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(Hypertension. 2007;49:672.)
© 2007 American Heart Association, Inc.

Original Articles, Part 2

Reactive Oxygen Species–Dependent Hypertension in Dopamine D₂ Receptor–Deficient Mice

Ines Armando; Xiaoyan Wang; Van Anthony M. Villar; John E. Jones; Laureano D. Asico; Crisanto Escano; Pedro A. Jose

From the Department of Pediatrics and Physiology and Biophysics, Georgetown University Medical Center, Washington, DC.

Correspondence to Ines Armando, Department of Pediatrics, Georgetown University Medical Center, 4000 Reservoir Rd, NW, Washington, DC 20057. E-mail ma383{at}georgetown.edu

Dysfunction of D₂-like receptors has been reported in essential hypertension. Disruption of D₂R in mice (D₂^–/–) results in high blood pressure, and several D₂R polymorphisms are associated with decreased D₂R expression. Because D₂R agonists have antioxidant activity, we hypothesized that increased blood pressure in D₂^–/– is related to increased oxidative stress. D₂^–/– mice had increased urinary excretion of 8-isoprostane, a parameter of oxidative stress; increased activity of reduced nicotinamide-adenine dinucleotide phosphate oxidase in renal cortex; increased expression of the reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits Nox1, Nox2, and Nox4; and decreased expression of the antioxidant enzyme heme-oxygenase-2 in the kidneys, suggesting that regulation of reactive oxygen species (ROS) production by D₂R involves both pro-oxidant and antioxidant systems. Apocynin, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, or hemin, an inducer of heme oxigenase-1, normalized the blood pressure in D₂^–/– mice. Because D₂Rs in the adrenal gland are implicated in aldosterone regulation, we evaluated whether alterations in aldosterone secretion contribute to ROS production in this model. Urinary aldosterone was increased in D₂^–/– mice and its response to a high-sodium diet was impaired. Spirolactone normalized the blood pressure in D₂^–/– mice and the renal expression of Nox1 and Nox4, indicating that the increased blood pressure and ROS production are, in part, mediated by impaired aldosterone regulation. However, spironolactone did not normalize the excretion of 8-isoprostane and had no effect on expression of Nox2 or heme-oxygenase-2. Our results show that the D₂R is involved in the regulation of ROS production and that, by direct and indirect mechanisms, altered D₂R function may result in ROS-dependent hypertension.

Key Words: aldosterone • mineralocorticoids • genetics-animal models • hypertension, kidney

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