Reactive Oxygen Species–Dependent Hypertension in Dopamine D 2 Receptor–Deficient Mice
- 1 March 2007
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 49 (3), 672-678
- https://doi.org/10.1161/01.hyp.0000254486.00883.3d
Abstract
Dysfunction of D 2 -like receptors has been reported in essential hypertension. Disruption of D 2 R in mice (D 2 −/− ) results in high blood pressure, and several D 2 R polymorphisms are associated with decreased D 2 R expression. Because D 2 R agonists have antioxidant activity, we hypothesized that increased blood pressure in D 2 −/− is related to increased oxidative stress. D 2 −/− 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 D 2 R 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 D 2 −/− mice. Because D 2 Rs 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 D 2 −/− mice and its response to a high-sodium diet was impaired. Spirolactone normalized the blood pressure in D 2 −/− 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 D 2 R is involved in the regulation of ROS production and that, by direct and indirect mechanisms, altered D 2 R function may result in ROS-dependent hypertension.Keywords
This publication has 36 references indexed in Scilit:
- Angiotensin-II Type 1 Receptor–Mediated Hypertension in D 4 Dopamine Receptor–Deficient MiceHypertension, 2006
- D5dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressureAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2006
- Functional genomics of the dopaminergic system in hypertensionPhysiological Genomics, 2004
- Possible Contributions of Reactive Oxygen Species and Mitogen-Activated Protein Kinase to Renal Injury in Aldosterone/Salt-Induced Hypertensive RatsHypertension, 2004
- Reactive Oxygen Species in the VasculatureHypertension, 2003
- Polymorphism in exon 6 of the dopamine D2 receptor gene (DRD2) is associated with elevated blood pressure and personality disorders in menJournal of Human Hypertension, 2001
- An Extreme-Sib-Pair Genome Scan for Genes Regulating Blood PressureAmerican Journal of Human Genetics, 1999
- Increased oxidative stress in renal proximal tubules of the spontaneously hypertensive ratJournal of Hypertension, 1998
- Attenuation of Oxidative Neuronal Necrosis by a Dopamine D1 Agonist in Mouse Cortical Cell CulturesExperimental Neurology, 1997
- Effects of Metoclopramide and Bromocriptine on the Renin-Angiotensin-Aldosterone System in ManJCI Insight, 1979