Role of reactive oxygen species in hyperadrenergic hypertension: biochemical, physiological, and pharmacological evidence from targeted ablation of the chromogranin a (Chga) gene.
BACKGROUND
Oxidative stress, an excessive production of reactive oxygen species (ROS) outstripping antioxidant defense mechanisms, occurs in cardiovascular pathologies, including hypertension. In the present study, we used biochemical, physiological, and pharmacological approaches to explore the role of derangements of catecholamines, ROS, and the endothelium-derived relaxing factor nitric oxide (NO(•)) in the development of a hyperadrenergic model of hereditary hypertension: targeted ablation (knockout [KO]) of chromogranin A (Chga) in the mouse.


RESULTS
Homozygous ⁻(/)⁻ Chga gene knockout (KO) mice were compared with wild-type (WT, +/+) control mice. In the KO mouse, elevations of systolic and diastolic blood pressure were accompanied by not only elevated catecholamine (norepinephrine and epinephrine) concentrations but also increased ROS (H₂O₂) and isoprostane (an index of lipid peroxidation), as well as depletion of NO(•). Renal transcript analyses implicated changes in Nox1/2, Xo/Xdh, and Sod1,2 mRNAs in ROS elevation by the KO state. KO alterations in blood pressure, catecholamines, H₂O₂, isoprostane, and NO(•) could be abrogated or even normalized (rescued) by either sympathetic outflow inhibition (with clonidine) or NADPH oxidase inhibition (with apocynin). In cultured renal podocytes, H₂O₂ production was substantially augmented by epinephrine (probably through β₂-adrenergic receptors) and modestly diminished by norepinephrine (probably through α₁-adrenergic receptors).


CONCLUSIONS
ROS appear to play a necessary role in the development of hyperadrenergic hypertension in this model, in a process mechanistically linking elevated blood pressure with catecholamine excess, renal transcriptional responses, ROS elevation, lipid peroxidation, and NO(•) depletion. Some of the changes appear to be dependent on transcription, whereas others are immediate. The cycle could be disrupted by inhibition of either sympathetic outflow or NADPH oxidase. Because common genetic variation at the human CHGA locus alters BP, the results have implications for antihypertensive treatment as well as prevention of target-organ consequences of the disease. The results document novel pathophysiological links between the adrenergic system and oxidative stress and suggest new strategies to probe the role and actions of ROS within this setting.
Gayen
Jiaur R
JR
University of California at San Diego, La Jolla, USA.
Zhang
Kuixing
K
RamachandraRao
Satish P
SP
Mahata
Manjula
M
Chen
Yuqing
Y
Kim
Hyung-Suk
HS
Naviaux
Robert K
RK
Sharma
Kumar
K
Mahata
Sushil K
SK
O'Connor
Daniel T
DT
D000098:Acetophenones / Q000494:pharmacology; D000308:Adrenocortical Hyperfunction / Q000150:complications / Q000503:physiopathology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism; D002460:Cell Line; D053379:Chromogranin A / Q000235:genetics* / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology; D028421:Isoprostanes / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D050199:Podocytes / Q000166:cytology; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000098:Acetophenones; D000959:Antihypertensive Agents; D002395:Catecholamines; D053379:Chromogranin A; D045462:Endothelium-Dependent Relaxing Factors; D004791:Enzyme Inhibitors; D028421:Isoprostanes; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C056165:acetovanillone; D006861:Hydrogen Peroxide; D003000:Clonidine