Resveratrol in the Hypothalamic Paraventricular Nucleus Attenuates Hypertension by Regulation of ROS and Neurotransmitters.

BACKGROUND: The hypothalamic paraventricular nucleus (PVN) is an important nucleus in the brain that plays a key role in regulating sympathetic nerve activity (SNA) and blood pressure. Silent mating-type information regulation 2 homolog-1 (sirtuin1, SIRT1) not only protects cardiovascular function but also reduces inflammation and oxidative stress in the periphery. However, its role in the central regulation of hypertension remains unknown. It is hypothesized that SIRT1 activation by resveratrol may reduce SNA and lower blood pressure through the regulation of intracellular reactive oxygen species (ROS) and neurotransmitters in the PVN. METHODS: The two-kidney one-clip (2K1C) method was used to induce renovascular hypertension in male Sprague-Dawley rats. Then, bilaterally injections of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 µL) or resveratrol (a SIRT1 agonist, 160 µmol/L, 0.4 µL) into rat PVN were performed for four weeks. RESULTS: PVN SIRT1 expression was lower in the hypertension group than the sham surgery (SHAM) group. Activated SIRT1 within the PVN lowered systolic blood pressure and plasma norepinephrine (NE) levels. It was found that PVN of 2K1C animals injected with resveratrol exhibited increased expression of SIRT1, copper-zinc superoxide dismutase (SOD1), and glutamic acid decarboxylase (GAD67), as well as decreased activity of nuclear factor-kappa B (NF-κB) p65 and NAD(P)H oxidase (NOX), particularly NOX4. Treatment with resveratrol also decreased expression of ROS and tyrosine hydroxylase (TH). CONCLUSION: Resveratrol within the PVN attenuates hypertension via the SIRT1/NF-κB pathway to decrease ROS and restore the balance of excitatory and inhibitory neurotransmitters.

Inhibition of Maternal c-Src Ameliorates the Male Offspring Hypertension by Suppressing Inflammation and Neurotransmitters in the Paraventricular Nucleus.

Long-term maternal salt intake induces the hypertension in offspring. Numerous studies have also indicated that high-salt diet causes the inflammation and an imbalance in neurotransmitters in the paraventricular nucleus (PVN) which increases the blood pressure and sympathetic activity. This study aimed to explore whether maternal salt intake induces hypertension in their male offspring by increasing the inflammation and changing the neurotransmitters balance in the paraventricular nucleus of offspring. This study includes two parts: Part I to explore the effect of high-salt diet on pregnant rats and the changes in inflammation and neurotransmitters in their male offspring PVN; Part II to reveal the influence on their offspring of bilateral PVN infusion of c-Src inhibitor dasatinib (DAS) in pregnant rats fed a high-salt diet. Maternal high-salt diet intake during copulation, pregnancy, and lactation impacted the offspring mean arterial pressure (MAP) and elevated the offspring PVN levels of p-Src, proinflammatory cytokines, and excitatory neurotransmitters. Bilateral PVN infusion of a c-Src inhibitor combined with maternal high-salt diets decreased MAP in the offspring. The infusion was also shown to suppress the Src-induced MAPK/NF-κB signaling pathway (p38 MAPK, JNK, Erk1/2), which attenuates inflammatory reactions. Finally, bilateral PVN infusion of the Src inhibitor in pregnant rat with high-salt diets improved the levels of inhibitory neurotransmitters in offspring PVN, which restored the excitatory-inhibitory neurotransmitter balance in male offspring. High-salt diets increase sympathetic activity and blood pressure in adult offspring, probably by activating the c-Src/MAPKs/NF-κB signaling pathway-induced inflammation. Moreover, NF-κB disrupts the downstream excitatory-inhibitory neurotransmitter balance in the PVN of male offspring.

Paraventricular Nucleus Infusion of Oligomeric Proantho Cyanidins Improves Renovascular Hypertension.

