Oxidative stress, an excessive production of reactive oxygen species (ROS) outstripping antioxidant defense mechanisms, occurs in cardiovascular pathologies including hypertension. Here, we used biochemical, physiological, and pharmacological approaches to explore the role of derangements of catecholamines, ROS, and NO• in the development of a hyper-adrenergic model of hereditary hypertension: targeted ablation (knockout, KO) of chromogranin A (Chga) in the mouse.
Methods and Results
Homozygous (−/−) Chga gene knockout (KO) mice were compared to wild-type (WT, +/+) controls. In the KO mouse, elevations of systolic and diastolic BP 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 BP, 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 (likely through b2-adrenergic receptors) and modestly diminished by norepinephrine (likely through a1-adrenergic receptors).
ROS seem to play a necessary role in the development of hyper-adrenergic hypertension in this model, in a process mechanistically linking elevated BP with catecholamine excess, renal transcriptional responses, ROS elevation, lipid peroxidation, and NO• depletion. Some of the changes seem to be dependent on transcription, while others are immediate. The cycle could be disrupted by inhibition of either sympathetic outflow or NADPH oxidase. Since 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 andc oxidative stress, and suggest new strategies to probe the role and actions of ROS within this setting.