oxygen species (ROS) produced in the neuronal renal and vascular systems not only influence cardiovascular physiology but are also strongly implicated in pathological signaling leading to hypertension. mechanisms have been established between ROS sources. Studies published in over the last few years are the focus of this review and they provide a framework with which to consider the functions of Nox enzymes in neuronal renal and vascular hypertensive mechanisms as well as cardiac remodeling and their associations with other ROS-generating systems. Neuronal ROS in hypertension Redox signaling in the central nervous system (CNS) is usually well recognized in neuronal control of blood pressure (BP) as well as in response to Angiotensin II (AngII) and aldosterone which are linked to ROS-dependent hypertension. Recently new functions for ROS have been described in the hypothalamus and brain stem nucleus tractus solitarius (NTS) subfornical organ (SFO) rostral ventrolateral medulla (RVLM) and area postrema (AP) (Physique 1). Physique 1 Neuronal NADPH oxidase-dependent ROS involved in central regulation of hypertension Several studies suggest that Nox are a primary source of superoxide (O2.?) in AngII-induced neuronal activity. In primary neuronal cultures from the hypothalamus and brain stem losartan an angiotensin type1 receptor (AT1R) antagonist gp91 ds-tat a peptide inhibitor of Nox2 and Tempol a superoxide dismutase (SOD) mimetic attenuate AngII-induced ROS production and reduce neuronal firing rate.1 Hypothalamic Nox Ritonavir is also implicated in norepinephrine secretion2 and renal sympathetic nerve activity3 of phenol-induced renal injury and Ritonavir Dahl salt-sensitive (DHSS) hypertensive rat models. NADPH oxidase activity and expression of Nox2 as well as its subunits p22phox and p47phox increase in these animals and this as well as BP is usually reversed by treatment with Tempol polyethylene glycolated SOD (PEG-SOD) or the nonspecific Nox inhibitor diphenylene iodonium Ritonavir (DPI).2 3 Systemic AngII infusion induces hypertension by increasing O2.? in the SFO a primary brain sensor for blood-borne AngII. Lob et al4 reported that selective deletion of SOD3 in the SFO specifically increases AngII-induced vascular T-cell and leukocyte infiltration in addition to increasing sympathetic modulation of heart rate BP and vascular O2.?. These observations suggest that ROS in the CNS influence peripheral organs in hypertension. Such effects seem to be specific for individual Nox homologues. Peterson et al5 showed that Nox2 Ritonavir and Nox4 mediate AngII-mediated ROS production in the SFO but although both are necessary for the vasopressor response to AngII only Nox2 participates in the dipsogenic response.5 In rats subjected to coronary artery ligation four-week intracerbroventricular (ICV) infusion of the ANPEP mineralocorticoid receptor (MR) antagonist RU28318 reduces AT1R p47phox and Nox2 expression as well as Nox-dependent ROS in the PVN with a concomitant reduction in plasma norepinephrine levels.6 This study suggests that cross talk exists between MR and AngII ROS-dependent signaling in the PVN (Physique 1).6 ROS signaling to hypertension is also implicated in the NTS. Compared to Wistar-Kyoto (WKY) rats stroke-prone spontaneously hypertensive rats (SHR) exhibit elevated activity of Rac1 a regulator of Nox1 and Nox2 in the NTS and adenoviral-mediated inhibition of Rac1 or expression of CuZnSOD decreases BP heart rate and urinary norepinephrine Ritonavir excretion.7 Additionally in the dorsomedial NTS (dmNTS) AngII Ritonavir stimulates Nox activity and modulates Ca2+ current a response that is blocked by gp91 ds-tat and apocynin a Nox subunit assembly inhibitor.8 Moreover in dmNTS neurons of mice lacking Nox2 AngII fails to elevate ROS or to potentiate L-type Ca2+ current.8 Short-term infusion of AngII elevates BP heart rate and renal sympathetic nerve activity in parallel with upregulated expression of Nox2 p22phox p47phox and p67phox in the RVLM9 a brain stem site that maintains sympathetic vasomotor tone. Additionally in SHR and AngII-infused WKY rats mitochondrial dysfunction in the RVLM and the subsequent production of mitochondrial-localized ROS play a critical role in cardiovascular pathology.10 Coenzyme Q10 treatment restores electron transport.