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Hypertension. Author manuscript; available in PMC Jan 1, 2012.
Published in final edited form as:
PMCID: PMC3021462

Dopamine Receptors: Important Antihypertensive Counterbalance Against Hypertensive Factors


Essential hypertension, which affects 25% of the middle-aged adult population, constitutes a major risk factor for stroke, myocardial infarction, and heart and kidney failure1. The kidney, vasculature, and nervous system govern the long-term control of blood pressure by regulating sodium homeostasis and peripheral resistance; they, in turn, are influenced by numerous hormones and neural and humoral factors. These hormones and neural and humoral factors can be divided into two groups based on their effects on sodium excretion and vascular smooth muscle contractility. One group leads to natriuresis and vasodilation while the other causes sodium retention and vasoconstriction. The balance between those two groups keeps the blood pressure within the normal range. Hypertension may be caused not only by increased activity of pro-hypertensive systems (e.g., renin-angiotensin and sympathetic nervous systems) but also by defects in anti-hypertensive systems that serve as counter-regulatory mechanisms. Aberrations in these counter-regulatory pathways, which include the dopaminergic pathway, may be involved in the pathogenesis of essential hypertension.

Dopamine has been shown to be an important regulator of renal and hormonal function and, ultimately, blood pressure, through an independent non-neural dopaminergic system2. There is a difference in the synthesis and metabolism of dopamine in neural and non-neural cells (see below). For example, dopamine synthesized in renal proximal tubule (RPT) cells is not converted into norepinephrine and epinephrine; it is transported across the basolateral and apical membranes and into the peritubular space and tubular lumen, respectively, where it acts on its receptors, locally, and in more distal nephron segments. Dopamine by occupation of its specific receptors, as well via direct or indirect interaction with other G protein-coupled receptors (GPCRs) (e.g., adenosine, angiotensin, endothelin, insulin, oxytocin, and vasopressin) and interaction with other hormones/humoral agents (e.g., aldosterone, angiotensins, atrial natriuretic peptide, eicosanoids, insulin, nitric oxide, prolactin, and urodilatin) regulates water and sodium chloride excretion3,4. During normal or moderately increased NaCl intake, inhibition of D1-like receptors decreases sodium chloride excretion by about 60%. In hypertensive states, the dopamine-mediated inhibition of sodium transport is often impaired. Although dopamine production is diminished in a few specific hypertensive states, this is not usually the case. Indeed, renal dopamine production is increased in young hypertensive patients. This review updates the role of dopamine and its receptors in the control of normal blood pressure and in the pathogenesis of hypertension. We will provide evidence that dopamine and its receptors act as important antihypertensive counterbalance against the prohypertensive effects of the α-adrenergic and renin-angiotensin systems.

I. Dopamine and its Receptors in Hypertension

1. Dopamine synthesis and blood pressure regulation

Dopamine, produced locally and independently of innervation, is important in the control of systemic blood pressure. This blood pressure regulation is achieved by actions on systemic arterial and venous vessels and renal hemodynamics, and water and electrolyte balance, via direct and indirect effects on renal and gastrointestinal epithelial ion transport2. The affinity of dopamine for its receptors is in the nanomolar to low micromolar range. Normal circulating concentrations of dopamine (picomolar range) are not sufficiently high to activate dopamine receptors but concentrations in the high nanomolar to low micromolar range can be attained in dopamine-producing tissues (both neural and non-neural tissues, such as the RPT and jejunum).

The synthesis of dopamine differs between neural and epithelial cells (Figure 1). Neural cells, unlike RPT cells, express tyrosine hydroxylase, which converts tyrosine into L-3, 4 dihydroxyphenylalanine (L-DOPA), the immediate precursor of dopamine. RPT cells don not express tyrosine hydroxylase and therefore, cannot produce L-DOPA; filtered or peritubular L-DOPA has to be transported into the RPT cells, via the Na+-independent and pH-sensitive type 2 L-type amino acid transporter (LAT2), LAT1, related to b0,+ amino acid transporter (rBAT), and as yet unidentified transporters5,6. Unlike neural cells, RPT cells do not express dopamine β-hydroxylase so that synthesized dopamine is not converted to norepinephrine2. Dopamine produced in RPT cells is not stored. It enters the peritubular space and the tubular lumen (predominantly the latter), where it acts on its receptors, locally, and in more distal nephron segments.