Oxidative stress plays an important role in the pathogenesis of hypertension. Oligomeric proantho cyanidins (OPC) is the main polyphenol presents in grape seed and is known for its potent antioxidant and anti-inflammatory properties. In the present study, we hypothesize that OPC can attenuate oxidative stress in the paraventricular nucleus of hypothalamus (PVN), ameliorate neurotransmitter imbalance, decrease the blood pressure and sympathetic activity in renovascular hypertensive rats. After induction of renovascular hypertension by the two-kidney one-clip (2K-1C) method, male Sprague-Dawley rats received chronic bilateral PVN infusion of OPC (20 µg/h) or vehicle via osmotic minipump for 4 weeks. We found that hypertension induced by 2K-1C was associated with the production of reactive oxygen species (ROS) in the PVN. Infusion of OPC in the PVN significantly reduced the systolic blood pressure and norepinephrine in plasma of 2K-1C rats. In addition, PVN infusion of OPC decreased the level of ROS and the expression of stress-related nicotinamide adenine dinucleotide phosphate (NADPH) oxidases subunit NOX4, increased the levels of nuclear factor E2-related factor 2 (Nrf2) and antioxidant enzyme, balanced the content of cytokines, increased expression of glutamic acid decarboxylase and decreased the expression of tyrosine hydroxylase in the PVN of 2K-1C rats. Our findings provided strong evidence that PVN infusion of OPC inhibited the progression of renovascular hypertension through its potent anti-oxidative and anti-inflammatory function in the PVN.

Chronic Infusion of Astaxanthin Into Hypothalamic Paraventricular Nucleus Modulates Cytokines and Attenuates the Renin-Angiotensin System in Spontaneously Hypertensive Rats.

ABSTRACT: Oxidative stress, the renin-angiotensin system (RAS), and inflammation are some of the mechanisms involved in the pathogenesis of hypertension. The aim of this study is to examine the protective effect of the chronic administration of astaxanthin, which is extracted from the shell of crabs and shrimps, into hypothalamic paraventricular nucleus (PVN) in spontaneously hypertensive rats. Animals were randomly assigned to 2 groups and treated with bilateral PVN infusion of astaxanthin or vehicle (artificial cerebrospinal fluid) through osmotic minipumps (Alzet Osmotic Pumps, Model 2004, 0.25 µL/h) for 4 weeks. Spontaneously hypertensive rats had higher mean arterial pressure and plasma level of norepinephrine and proinflammatory cytokine; higher PVN levels of reactive oxygen species, NOX2, NOX4, IL-1ß, IL-6, ACE, and AT1-R; and lower PVN levels of IL-10 and Cu/Zn SOD, Mn SOD, ACE2, and Mas receptors than Wistar-Kyoto rats. Our data showed that chronic administration of astaxanthin into PVN attenuated the overexpression of reactive oxygen species, NOX2, NOX4, inflammatory cytokines, and components of RAS within the PVN and suppressed hypertension. The present results revealed that astaxanthin played a role in the brain. Our findings demonstrated that astaxanthin had protective effect on hypertension by improving the balance between inflammatory cytokines and components of RAS.

Central Blockade of E-Prostanoid 3 Receptor Ameliorated Hypertension Partially by Attenuating Oxidative Stress and Inflammation in the Hypothalamic Paraventricular Nucleus of Spontaneously Hypertensive Rats.

Hypertension, as one of the major risk factors for cardiovascular disease, significantly affects human health. Prostaglandin E2 (PGE2) and the E3-class prostanoid (EP3) receptor have previously been demonstrated to modulate blood pressure and hemodynamics in various animal models of hypertension. The PGE2-evoked pressor and biochemical responses can be blocked with the EP3 receptor antagonist, L-798106 (N-[(5-bromo-2methoxyphenyl)sulfonyl]-3-[2-(2-naphthalenylmethyl) phenyl]-2-propenamide). In the hypothalamic paraventricular nucleus (PVN), sympathetic excitation can be introduced by PGE2, which can activate EP3 receptors located in the PVN. In such a case, the central knockdown of EP3 receptor can be considered as a potential therapeutic modality for hypertension management. The present study examined the efficacy of the PVN infusion of L-798106, by performing experiments on spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). The rats were administered with chronic bilateral PVN infusion of L-798106 (10 µg/day) or the vehicle for 28 days. The results indicated that the SHRs had a higher mean arterial pressure (MAP), an increased Fra-like (Fra-LI) activity in the PVN, as well as a higher expression of gp91phox, mitogen-activated protein kinase (MAPK), and proinflammatory cytokines in the PVN compared with the WKYs. Additionally, the expression of Cu/Zn-SOD in the PVN of the SHRs was reduced compared with the WKYs. The bilateral PVN infusion of L-798106 significantly reduced MAP, as well as plasma norepinephrine (NE) levels in the SHRs. It also inhibited Fra-LI activity and reduced the expression of gp91phox, proinflammatory cytokines, and MAPK, whereas it increased the expression of Cu/Zn-SOD in the PVN of SHRs. In addition, L-798106 restored the balance of the neurotransmitters in the PVN. On the whole, the findings of the present study demonstrate that the PVN blockade of EP3 receptor can ameliorate hypertension and cardiac hypertrophy partially by attenuating ROS and proinflammatory cytokines, and modulating neurotransmitters in the PVN.

