Abstract-Dopamine plays an important role in the regulation of renal sodium excretion. The synthesis of dopamine and the presence of dopamine receptor subtypes (D 1A , D 1B as D 1 -like and D 2 , and D 3 as D 2 -like) have been shown within the kidney. The activation of D 1 -like receptors located on the proximal tubules causes inhibition of tubular sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase activity. The D 1 -like receptors are linked to the multiple cellular signaling systems (namely, adenylyl cyclase, phospholipase C, and phospholipase A 2 ) in the different regions of the nephron. Defective renal dopamine production and/or dopamine receptor function have been reported in human primary hypertension as well as in genetic models of animal hypertension. There may be a primary defect in D 1 -like receptors and an altered signaling system in the proximal tubules that lead to reduced dopamine-mediated effects on renal sodium excretion in hypertension. Recently, it has been shown in animal models that the disruption of either D 1A or D 3 receptors at the gene level causes hypertension in mice. Dopamine and dopamine receptor agonists also provide therapeutic potential in treatment of various cardiovascular pathological conditions, including hypertension. However, because of the poor bioavailability of the currently available compounds, the use of D 1 -like agonists is limited to the management of patients with severe hypertension when a rapid reduction of blood pressure is clinically indicated and in acute management of patients with heart failure. In conclusion, there is convincing evidence that dopamine and dopamine receptors play an important role in regulation of renal function, suggesting that a defective dopamine receptor/signaling system may contribute to the development and maintenance of hypertension. Further studies need to be directed toward establishing a direct correlation between defective dopamine receptor gene in the kidney and development of hypertension. Subsequently, it may be possible to use a therapeutic approach to correct the defect in dopamine receptor gene causing the hypertension. (Hypertension. 1998;32:187-197.)Key Words: dopamine Ⅲ receptors, dopamine Ⅲ kidney tubules, proximal Ⅲ kidney Ⅲ hypertension, renal D opamine is known to play an important role in the control of renal sodium excretion. Specific receptors for dopamine have been identified in various regions of the nephron, and it is reported that dopamine is synthesized within the renal proximal tubules. Endogenously produced dopamine, as well as exogenously administered dopamine, exerts pronounced effects on renal function. There are reports suggesting that a defect in renal dopamine receptor function and/or dopamine production may play a role in the pathogenesis of hypertension. For example, reduced urinary dopamine/ sodium excretion is reported in some forms of human primary hypertension. [1][2][3] It is reported that a defect in dopamine receptor-G protein coupling and alterations in the signaling component...

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 D(1) 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 D(1) 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.

Oxidative stress plays a pathogenic role in hypertension, particularly the one associated with diabetes and obesity. Here, we test the hypothesis that renal dopamine D1 receptor dysfunction in obese Zucker rats is caused by oxidative stress. One group each from lean and obese Zucker rats received tempol, a superoxide dismutase mimetic in drinking water for 2 weeks. Obese animals were hypertensive, hyperglycemic, and hyperinsulinemic, exhibited renal oxidative stress, and increased protein kinase C activity. Also, there was hyperphosphorylation of D1 receptor, defective receptor-G-protein coupling, blunted dopamine-induced Na ؉ -K ؉ -ATPase inhibition, and diminished natriuretic response to D1 receptor agonist, SKF-38393. However, obese animals had elevated levels of plasma nitric oxide and urinary cGMP. In addition, L-N-nitroarginine and sodium nitroprusside showed similar effect on blood pressure in lean and obese rats. In obese animals, tempol reduced blood pressure, blood glucose, insulin, renal oxidative stress, and protein kinase C activity. Tempol also decreased D1 receptor phosphorylation and restored receptor G-protein coupling. Dopamine inhibited Na ؉ -K ؉ -ATPase activity, and SKF-38393 elicited a natriuretic response in tempol-treated obese rats. Thus in obese Zucker rats, tempol ameliorates oxidative stress and improves insulin sensitivity. Consequently, hyperphosphorylation of D1 receptor is reduced, leading to restoration of receptor-G-protein coupling and the natriuretic response to SKF-38393. Diabetes 54: 2219 -2226, 2005

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Dopamine receptors of DA-1 and DA-2 subtypes are localized in various regions within the kidney including the renal vasculature (DA-1) as well as sympathetic nerve terminals innervating the renal blood vessels (DA-2). More recent studies using receptor-ligand binding and receptor autoradiography have shown that DA-1 receptors are localized at both the luminal and basolateral membranes at the level of the proximal tubules. Activation of these DA-1 receptors by dopamine and by selective DA-1 receptor agonists results in natriuresis and diuresis. The cellular signaling mechanisms responsible for this response appear to be DA-1 receptor-induced activation of adenylate cyclase and phospholipase C, which via the generation of various intracellular messenger systems cause inhibition of Na(+)-H+ antiport (luminal) and Na+, K(+)-ATPase (basolateral), respectively. Both of these events consequently inhibit sodium reabsorption leading to natriuresis and diuresis. It is also known that dopamine can be synthesized within proximal tubular cells from L-dopa, which is taken up from the tubular lumen, and this locally produced dopamine plays an important role in the regulation of sodium excretion particularly during increases in sodium intake. Furthermore, a defect in the renal dopaminergic mechanism may be one of the pathogenic factors in certain forms of hypertension. Finally, whereas DA-1 receptor agonists are shown to be of therapeutic benefit in the treatment of hypertension, heart failure, and acute renal failure, some selective DA-2 receptor agonists are effective antihypertensive agents.