Figure 1
Synthesis and metabolism of dopamine in neural and renal proximal tubule cells

Decreased renal synthesis of dopamine may be involved in the pathogenesis of essential hypertension in some human subjects. Some black and Japanese salt-sensitive subjects, with or without hypertension, do not increase renal dopamine production in response to a NaCl or protein load7. However, urinary dopamine and dopamine metabolites are actually increased in young subjects with essential hypertension8 or European Caucasians with borderline hypertension9. Renal dopamine synthesis is also increased in the Dahl salt-sensitive (Dahl-SS) and SHRs10. Inhibition of renal dopamine synthesis accelerates the development of hypertension in SHRs11. However, increasing renal dopamine production in SHRs does not lower their blood pressures or inhibit renal cortical NHE3 activity as is observed in WKY rats and does not increase sodium excretion to the same degree as that observed in WKY rats12. Therefore, decreased renal production of dopamine does not explain the impaired function of endogenous renal dopamine in many cases of hypertension. The increase in urinary dopamine levels in early hypertension may represent an attempt to compensate for the renal dopamine receptor defect9.

2. Dopamine receptors in health and hypertension

Dopamine receptors are classified into the D1- and D2-like receptor subtypes, based on their molecular structure and pharmacology. D1-like receptors, comprised of D1 and D5 receptors, stimulate adenylyl cyclase activity, whereas D2-like receptors, comprised of D2, D3, and D4 receptors, inhibit adenylyl cyclase activity and regulate/modulate the activity of several ion channels. In this review, the term “D1-like receptor” is used if the effect is not specifically attributable to the D1 receptor or D5 receptor, and the term “D2-like receptor” is used if the effect is not specifically attributable to the D2, D3, or D4 receptor. This is particularly apt for D1-like receptors because no commercially available drugs can distinguish the D1 from the D5 receptor.

The normal circulating levels of dopamine are too low to stimulate vascular dopamine receptors and vascular smooth muscle cells (VSMCs) do not synthesize dopamine. Because the direct vascular effect of dopamine is not important in the normal regulation of blood pressure, the contribution of arterial dopamine receptors to hypertension is not discussed.

2.1. Renal D1-like receptors

2.1.1. Physiological role of D1-like receptors

As stated above, during normal or moderately increased NaCl intake, dopamine, by direct or indirect interaction with other hormones/humoral agents, regulates sodium chloride excretion. In salt-loaded dogs and rats, the systemic or renal arterial infusion of the D1-like receptor antagonist SCH-23390 decreases sodium excretion by about 60%12,13. Chronic administration of the long acting D1-like receptor antagonist, ecopipam, in humans, increases blood pressure14. The differential contribution of D1 and D5 receptors in this process remains to be determined. Preliminary data suggest that the D5 receptor is expressed preferentially over the D1 receptor in the thick ascending limb of Henle and the cortical collecting duct while the D1 receptor is expressed preferentially over the D5 receptor in the proximal tubule. Indeed, in RPT cells, 70% of cAMP generated following D1-like receptor stimulation is due to the D1 receptor15. Therefore, the D1 receptor function is exerted preferentially over the D5 receptor in the proximal nephron while the converse is true in the distal nephron.