Blockade of c-Src Within the Paraventricular Nucleus Attenuates Inflammatory Cytokines and Oxidative Stress in the Mechanism of the TLR4 Signal Pathway in Salt-Induced Hypertension.

Toll-like receptor 4 (TLR4) and cellular Src (c-Src) are closely associated with inflammatory cytokines and oxidative stress in hypertension, so we designed this study to explore the exact role of c-Src in the mechanism of action of the TLR4 signaling pathway in salt-induced hypertension. Salt-sensitive rats were given a high salt diet for 10 weeks to induce hypertension. This resulted in higher levels of TLR4, activated c-Src, pro-inflammatory cytokines, oxidative stress, and arterial pressure. Infusion of a TLR4 blocker into the hypothalamic paraventricular nucleus (PVN) decreased the activated c-Src, while microinjection of a c-Src inhibitor attenuated the PVN levels of nuclear factor-kappa B, pro-inflammatory cytokines, and oxidative stress. Our findings suggest that a long-term high-salt diet increases TLR4 expression in the PVN and this promotes the activation of c-Src, which upregulates the expression of pro-inflammatory cytokines and results in the overproduction of reactive oxygen species. Therefore, inhibiting central c-Src activity may be a new target for treating hypertension.

Silencing salusin ß ameliorates heart failure in aged spontaneously hypertensive rats by ROS-relative MAPK/NF-κB pathways in the paraventricular nucleus.

OBJECTIVE: Sustained hypertension is a major cause of heart failure in aging hypertensive patients. Salusin ß, a novel bioactive peptide of 20 amino acids, has been reported to participate in various cardiovascular diseases, including hypertension. We therefore hypothesized that central knockdown of salusin ß might be effective for hypertension-induced heart failure treatment. METHODS AND RESULTS: Eighteen-month-old male aged spontaneously hypertensive rats (SHR) with heart failure and WKY rats were microinjected with either a specific adenoviral vector encoding salusin ß shRNA (Ad-Sal-shRNA) or a scramble shRNA (Ad-Scr-shRNA) in the hypothalamic paraventricular nucleus (PVN) for 4 weeks. Radiotelemetry and echocardiography were used for measuring blood pressure and cardiac function, respectively. Blood samples and heart were harvested for evaluating plasma norepinephrine, tyrosine hydroxylase, and cardiac morphology, respectively. The mesenteric arteries were separated for measurement of vascular responses. The PVN was analyzed for salusin ß, proinflammatory cytokines (PICs), mitogen-activated protein kinase (MAPK), NF-κB, and reactive oxygen species (ROS) levels. Compared with normotensive rats, aging SHR with heart failure had dramatically increased salusin ß expression. Silencing salusin ß with Ad-Sal-shRNA attenuated arterial pressure and improved autonomic function, cardiac and vascular dysfunction in aging SHR with heart failure, but not in aging WKY rats. Knockdown of salusin ß significantly reduced paraventricular nucleus PICs levels, MAPK and NF-κB activity, and ROS levels in aging SHR with heart failure. CONCLUSION: These data demonstrate that in aging SHR, the heart failure that was developed during the end stage of hypertension could be ameliorated by silencing salusin ß.

Hydrogen sulfide in paraventricular nucleus attenuates blood pressure by regulating oxidative stress and inflammatory cytokines in high salt-induced hypertension.