The dopamine DA1 receptor transduces its signal via adenylyl cyclase and phospholipase C in the renal proximal tubule, which has been suggested to be defective at the level of receptor-G protein coupling in spontaneously hypertensive rats (SHR). We prepared basolateral membranes from Wistar-Kyoto (WKY) rats and SHR to determine the coupling of DA1 receptor with G proteins, especially G(q/11). Fenoldopam, a DA1-receptor agonist, produced a time- and concentration-dependent stimulation in 35S-labeled guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding in WKY rats. Fenoldopam-induced (10 microM) stimulation was significantly inhibited by a DA1-receptor antagonist, Sch-23390. Specific antibodies against COOH terminals of G(S)alpha and G(q/11)alpha produced 50-60% and 40-50% inhibition, respectively, in fenoldopam stimulation of [35S]GTPgammaS binding. Western analysis of basolateral membranes with these antibodies revealed the presence of G(S)alpha (45 kDa) and G(q/11)alpha (42 kDa). Fenoldopam stimulation of [35S]GTPgammaS binding was significantly attenuated in SHR compared with WKY rats. Parathyroid hormone stimulation of [35S]GTPgammaS binding was similar in SHR and WKY rats, whereas stimulation by phenylephrine was significantly reduced in SHR. Densitometric quantification of 42-kDa band showed a reduced amount in SHR, whereas the density of 45-kDa band was not significantly different compared with WKY rats. We provide the direct evidence showing the coupling of DA1 receptor with G(q/11)alpha and G(S)alpha and propose that, in addition to a defect in the receptor-G protein coupling, a reduced amount of G(q/11)alpha observed in the hypertensive animals may also contribute to the diminished dopamine-induced inhibition of Na+-K+-adenosinetriphosphatase in SHR.

We have previously reported that dopamine-1 receptor-mediated activation of phospholipase C is diminished in renal cortical slices of adult spontaneously hypertensive rats. To determine the potential consequences of this phenomenon, we performed the present studies in which renal proximal tubule suspensions obtained from spontaneously hypertensive and Wistar-Kyoto rats of 10-12 weeks of age were used. The tubule suspensions were incubated with dopamine in the presence or absence of dopamine receptor antagonists, and sodium, potassium adenosine trisphosphatase (sodium pump) activity was measured as the ouabain-sensitive adenosine trisphosphate hydrolysis. We found that dopamine produced a concentration-related inhibition of sodium pump activity in the normotensive rats but not in the hypertensive rats. Dopamine-induced inhibition of sodium pump activity in the normotensive rats was abolished by the phospholipase C inhibitor U-73122 or the protein kinase C inhibitor sphingosine, suggesting the involvement of a phospholipase C-coupled protein kinase C pathway in this response. Dopamine-induced inhibition in the normotensive rats was attenuated by the dopamine-1 receptor antagonist SCH 23390 but not by the dopamine-2 receptor antagonist domperidone. To identify possible sites of defect in dopamine-1 receptor-coupled signaling pathways in the hypertensive rats, we incubated the proximal tubules with phorbol 12,13-dibutyrate or the synthetic diacylglycerol analogue l-oleoyI-2-acetyl-rac-glycerol. The results showed that both compounds inhibited sodium pump activity as effectively in the hypertensive as in the normotensive rats, suggesting that the protein kinase C-coupled sodium pump pathway was not defective in the hypertensive animals. Failure of dopamine to inhibit sodium pump activity in the hypertensive rats could not be due to a defective dopamine-1 receptor adenylate cyclase coupling, because dopamine was still unable to inhibit sodium pump activity in the presence of dibutyryl cyclic adenosine monophosphate or forskolin. These results show that dopamine failed to inhibit sodium pump activity in the proximal tubules of adult hypertensive rats, which may be mainly due to a defect in the dopamine-1 receptor-mediated signal transduction pathway. The site of this defect is most likely proximal to the activation of protein kinase C and may involve a defect in the dopamine-1 receptor phospholipase C coupling process. (Hypertension 1993;21:364-372) KEY WORDS • receptors, dopamine • dopamine • sodium • phospholipase C • adenosine trisphosphatase, sodium, potassium A bnormal renal sodium handling has been known / \ to be one of the major factors involved in the -Z A . initiation and maintenance of high blood pressure in several models of hypertension, including genetic hypertension. 1 -2 Endogenous kidney dopamine plays an important role in regulation of renal sodium excretion, so it has been proposed that impaired renal sodium handling in spontaneously hypertensive rats (SHR) may partly be due to a malfunction or a d...

Dopamine, via activation of renal D(1) receptors, inhibits the activities of Na-K-ATPase and Na/H exchanger and subsequently increases sodium excretion. Decreased renal dopamine production and sodium excretion are associated with type I diabetes. However, it is not known whether the response to D(1) receptor activation is altered in type I diabetes. The present study was designed to examine the effect of streptozotocin-induced type I diabetes on renal D(1) receptor expression and function. Streptozotocin treatment of Sprague-Dawley rats caused a fourfold increase in plasma levels of glucose along with a significant decrease in insulin levels compared with control rats. Intravenous administration of SKF-38393, a D(1) receptor agonist, caused a threefold increase in sodium excretion in control rats. However, SKF-38393 failed to produce natriuresis in diabetic rats. SKF-38393 caused a concentration-dependent inhibition of Na-K-ATPase activity in renal proximal tubules of control rats. However, the ability of SKF-38393 to inhibit Na-K-ATPase activity was markedly diminished in diabetic rats. D(1) receptor numbers and protein abundance as determined by [(3)H]SCH-23390 ligand binding and Western blot analysis were markedly reduced in diabetic rats compared with control rats. Moreover, SKF-38393 failed to stimulate GTP gamma S binding in proximal tubular membranes from diabetic rats compared with control rats. We conclude that the natriuretic response to D(1) receptor activation is reduced in type I diabetes as a result of a decrease in D(1) receptor expression and defective receptor G protein coupling. These abnormalities may contribute to the sodium retention associated with type I diabetes.