The infusion of D1 receptor antisense oligodeoxynucleotides directly into the renal interstitial space in uninephrectomized Sprague-Dawley rats causes a transient decrease in sodium excretion and does not affect blood pressure16. The failure of the selective renal silencing of the D1 receptor to increase blood pressure may suggest that non-renal D1 receptors, location(s) to be determined, are also important in the overall regulation of blood pressure. Indeed, general disruption of the D1 receptor gene in mice leads to the development of hypertension17. The D5 receptor also plays a role in the regulation of blood pressure because deletion of the D5 receptor gene (D5-/-) in mice produces hypertension that is aggravated by a high NaCl intake18(Asico LD, Jose PA. unpublished data, 2010). Cross-renal transplantation experiments indicate that the hypertension in D5-/- mice is due to renal mechanisms to a greater extent and to extra renal mechanisms to a lesser extent (Asico LD, Jose PA. unpublished data, 2010).

The natriuretic and diuretic effects of D1-like receptors are dependent on sodium balance. In sodium-depleted states, a D1-like receptor-mediated natriuresis may not be evident, while during sodium-replete states, the natriuretic effect of D1-like receptors appears2,12,13. D1-like receptors can inhibit sodium hydrogen exchanger type 3 (NHE3), sodium phosphate co-transporter type IIa (NaPi-IIa), chloride bicarbonate exchanger (Cl-/HCO3-), probably the NaCl cotransporter (NCC), and the epithelial sodium channel (ENaC) at the luminal membrane, as well as Na+-K+ ATPase and the sodium bicarbonate co-transporter (Na+/HCO3-) at the basolateral membrane2,4,12,19,20.

2.1.2. Renal D1-like receptors and hypertension

Impaired D1-like receptor function plays a role in the pathogenesis of hypertension. In rodents with genetic hypertension (Dahl-SS and SHRs), D1-like receptor agonist-mediated diuretic and natriuretic responses are consistently impaired2,12,21. The decreased ability of D1-like receptor agonists to inhibit renal sodium transport in rodent genetic hypertension is consistently caused by diminished D1-like receptor inhibition of NHE3, Cl-/HCO3- exchanger, Na+/HCO3- co-transporter and Na+-K+ ATPase activities2,12,20,22.

The ability of D1-like receptor agonists to decrease RPT sodium transport is also impaired in humans with essential hypertension23. The impaired inhibitory effect of D1-like receptors on renal epithelial sodium transport in the proximal tubule and thick ascending limb in human essential hypertension, SHRs, and Dahl-salt sensitive rats is due to an uncoupling of the D1 (but not the D5) receptor from its G protein/effector complex2,12,,24(Figure 2); decreased expressions of D1 and D5 receptors also play a role2. The uncoupling of the D1 receptor in hypertension is receptor-specific, organ-selective, nephron-segment specific, precedes the onset of hypertension, and co-segregates with the hypertensive phenotype12.

Figure 2
Dysfunction of renal D1-like receptors in hypertension

In the human kidney, the D1 receptor uncoupling in hypertension is due to increased constitutive activity of G protein-coupled receptor kinase type 4 (GRK4), which is caused by the presence of GRK4 variants (especially R65L, A142V and A486V)24 (Figure 2). Whether or not the D5 receptor is regulated by these GRK4 gene variants remains to be determined. There are polymorphisms in the promoter region of human GRK4 but their role in essential hypertension remains to be determined25. However, increased expression of renal GRK4 has been shown to be responsible for the renal D1 receptor uncoupling in the SHR12,24 and the salt-sensitivity of C57BL/6J mice from the Jackson Laboratory26. Deletion of the GRK4 gene in C57BL/6J mice (GRK4-/-) decreases basal blood pressure and prevents salt sensitivity26. It should be noted, however, that a normal expression of wild-type GRK4 is needed for normal D1 and D3 receptor function.

In summary, D1-like receptor function outside the central nervous system is impaired in essential hypertension. Whereas D1-like receptor function is fully functional in some tissues (e.g., artery) in hypertension, the predominant organ involved in humans is probably the kidney.

