Inhibition of Rac1-Derived Reactive Oxygen Species in Nucleus Tractus Solitarius Decreases Blood Pressure and Heart Rate in Stroke-Prone Spontaneously Hypertensive Rats

Abstract

Abstract-Reactive oxygen species (ROS) in the brain are thought to contribute to the neuropathogenesis of hypertension by enhancing sympathetic nervous system activity. The nucleus tractus solitarius (NTS), which receives afferent input from baroreceptors, has an important role in cardiovascular regulation. reduced nicotinamide-adenine dinucleotide phosphate oxidase is thought to be a major source of ROS in the NTS. Rac1 is a small G protein and a key component of reduced nicotinamide-adenine dinucleotide phosphate oxidase. The role of Rac1-derived ROS in the NTS in cardiovascular regulation of hypertension is unknown. Therefore, we examined whether inhibition of Rac1 in the NTS decreases ROS generation, thereby reducing blood pressure in stroke-prone spontaneously hypertensive rats (SHRSPs).The basal Rac1 activity level in the NTS was greater in SHRSPs than in Wistar-Kyoto rats. Inhibition of Rac1, induced by transfecting adenovirus vectors encoding dominant-negative Rac1 into the NTS, decreased blood pressure, heart rate, and urinary norepinephrine excretion in SHRSPs but not in Wistar-Kyoto rats. Inhibition of Rac1 also reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and ROS generation. In addition, Cu/Zn-superoxide dismutase activity in the NTS of SHRSPs was decreased compared with that of Wistar-Kyoto rats, despite the increased ROS generation. Overexpression of Cu/Zn-superoxide dismutase in the NTS decreased blood pressure and heart rate in SHRSPs. These results indicate that the activation of Rac1 in the NTS generates ROS via reduced nicotinamide-adenine dinucleotide phosphate oxidase in SHRSPs, and this mechanism might be important for the neuropathogenesis of hypertension in SHRSPs. Key Words: blood pressure Ⅲ heart rate Ⅲ sympathetic nervous system Ⅲ hypertension Ⅲ brain T here is accumulating evidence that reactive oxygen species (ROS) in the cardiovascular regulatory nuclei in the brain have a crucial role in blood pressure regulation in hypertension via modulating the sympathetic nervous system. 1-5 Reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase is a major source of ROS in hypertension 6 and has a critical role in generating ROS in the brain. 2,5,7 Rac1 is a small G protein that is an important signaling molecule involved in integrating intracellular transduction pathways toward NAD(P)H oxidase activation. 2,8,9 Rac1 requires lipid modifications to migrate from the cytosol to the plasma membrane, which is a necessary step for activating the ROSgenerating NAD(P)H oxidase enzyme system. 8,9 The nucleus tractus solitarius (NTS) in the brain stem has an important role in cardiovascular regulation. 10 -16 The NTS receives afferent input from baroreceptors and chemoreceptors 12 and has reciprocal interconnections with other nuclei involved in central autonomic regulation. 17 In addition, the essential NAD(P)H oxidase subunit gp91 phox is present in somatodendritic and axonal profiles that contain angiotensin II (Ang II) subtype 1 receptors in the NTS, and Ang I...

Olmesartan reduces oxidative stress in the brain of stroke-prone spontaneously hypertensive rats assessed by an in vivo ESR method

“…It is possible, however, that olmesartan affects the brain, thereby inhibiting the sympathetic nervous system, at least in part, by reducing oxidative stress in the autonomic nuclei, such as the paraventricular nucleus of the hypothalamus, nucleus tractus solitarus 39 and RVLM. 3,5,13,16 We previously showed that increased oxidative stress in the RVLM is involved in the neural mechanisms of hypertension in SHRSP. 13 Angiotensin II (Ang II) binds AT1 receptors, then activates the NAD(P)H oxidase/Rac1 pathway, producing superoxide in the brain.…”

“…Urinary NE concentration was measured by high-performance liquid chromatography to calculate urinary NE excretion as a marker of sympathetic nervous system activity. 13,14,16 NADPH oxidase activity Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was evaluated using lucigenin chemiluminescence as described elsewhere, 25 in membrane fraction proteins. Briefly, a deeply anesthetized rat (sodium pentobarbital, 75 mg kg À1 , intraperitoneal) was perfused transcardially with 200 ml chilled saline.…”

“…Luminescence measurements were performed as previously described. 16 Data were expressed as relative light units per minute per microgram protein.…”

“…[6][7][8][9][10] Oxidative stress in the brain increases blood pressure through activation of the sympathetic nervous system. [11][12][13][14] The major source of reactive oxygen species (ROS) is nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, 12,15,16 which is activated by AT1 receptor stimulation. AT1 receptor expression levels in the brain, such as in the RVLM, are upregulated in hypertensive animal models compared with normotensive controls.…”

Redox Control of Renal Function and Hypertension

“…In salt-loaded DSS rats, administration of intracerebroventricular tempol (SOD-mimetic) and DPI reversed increased systemic arterial pressure, SNS activity, and heart rate (73). Furthermore, inhibition of Rac1-derived ROS in nucleus tractus solitarius decreased blood pressure and heart rate in stroke-prone SHRs (236). The antioxidant adrenomedullin was shown to inhibit SNS-induced hypertension in salt-loaded mice (74).…”