Adrenergic and Endothelin B Receptor-Dependent Hypertension in Dopamine Receptor Type-2 Knockout Mice

Abstract

Abstract-Polymorphism of the dopamine receptor type-2 (D 2 ) gene is associated with essential hypertension. To assess whether D 2 receptors participate in regulation of blood pressure (BP), we studied mice in which the D 2 receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D 2 homozygous and heterozygous mutant mice than in D 2 ϩ/ϩ littermates. BP after ␣-adrenergic blockade decreased to a greater extent in D 2 Ϫ/Ϫ mice than in D 2 ϩ/ϩ mice. Epinephrine excretion was greater in D 2 Ϫ/Ϫ mice than in D 2 ϩ/ϩ mice, and acute adrenalectomy decreased BP to a similar level in D Disruption of D 3 receptors in mice produces hypertension mediated, at least in part, by activation of the renin-angiotensin system. 7 The D 2 receptor could be involved in D 2 -likemediated hypertension because it is the major D 2 -like dopamine receptor. 3,8 -11 Moreover, BP decreased when a segment of chromosome 8 that contained the D 2 receptor gene was transferred from a normotensive Brown Norway rat to a spontaneously hypertensive rat background. 12 Several variants of the human D 2 dopamine receptor have been reported. 13 Abnormalities of D 2 receptor genes could play a role in the pathogenesis of essential hypertension, because the association of a D 2 dopamine receptor polymorphism with obesity and hypertension has been reported. 14 To determine whether D 2 receptors play a role in the regulation of BP, we measured arterial pressure in congenic B6 mice mutants for the D 2 receptor. 8,9 Because D 2 -like receptors have been shown to interact with vasopressor systems, 1,6,15,16 interactions between D 2 receptors and other vasopressor systems were also studied. Methods D 2 Receptor-Deficient MiceThe original F 2 hybrid strain (129/SvXC57BL/6J, Oregon Health Sciences University, Portland) that contained the mutated D 2 recep-

Chronic regulation of the renal Na+/H+exchanger NHE3 by dopamine: translational and posttranslational mechanisms

“…Maneuvers that chronically disrupt DA-dependent natriuresis such as blockade of DA generation by inhibitors of aromatic amino acid decarboxylase (14,95), pharmacological antagonism of dopamine receptors (51,55,70,84,94), and genetic deletion of DA receptors (DR 1 through DR 5 in isolation) all lead to systemic hypertension with a plethora of renal and extrarenal pathophysiological changes (1, 10,19,58,75,114,118,120). Some degree of impaired natriuresis has been described in several although not all of the single DA receptor gene deletion models (10,98).…”

Acute regulation of renal Na+/H+ exchanger NHE3 by dopamine: role of protein phosphatase 2A

“…Hypertension was found in mice with deletion of both D 1 -like receptors (D 1 and D 5 ) (1, 31) and D 2 -like receptors (D 2 , D 3 , and D 4 ) (6,11,42). A multitude of cardiovascular, neurohumoral, and renal mechanisms may contribute to the phenotypes of these mice, but both D 1 -like and D 2 -like receptor deletions have been associated with sodium retention, extracellular fluid expansion, and salt-sensitive hypertension (1,6,42,54).…”

“…Hypertension was found in mice with deletion of both D 1 -like receptors (D 1 and D 5 ) (1, 31) and D 2 -like receptors (D 2 , D 3 , and D 4 ) (6,11,42). A multitude of cardiovascular, neurohumoral, and renal mechanisms may contribute to the phenotypes of these mice, but both D 1 -like and D 2 -like receptor deletions have been associated with sodium retention, extracellular fluid expansion, and salt-sensitive hypertension (1,6,42,54). The importance of the intrarenal autocrine/paracrine dopamine system in the natriuretic response to both acute and chronic sodium loading has also been demonstrated by pharmacological inhibition of the aromatic amino acid decarboxylase (8,53) and blockade of the renal dopamine receptors (28,29,39,47,49).…”

Activation of D 3 Dopamine Receptor Decreases Angiotensin II Type 1 Receptor Expression in Rat Renal Proximal Tubule Cells

“…[7][8][9][10] The distribution of D 2 receptor protein along the nephron is still uncertain. 8,19 The effect of D 2 receptors on renal sodium transport is also not clear because of the lack of agonists that are highly selective to the D 2 over the D 3 receptor. 16,17 However, 7-OH-DPAT, a ligand with a 50-fold selectivity to the D 3 over the D 2 receptor, 16 increases sodium excretion in rats.…”