2.2. D2-like receptors

As indicated earlier, the D2-like receptor family includes D2, D3 and D4 receptors. The D2 receptors in the rat kidney are located prejunctionally in dopaminergic nerves and postjunctionally in the proximal (S2 segment) and distal convoluted tubules, and cortical collecting duct, while the D4 receptor is expressed in the proximal (S1 segment) and distal convoluted tubules, and especially in the cortical and medullary collecting ducts. In the rat kidney, the major D2-like receptor in RPTs is the D3 receptor, therefore, this review deals only with role of the D3 receptor and not the other D2-like receptors in hypertension.

2.2.1. Physiological role of the renal D3 receptor

As with D1-like receptors, stimulation of renal D3 receptors induces natriuresis and diuresis. D3 receptor agonists, infused systemically or directly into the renal artery, increase sodium excretion27. The D3 receptor, like the D1-like receptors2,12,19,20, inhibits NHE328 and Na+-K+ ATPase activity29 and may also inhibit NCC and α-ENaC. However, the D3 receptor, unlike the D1-like receptor, does not inhibit NaPiIIa or the apical Cl-/HCO3- exchanger20.

We have reported that the D3 receptor, as with D1-like receptors, is also important in the regulation of blood pressure. D3-/- and D3-/+ mice have higher systolic and diastolic blood pressures than their wild-type littermates either on a mixed C57/BL6 and B129 background, or in congenic C57BL/6 background30. However Staudacher et al., reported that D3-/- mice, in a congenic C57BL/6 background on a low, normal, or high salt intake, have normal blood pressure31. This report has to be interpreted with caution because C57BL/6 mice from Jackson Laboratories may develop hypertension when fed a high NaCl diet, while C57BL/6 mice from Taconic do not26. Nevertheless, these two strains of D3-/- mice have a decreased ability to excrete an acute or a chronic NaCl load30,31, which would lead to an expansion of the extracellular fluid volume.

2.2.2. D3 receptors and hypertension

Renal D3 receptor-mediated natriuresis and diuresis are impaired in rodent models of essential hypertension. Dahl salt-resistant (Dahl-SR) rats, treated with D3 receptor antagonist, remain normotensive when sodium intake is normal but become hypertensive when sodium intake is increased32. Activation of D3 receptors induces natriuresis in normotensive Dahl-SS rats on a normal sodium diet but not in hypertensive Dahl-SS rats on a high sodium diet. On normal salt intake, renal D3 receptor density is decreased in Dahl-SS relative to Dahl-SR rats. High salt diet decreases renal D3 receptor agonist binding to a greater extent in Dahl-SS than Dahl-SR rats, suggesting that this may be the cause of the decreased natriuretic effect of D3 receptor stimulation in Dahl-SS rats32. We have studied the renal effects of another selective D3 receptor agonist, PD128907, infused directly into the renal artery of WKY and SHRs. PD128907 increases sodium excretion in WKY rats but not in SHRs27. Renal D3 receptor expression is lower while its degree of phosphorylation is greater in SHRs than in WKY rats, which may, in part, explain the impaired natriuretic effect of D3 receptors in SHRs21,27. As indicated earlier, the hypertension in the SHR is, in part, due to increased renal expression of GRK426; the D3 receptor33, like the D1 receptor, is regulated by GRK4.

II. Interaction between Dopamine and other Blood Pressure Regulatory Systems

1. Interaction with catecholamines and their receptors

Catecholamines have long been recognized to be important in the initiation and maintenance of high blood pressure34. Increased sympathetic activity contributes to hypertension not only by increasing vascular tone and inducing cardiac and vascular remodeling but also by altering renal sodium and water homeostasis.

1.1. Dopamine receptors regulate catecholamine release and adrenergic receptor function

Stimulation of dopamine receptors inhibits catecholamine release. D2-like receptors inhibit the release of norepinephrine in gastric and uterine arteries35 and circulating norepinephrine levels in humans with heart failure. An inhibitory effect of D1-like receptors on sympathetic tone or endogenous production of catecholamines has also been reported36 (Figure 3).

Figure 3
Dopamine counterbalances the prohypertensive effects of α–adrenergic nervous and renin-angiotensin systems

Dopamine has also been reported to inhibit the ability of arginine vasopressin to increase water permeability and cAMP accumulation, via α2-adrenergic receptors, in the rat inner medullary collecting duct37.