Hydrogen sulfide (H2S) is an important gaseous signaling molecule in neuro-modulation, anti-inflammatory, anti-oxidant and anti-hypertensive effects. The paraventricular nucleus (PVN) is a major integrative nucleus in regulating BP and SNA. The aim of this study is to explore whether endogenous or exogenous H2S changed by hydroxylamine hydrochloride (HA) or GYY4137 infused in the PVN affects RSNA and MAP by regulating oxidative stress or the balance between pro-inflammatory cytokines (PICs) and anti-inflammatory cytokines in high salt-induced hypertensive rats. Male Dahl rats were fed by high-salt or normal-salt diet. At the end of the 4th week, GYY4137, HA or vehicle was microinjected into bilateral PVN for 6 weeks. The levels of MAP, HR, plasma norepinephrine (NE), reactive oxygen species (ROS), NOX2, NOX4 and IL-1ß were increased significantly in high salt-induced hypertensive rats. Higher levels of these parameters were detected in the group treated by HA, but lower levels in the GYY4137 group. The trends of H2S, CBS, IL-10 and Cu/Zn SOD were opposite to the parameters described above. These findings suggest that endogenous or exogenous H2S in the PVN attenuates sympathetic activity and hypertensive response, which are partly due to decrease of ROS and PICs within the PVN in high salt-induced hypertension.

PVN Blockade of p44/42 MAPK Pathway Attenuates Salt-induced Hypertension through Modulating Neurotransmitters and Attenuating Oxidative Stress.

The imbalance of neurotransmitters and excessive oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether blockade of p44/42 MAPK pathway in the hypothalamic paraventricular nucleus (PVN) ameliorates the development of hypertension through modulating neurotransmitters and attenuating oxidative stress. Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 6 weeks and were treated with bilateral PVN infusion of PD-98059 (0.025 µg/h), a p44/42 MAPK inhibitor, or vehicle via osmotic minipump. HS resulted in higher mean arterial pressure (MAP) and Fra-like (Fra-LI) activity, and plasma and PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. PD-98059 infusion reduced NE, TH, NOX2 and NOX4 in the PVN, and induced Cu/Zn-SOD and GAD67 in the PVN. It suggests that PVN blockade of p44/42 MAPK attenuates hypertension through modulating neurotransmitters and attenuating oxidative stress.

Chronic infusion of epigallocatechin-3-O-gallate into the hypothalamic paraventricular nucleus attenuates hypertension and sympathoexcitation by restoring neurotransmitters and cytokines.

Reactive oxygen species (ROS) in the brain are involved in the pathogenesis of hypertension. Epigallocatechin-3-O-gallate (EGCG), one of the active compounds in green tea, has anti-oxidant, anti-inflammatory and vascular protective properties. This study was designed to determine whether chronic infusion of EGCG into the hypothalamic paraventricular nucleus (PVN) attenuates ROS and sympathetic activity and delays the progression of hypertension by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs) and decreasing nuclear factor-kappa B (NF-κB) activity, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar-Kyoto (WKY) rats and SHR received bilateral PVN infusion of EGCG (20µg/h) or vehicle via osmotic minipumps for 4 weeks. SHR showed higher mean arterial pressure, plasma proinflammatory cytokines and circulating norepinephrine (NE) levels compared with WKY rats. SHR also had higher PVN levels of the subunit of NAD(P)H oxidase (gp91phox), ROS, tyrosine hydroxylase, and PICs; increased NF-κB activity; and lower PVN levels of interleukin-10 (IL-10) and 67kDa isoform of glutamate decarboxylase (GAD67) than WKY rats. PVN infusion of EGCG attenuated all these changes in SHR. These findings suggest that SHR have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN. Chronic inhibition of ROS in the PVN restores the balance of neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive response and sympathetic activity.

Oral CoQ10 attenuates high salt-induced hypertension by restoring neurotransmitters and cytokines in the hypothalamic paraventricular nucleus.

High salt intake leads to an increase in some proinflammatory cytokines and neurotransmitters involved in the pathogenesis of hypertension. The purpose of this work was to know if oral administration of anti-oxidant and free-radical scavenger CoQ10 may attenuate high salt-induced hypertension via regulating neurotransmitters and cytokines in the hypothalamic paraventricular nucleus (PVN). Adult male Sprague-Dawley (SD) rats were fed with a normal salt diet (NS, 0.3% NaCl) or a high salt diet (HS, 8% NaCl) for 15 weeks to induce hypertension. These rats received CoQ10 (10 mg/kg/day) dissolved in olive oil was given by gavage (10 mg/kg/day) for 15 weeks. HS resulted in higher mean arterial pressure (MAP) and the sympathetic nerve activity (RSNA). These HS rats had higher PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), interleukin (IL)-1ß, NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), IL-10, copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. CoQ10 supplementation reduced NE, TH, IL-1ß, NOX2 and NOX4 in the PVN, and induced IL-10, Cu/Zn-SOD and GAD67 in the PVN. These findings suggest that CoQ10 supplementation restores neurotransmitters and cytokines in the PVN, thereby attenuating high salt-induced hypertension.

