Blockade of Endogenous Angiotensin-(1–7) in Hypothalamic Paraventricular Nucleus Attenuates High Salt-Induced Sympathoexcitation and Hypertension

Abstract

Angiotensin (Ang)-(1-7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1-7) in the hypothalamic paraventricular nucleus (PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines (PICs) and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt (8% NaCl) or a normal salt diet (0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1-7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma norepinephrine (NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91 phox expression and superoxide production in the PVN. Microinjection of A-779 (3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1-7) in the PVN, through modulation of PICs and oxidative stress.

Angiotensin Type 1 Receptors and Superoxide Anion Production in Hypothalamic Paraventricular Nucleus Contribute to Capsaicin-Induced Excitatory Renal Reflex and Sympathetic Activation

“…Tempol mimics the role of superoxide dismutase in scavenging superoxide anions [41], and NAC is another antioxidant with superoxide scavenging properties [42]. Ang II is an important stimulus for superoxide anion production in the brain [43] and vasculature [44], and superoxide anion production in the PVN plays a role in the sympathetic activation in hypertension [45]. Furthermore, our previous study has shown that superoxide anions in the PVN contribute to the enhanced CSAR in chronic heart failure [25], so we further investigated whether this mechanism is involved in the ERR.…”

Chemical Stimulation of Renal Tissue Induces Sympathetic Activation and a Pressor Response via the Paraventricular Nucleus in Rats

“…Neuroanatomical evidence has shown that renal afferent activity is closely connected with various sites in the brain associated with sympathetic outflow and cardiovascular regulation, including the nucleus of the solitary tract, rostral ventrolateral medulla, PVN, subfornical organ, and preoptic area [10]. The PVN is important in the control of cardiovascular activity and sympathetic outflow via its descending projections to the rostral ventrolateral medulla and intermediolateral column of spinal cord [40][41][42][43]. Stimulation of the renal afferent nerve altered the activity of 197 neurons in 407 neurons in the PVN, most of which were excited, but 8% were suppressed [44].…”

Na+/K+-ATPase Alpha 2 Isoform Elicits Rac1-Dependent Oxidative Stress and TLR4-Induced Inflammation in the Hypothalamic Paraventricular Nucleus in High Salt-Induced Hypertension

“…Additionally, long-term salt intake elevates reactive oxygen species (ROS) accumulation in the neurons, blood vessels, and kidneys, which takes part in the metabolic disorders and cardiovascular diseases process. Previous studies have also found that a high salt diet exacerbates oxidative stress and the inflammatory responses in the paraventricular nucleus (PVN) of the hypothalamus, an important area for the regulation of cardiovascular activity and blood pressure [ 20 , 21 , 22 , 23 , 24 , 25 ]. Ras-related C3 botulinum toxin substrate 1 (Rac1) is a vital NAD(P)H subunit that promotes ROS production.…”