1.2. Adrenergic receptors can regulate dopamine production and receptor function

Blockade of α2-adrenergic receptors enhances brain cortical dopamine output38. Activation of the β-adrenergic receptor with isoproterenol increases D1 receptor translocation from the cytosol to the plasma membrane and augments D1-like receptor-mediated inhibition of Na+-K+ ATPase activity in RPT cells39.

1.3. The interaction between dopamine and adrenergic receptors is supported by studies in dopamine receptor deficient mice

D5-/- mice, which are hypertensive, have an elevated urinary epinephrine/norepinephrine ratio, indicating increased adrenal catecholamine production (Asico LD, Jose PA. unpublished data, 2010). Adrenalectomy or α-adrenergic blockade decreases blood pressure to a greater extent in D5-/- mice than D5+/+ littermates. Similarly, D2-/- mice, which are also hypertensive, have higher epinephrine excretion than their D2+/+ littermates. Alpha-adrenergic blockade also decreases the blood pressure to a greater extent in D2-/- than in D2+/+ mice40. These results suggest that the hypertension in D2-/- and D5-/- mice is caused, in part, by increased sympathetic activity. The salt sensitivity of D5-/- mice may be related to renal nerve activity (Asico LD, Jose PA. unpublished data, 2010).

2. Interaction with the renin-angiotensin system (RAS)

The RAS, especially in the kidney, is pre-eminent in the regulation of arterial pressure and sodium homeostasis, especially during conditions of sodium depletion41. As noted below, different dopamine receptor subtypes interact with different components of the RAS with the ultimate effect of increasing renal sodium excretion and maintaining a normal blood pressure (Figure 3).

2.1. The RAS regulates dopamine release

In rats on a low-salt diet, angiotensin II decreases urinary dopamine by increasing renal MAO activity42. In contrast, angiotensin 1-7 increases the release of extracellular dopamine in the rat striatum and hypothalamus, which becomes more evident with blockade of AT1 receptors43. Inhibition of angiotensin converting enzyme also increases dopamine content in the mouse striatum44. Whether or not these effects also occur in the kidney remains to be determined.

2.2. The interactions between dopamine and RAS also occur at the receptor level

The interaction between dopamine and RAS becomes very evident in receptor deficient mice. Blockade of AT1 receptors results in a decrease in blood pressure that is greater and longer in D3-/-, D4-/-, and D5-/- mice than their wild-type littermates30,45. In contrast, the hypertension of D2-/- mice is not related to activation of the RAS but rather to increased aldosterone secretion46.

2.2a. D1-like receptors

Negatively interact with angiotensin II, including a negative regulation of AT1 receptor action/expression and a positive regulation of AT2 receptor action/expression. The natriuretic effect of D1-like receptors is enhanced when angiotensin II production is decreased or when AT1 receptors are blocked47. These short-term effects probably occur via protein-protein interaction48 that includes D1-like receptor-mediated internalization of the AT1 receptor4. Not only do D1-like receptors interfere with the antinatriuretic effect of AT1 receptors, they also interact with AT2 receptors to increase sodium excretion; Salomone et al. reported that D1-like receptors increase AT2 receptor expression in RPT cells49. The intermediate-term effects of dopamine on AT1 receptor actions are probably exerted at the post-translational level (e.g., increased degradation)50, while the long-term antagonistic effect of dopamine receptors on AT1 receptor actions is probably exerted at the transcriptional level48. Harris and co-workers reported that in rabbit RPT cells, dopamine, via D1-like receptors, decreases AT1 receptor mRNA and protein levels51.

