yamaguchi I, Williams S, Gainer J, Brown NJ, Hazen-Martin D, Wong LJC, Rollibard JE, Carey RM, Eisner GM, Jose PA. G protein-coupled receptor kinase 4 gene variants in human essential hypertension. Proc Natl Acad Sci USA 99:3872–3877, 2002.[Abstract/Free Full Text]
  84. DeFeo ML, Jadhav AL, Lokhandwala MF. Dietary sodium intake and urinary dopamine and sodium excretion during the course of blood pressure development in Dahl salt-sensitive and salt-resistant rats. Clin Exp Hypertens 12:2049–2060, 1987.
  85. Racz K, Kuchel O, Buu NY. Abnormal adrenal catecholamine synthesis in salt-sensitive Dahl rats. Hypertension 9:76–80, 1987.[Abstract/Free Full Text]
  86. Sakamoto T, Chen C, Lokhandwala MF. Lack of renal dopamine production during acute volume expansion in Dahl salt-sensitive rats. Clin Exp Hypertens 16:197–206, 1994.
  87. Felder RA, Kinoshita S, Sidhu A, Ohbu K, Kaskel FJ. A renal dopamine-1 receptor defect in two genetic models of hypertension. Am J Hypertens 3:96S–99S, 1990.[Medline]
  88. Ohbu K, Kaskel FJ, Kinoshita S, Felder RA. Dopamine-1 receptors in the proximal convoluted tubule of Dahl rats: defective coupling to adenylate cyclase. Am J Physiol 268:R231–R235, 1995.[Abstract/Free Full Text]
  89. Nishi A, Bertorello AM, Aperia A. High salt diet down-regulates proximal tubule Na,K-ATPase activity in Dahl salt-resistant but not in Dahl salt-sensitive rats: evidence of defective dopamine regulation. Acta Physiol Scand 144:263–267, 1992.[Medline]
  90. Nishi A, Eklof AC. BertorelloA, 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]
  91. Stier CT Jr, Itskovitz HD, Chen YH. Urinary dopamine and sodium excretion in spontaneously hypertensive rats. Clin Exp Hypertens 15:105–123, 1993.
  92. Kambra S, Yoshimura M, Takahashi H, Ijichi H. Enhanced synthesis of renal dopamine and impaired natriuresis in spontaneously hypertensive rats. Jap Heart J. 28:594, 1987.
  93. 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]
  94. Chen CJ, Lokhandwala MF. An impairment of tubular DA-1 receptor function as a causative factor for diminished natriuresis to volume expansion in spontaneously hypertensive rats. Clin Exp Hypertens 14:615–628, 1992.
  95. 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.
  96. Uh M, White BH, Sidhu A. Alteration of association of agonist-activated renal D1(A) dopamine receptors with G proteins in proximal tubules of the spontaneously hypertensive rat. J Hypertens 16:1307–1313, 1998.[Medline]
  97. Xu J, Li XX, Albrecht FE, Hopfer U, Carey RM, Jose PA. Dopamine1 receptor, Gsalpha, and Na+-H+ exchanger interactions in the kidney in hypertension. Hypertension 36:395–399, 2000.[Abstract/Free Full Text]
  98. Ohbu K, Felder RA. Nephron specificity of dopamine receptor-adenylyl cyclase defect in spontaneous hypertension. Am J Physiol 264:F274–F279, 1993.[Abstract/Free Full Text]
  99. Felder RA, Kinoshita S, Ohbu K, Mouradian MM, Sibley DR, Monsma FJ Jr, Minowa T, Minowa MT, Canessa LM, Jose PA. Organ specificity of the dopamine receptor/adenylyl cyclase coupling defect in spontaneously hypertensive rats. Am J Physiol 264:R726– R732, 1993.[Abstract/Free Full Text]
  100. Gesek FA, Schoolwerth AC. Hormone response to proximal Na+,H+-exchanger in spontaneously hypertensive rats. Am J Physiol 261:F526–F536, 1991.[Abstract/Free Full Text]
  101. Li XX, Xu J, Zheng S, Albrecht FE, Robillard JE, Eisner GM, Jose PA. D1 dopamine receptor regulation of NHE3 during development in spontaneously hypertensive rats. Am J Physiol 280:R1650–R1656, 2001.
  102. Chen CC, Vyas SJ, Eichberg J, Lokhandwala MF. Diminished phospholipase-C activation by dopamine in spontaneously hypertensive rats. Hypertension 19:102–108, 1992.[Abstract/Free Full Text]
  103. Kansra V, Chen CJ, Lokhandwala MF. Dopamine fails to stimulate protein kinase C activity in renal proximal tubules of hypertensive rats. Clin Exp Hypertens 17:837–845, 1995.
