Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones/humoral factors, such as aldosterone, angiotensin, catecholamines, endothelin, oxytocin, prolactin pro-opiomelancortin, reactive oxygen species, renin, and vasopressin. Dopamine receptors are classified into D(1)-like (D(1) and D(5)) and D(2)-like (D(2), D(3), and D(4)) subtypes based on their structure and pharmacology. In recent years, mice deficient in one or more of the five dopamine receptor subtypes have been generated, leading to a better understanding of the physiological role of each of the dopamine receptor subtypes. This review summarizes the results from studies of various dopamine receptor mutant mice on the role of individual dopamine receptor subtypes and their interactions with other G protein-coupled receptors in the regulation of blood pressure.
Abstract-Abnormalities in D 1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D 1 receptor function in hypertension. We measured renal GRK4 and D 1 and serine-phosphorylated D 1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious-uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D 1 receptors were Ϸ90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D 1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D 1 receptor control of sodium excretion and blood pressure in genetic hypertension. The uncoupling of the D 1 -like receptor from its effector proteins in the kidney in hypertension is associated with increased phosphorylation of the D 1 receptor. 4,5 In human essential hypertension, single nucleotide polymorphisms of the G protein-coupled receptor (GPCR) kinase 4 (GRK4) are associated with constitutive phosphorylation and desensitization of the D 1 receptor in renal proximal tubules. 4 -6 These lead to sodium retention and hypertension. Indeed, transgenic mice expressing the GRK4 variant, GRK4␥A142V, develop hypertension that is associated with an impaired D 1 receptormediated natriuresis. 5 To determine whether aberrant GRK4 function contributes to the impaired renal D 1 receptor function in SHRs, we studied the renal expression of GRK4 and the effects of decreasing its expression in the kidney by a chronic renal cortical interstitial infusion of GRK4 antisense (As) oligodeoxynucleotides (Odns) in conscious SHRs and their normotensive controls, Wistar-Kyoto (WKY) rats. If an increased GRK4 activity in the kidney is responsible for the increased blood pressure in SHRs, this maneuver should improve D 1 receptor-mediated renal tubular handling of sodium and ameliorate the high blood pressure in SHRs without affecting these variables in WKY rats.
Abstract-The dopaminergic and renin-angiotensin systems interact to regulate blood pressure. Because this interaction may be perturbed in genetic hypertension, we studied D 1 dopamine and AT 1 angiotensin receptors in immortalized renal proximal tubule (RPT) and A10 aortic vascular smooth muscle cells. Whereas the D 1 -like receptors couple to the stimulatory G protein, G␣ S and thus, activate adenylyl cyclases, the receptors of the D 2 -like subfamily couple to the inhibitory G protein, G␣ i /G␣ O and inhibit adenylyl cyclases and calcium channels and modulate potassium channels. [1][2][3] Under euvolemic conditions and magnified during moderate volume expansion, dopamine, through D 1 -like and D 3 receptors, acts to increase sodium excretion and decrease blood pressure. 1,4,5 The renin-angiotensin system is another important regulator of sodium transport and blood pressure. 6 Like dopamine, angiotensin exerts its action through several receptor subtypes. AT 1 receptors are linked to Gq/11 and G␣ i /G␣ O , whereas AT 2 receptors are linked to G␣ i 2/3 2,7 ; the G protein linkage of AT 4 receptors is not clear. 8 Although angiotensin, through AT 2 and AT 4 receptors, can decrease blood pressure by vasodilation and increase in sodium excretion, the major effect of angiotensin II is increasing sodium reabsorption and blood pressure, counteracting the effect of dopamine. 6 -10 Dopamine and angiotensin receptors counteract each other in the paracrine regulation of renal sodium transport. Thus, the natriuretic effect of D 1 -like receptors is enhanced when angiotensin II production is decreased or when AT 1 receptors are blocked. 11 Dopamine, through D 1 -like and D 2 -like receptors, by themselves or in concert, antagonizes the stimulatory actions of angiotensin II on proximal tubular luminal sodium transport. Dopamine, through D 1 -like receptors, also decreases AT 1 receptor expression and angiotensin II binding sites in renal proximal tubules. 12-15 D 2 -like receptors, 14 and more specifically, the D 3 receptor, also decrease AT 1 receptor expression in immortalized renal proximal tubule (RPT) cells from normotensive Wistar-Kyoto (WKY) rats. 16 Immortal-
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.