2.2b. D2-like receptors

Also negatively interact with angiotensin II, including a D3 and D4 receptor-mediated decrease in AT1 receptor action/expression45,52. AT1 receptor expression is increased in mice lacking the D3 or D4 receptor45,52. D3 receptor agonist decreases AT1 receptor expression in RPT cells from WKY rats52. Bromocriptine, which has a greater affinity for the D2 and D3 receptors than the D4 receptor, prevents angiotensin II-mediated stimulation of Na+-K+ ATPase activity, and decreases AT1 receptor protein expression in rat RPTs53. The negative regulatory effect of bromocriptine on AT1 receptor expression is probably exerted at the D3 receptor because AT1 receptor expression is not increased in mice in which the D2 receptor gene is disrupted (Jose PA. unpublished observations, 2008).

2.3. Dopamine interacts with other components of the RAS

The D1 receptor is expressed in juxtaglomerular cells in rodents but not in humans54,55. In contrast, the D5 receptor, the other D1-like receptor, is not expressed in juxtaglomerular cells in all species studied. In vivo, the D1 receptor inhibits renin release in rodents via inhibition of macula densa cyclooxygenase 2 (COX2)56. When COX2 activity in the macula densa is suppressed56 or when the macula densa is not present, as in juxtaglomerular cells in culture, the D1 receptor stimulates renin secretion55. The D3 but not the D4 receptor also inhibits renin secretion57. Preliminary data show that stimulation of D3 receptors increases angiotensin converting enzyme (ACE) 2 expression and activity in RPT cells from WKY rats (Chen XJ, Zeng C, Jose PA. unpublished data, 2010), which may have physiological significance; ACE2 converts angiotensin II into angiotensin 1-7, which has natriuretic and vasodilatory properties. D1-like receptors have been reported to increase rat angiotensinogen gene expression in opossum kidney cells with a gene containing the 5′- flanking regulatory sequence of the rat angiotensinogen gene fused with a human growth hormone gene, as a reporter58. This effect, which would negate the natriuretic effects of dopamine receptors, remains to be confirmed. It is also not known whether or not any such interaction occurs in vivo.

2.4. An abnormal interaction between dopamine and AT1 receptors occurs in RPT cells in hypertensive states

In RPT cells from WKY rats, D1 and AT1 receptors heterodimerize and inhibit each other's function; the ability of the D1 receptor to heterodimerize and inhibit AT1 receptor function is impaired in SHRs48. The D3 receptor decreases AT1 receptor expression in RPT cells from WKY rats while D3 receptor stimulation increases AT1 receptor expression in SHRs52. The impaired natriuretic effect of the D3 receptor in SHRs21,27, may be, in part, related to aberrant D3 receptor inhibitory regulation of the AT1 receptor53. AT1 receptor expression is increased in D5-/- mice59.


Renal function is regulated by physical factors and numerous hormones and neural and humoral factors. Among those factors is dopamine; activation of any of the dopamine receptor subtypes (D1-D5), especially in salt-replete conditions, induces natriuresis. These actions of dopamine are impaired in human essential hypertension and rodent models of essential hypertension. Additionally, the numerous other abnormalities in essential hypertension may well prove to be linked to the regulation of dopamine receptor function. For example, GRK4 gene variants which impair dopamine receptor function (e.g., D1 and D3 receptors) or expression, may increase the activity of pro-hypertensive mechanisms. The natriuretic effects of dopamine are due synergistic interaction with other natriuretic factors and negative interaction with antinatriuretic factors. The presence of constitutively active variants of GRK4, e.g., GRK4 142V, increases AT1 receptor expression and function. Therefore, abnormal interactions between dopamine receptors on the one hand and the α-adrenergic system and RAS on the other may be involved in the pathogenesis of hypertension. Restoration of dopamine receptor function could be a complementary or even an alternative method to lower blood pressure in hypertensive patients.


Source of Funding: These studies were supported in part by grants from the National Institutes of Health, USA (HL023081, HL074940, DK039308, HL068686, HL092196), the National Natural Science Foundation of China (30470728, 30672199), Natural Science Foundation Project of CQ CSTC (CSTC,2009BA5044), and the grants for Distinguished Young Scholars of China from the National Natural Science Foundation of China (30925018).


Disclosures: None.


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