  104. Horiuchi A, Albrecht FE, Eisner GM, Jose PA, Felder RA. Renal dopamine receptors and pre- and post-cAMP-mediated Na+ transport defect in spontaneously hypertensive rats. Am J Physiol 263:F1105– F1111, 1992.[Abstract/Free Full Text]
  105. Sidhu A, Vachvamichsanong P, Jose PA, Felder RA. Persistent defective coupling of dopamine-1 receptors to G proteins after solubilization from kidney proximal tubules of hypertensive rats. J Clin Invest 89:789–793, 1992.
  106. Vachvanichsannong P, Kimura K, Sidhu A. Differences in photolabeling of DA1 receptors in renal proximal tubules from normotensive rat and SHR. Am J Physiol 268:F1009–F1016, 1995.[Abstract/Free Full Text]
  107. Sela S, Sidhu A. Sulfhydryl groups of renal D1A dopamine receptors: differential sensitivity of receptors to N-ethylmaleimide in normotensive and hypertensive rats. J Hypertens 14:615–622, 1996.[Medline]
  108. Yu P, Asico LD, Eisner GM, Hopfer U, Felder RA, Jose PA. Renal protein phosphatase 2A activity and spontaneous hypertension in rats. Hypertension 36:1053–1058, 2000.[Abstract/Free Full Text]
  109. 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.[Medline]
  110. Asico LD, Fuchs S, Accili D, Carey RM, Eisner GM, Jose PA. Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension. J Am Soc Nephrol. 8:295A, 1997.
  111. Chen CJ, Apparsundarum S, Lokhandwala MF. Intrarenally produced angiotensin II opposes the natriuretic effect of the dopamine-1 receptor agonist fenoldopam in rats. J Pharmacol Exp Ther 256:486–491, 1991.[Abstract/Free Full Text]
  112. Cheng HF, Becker BN, Harris RC. Dopamine decreases expression of type-1 angiotensin II receptors in renal proximal tubules. J Clin Invest 97:2745–2752, 1996.[Medline]
  113. Sheikh-Hamad D, Wang YP, Jo OD, Yanagawa Y. Dopamine antagonizes the actions of angiotensin II in renal brush border membrane. Am J Physiol 264:F737–F743, 1993.[Abstract/Free Full Text]
  114. Hussain T, Abdul-Wahab R, Lokhandwala MF. Bromocriptine regulates angiotensin II response sodium pump in proximal tubules. Hypertension 32:1054–1059, 1998.[Abstract/Free Full Text]
  115. Li XX, Bek MJ, Asico LD, Low M, Rubinstein M, Grandy DK, Goldstein DS, Eisner GM, Jose PA. Disruption of D2 dopamine receptor gene produces {alpha}-adrenergic and endothelin B (ETB) receptor-dependent hypertension. J Am Soc Nephrol 11:A1763, 2000.



This article has been cited by other articles:


Home page
 Am. J. Physiol. Cell Physiol.Home page
M. Asghar, A. Chillar, and M. F. Lokhandwala
Renal proximal tubules from old Fischer 344 rats grow into epithelial cells in cultures and exhibit increased oxidative stress and reduced D1 receptor function
Am J Physiol Cell Physiol, November 1, 2008; 295(5): C1326 - C1331.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
S. J. Khundmiri, M. Ameen, N. A. Delamere, and E. D. Lederer
PTH-mediated regulation of Na+-K+-ATPase requires Src kinase-dependent ERK phosphorylation
Am J Physiol Renal Physiol, August 1, 2008; 295(2): F426 - F437.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
Z. Li, C. Yu, Y. Han, H. Ren, W. Shi, C. Fu, D. He, L. Huang, C. Yang, X. Wang, et al.
Inhibitory effect of D1-like and D3 dopamine receptors on norepinephrine-induced proliferation in vascular smooth muscle cells
Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2761 - H2768.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
C. Zeng, V. A. M. Villar, G. M. Eisner, S. M. Williams, R. A. Felder, and P. A. Jose
G Protein-Coupled Receptor Kinase 4: Role in Blood Pressure Regulation
Hypertension, June 1, 2008; 51(6): 1449 - 1455.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
C. Zeng, I. Armando, Y. Luo, G. M. Eisner, R. A. Felder, and P. A. Jose
Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice
Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H551 - H569.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
W. Han, H. Li, V. A. M. Villar, A. M. Pascua, M. I. Dajani, X. Wang, A. Natarajan, M. T. Quinn, R. A. Felder, P. A. Jose, et al.
Lipid Rafts Keep NADPH Oxidase in the Inactive State in Human Renal Proximal Tubule Cells
Hypertension, February 1, 2008; 51(2): 481 - 487.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
A. A. Banday, F. R. Fazili, and M. F. Lokhandwala
Insulin causes renal dopamine D1 receptor desensitization via GRK2-mediated receptor phosphorylation involving phosphatidylinositol 3-kinase and protein kinase C
Am J Physiol Renal Physiol, September 1, 2007; 293(3): F877 - F884.
[Abstract] [Full Text] [PDF]