Renal Dopamine Receptor Function in Hypertension

Abstract

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, hypertension and obesity

“…13 These effects have been thoroughly analysed and characterised by two kinds of response, depending on whether it is produced by D 1 or D 2 . Activation with selective agonists to D 1 receptors results in hypotension, increase in renal flow, 14 diuresis, and natriuresis, whereas stimulation of D 2 produces hypotension, bradycardia, decrease in afterload and vasodilatation in certain vascular beds 15 (see Table 1). These effects are Na + dependant, ie, increases in plasma [Na + ] induce higher excretion of water and Na + , and result in high dopamine levels in urine.…”

“…DA reversibly inhibits this pump, mainly through type 1 receptors, which results in an increase in natriuresis. 4,15 The second messengers responsible for the enzyme phosphorylation are apparently phospholipase A 2 (PLA 2 ), with the subsequent release of arachidonic acid and its metabolites, and phospholipase C (PLC). Their actual distribution and mediation seem to be of dependent nature.…”

Agonist-dependent Regulation of Renal Na+, K+-ATPase Activity Is Modulated by Intracellular Sodium Concentration

“…In vivo, increases in dietary sodium intake or acute sodium loading lead to natriuresis accompanied by elevated urinary dopamine excretion, which suggested that dopamine produced endogenously by the epithelial proximal tubule cells might contribute to the natriuretic response (2)(3)(4). In this model, endogenously produced dopamine would be transported outside the proximal tubule cells where it binds to specific cell membrane receptors.…”

“…In recent years, an increasing number of publications (1)(2)(3)(4) have reported the short term regulation of kidney Na ϩ ,K ϩ -ATPase by hormones and intracellular second messengers that modulate proximal tubule sodium reabsorption. Renal Na ϩ ,K ϩ -ATPase activity is regulated by phosphorylation/dephosphorylation processes, and both cAMP-dependent protein kinase and protein kinase C (PKC) phosphorylate the Na ϩ ,K ϩ -ATPase (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). We have demonstrated that Ser-18 of the ␣-subunit is essential for the inhibition of the Na ϩ -pump activity by dopamine and that both Ser-18 and Ser-11 are essential for the stimulation of this activity by PMA (10 -15).…”

“…Decreased Na ϩ ,K ϩ -ATPase activity induced by dopamine is partly responsible for reduced sodium reabsorption during a high salt diet, and impaired regulation of the Na ϩ ,K ϩ -ATPase activity in renal tubules has been linked to the development of high blood pressure (1)(2)(3)(4). In vivo, increases in dietary sodium intake or acute sodium loading lead to natriuresis accompanied by elevated urinary dopamine excretion, which suggested that dopamine produced endogenously by the epithelial proximal tubule cells might contribute to the natriuretic response (2)(3)(4).…”