Paraventricular Nucleus Infusion of Epigallocatechin-3-O-Gallate Improves Renovascular Hypertension.

Oxidative stress plays an important role in the pathogenesis of hypertension. Epigallocatechin-3-O-gallate (EGCG) is the main polyphenol present in green tea and is known for its potent antioxidant and anti-inflammatory properties. In the present study, we hypothesize that EGCG attenuates oxidative stress in the paraventricular nucleus of hypothalamus (PVN), thereby decreasing the blood pressure and sympathetic activity in renovascular hypertensive rats. After renovascular hypertension was induced in male Sprague-Dawley rats by the two-kidney one-clip (2K-1C) method, the rats received bilateral PVN infusion of EGCG (20 µg/h) or vehicle via osmotic minipump for 4 weeks. Our results were shown as follows: (1) Hypertension induced by 2K-1C was associated with the production of reactive oxygen species in the PVN; (2) chronic infusion of EGCG in the PVN decreased stress-related NAD(P)H oxidase subunit gp91(phox) and NOX-4 and increased the activity of antioxidant enzymes (SOD-1), also balanced the content of cytokines (IL-1ß, IL-6, IL-10 and MCP-1) in the PVN, and attenuated the level of norepinephrine in plasma of 2K-1C rats. Our findings provide strong evidence that PVN infusion of EGCG inhibited renovascular hypertension progression through its potent anti-oxidative and anti-inflammatory activity in the PVN.

Targeting Interleukin-1 beta to Suppress Sympathoexcitation in Hypothalamic Paraventricular Nucleus in Dahl Salt-Sensitive Hypertensive Rats.

Findings from our laboratory indicate that expressions of some proinflammatory cytokines such as tumor necrosis factor, interleukin-6 and oxidative stress responses are increased in the hypothalamic paraventricular nucleus (PVN) and contribute to the progression of salt-sensitive hypertension. In this study, we determined whether interleukin-1 beta (IL-1ß) activation within the PVN contributes to sympathoexcitation during development of salt-dependent hypertension. Eight-week-old male Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8 % NaCl) or a normal-salt diet (NS, 0.3 % NaCl) for 6 weeks, and all rats were treated with bilateral PVN injection of gevokizumab (IL-1ß inhibitor, 1 µL of 10 µg) or vehicle once a week. The mean arterial pressure (MAP), heart rate (HR) and plasma norepinephrine (NE) were significantly increased in high-salt-fed rats. In addition, rats with high-salt diet had higher levels of NOX-2, NOX-4 [subunits of NAD (P) H oxidase], IL-1ß, NLRP3 (NOD-like receptor family pyrin domain containing 3), Fra-LI (an indicator of chronic neuronal activation) and lower levels of IL-10 in the PVN than normal-diet rats. Bilateral PVN injection of gevokizumab decreased MAP, HR and NE, attenuated the levels of oxidative stress and restored the balance of cytokines. These findings suggest that IL-1ß activation in the PVN plays a role in salt-sensitive hypertension.

NF-κB Blockade in Hypothalamic Paraventricular Nucleus Inhibits High-Salt-Induced Hypertension Through NLRP3 and Caspase-1.

High-salt-induced inflammation and oxidative stress in the hypothalamic paraventricular nucleus (PVN) contribute to the pathogenesis of salt-sensitive hypertension. In this study, we hypothesized that chronic inhibition of nuclear factor-κB (NF-κB) activity in the PVN delays the progression of hypertension by upregulating anti-inflammatory cytokines, reducing NLRP3 (NOD-like receptor family pyrin domain containing 3) and IL-1ß and attenuating p-IKKß, NF-κB p65 activity and NAD(P)H oxidase in the PVN of salt-sensitive hypertensive rats. Dahl salt-sensitive rats received a high-salt diet (HS, 8 % NaCl) or a normal-salt diet (NS, 0.3 % NaCl) for 6 weeks and were treated with bilateral PVN infusion with either vehicle or pyrrolidine dithiocarbamate (PDTC, 5 µg/h), a NF-κB inhibitor via osmotic minipump. The mean arterial pressure and plasma levels of norepinephrine (NE) and epinephrine (EPI) were significantly increased in high-salt-fed rats. In addition, rats with high-salt diet had higher levels of p-IKKß, NF-κB p65 activity, Fra-like (Fra-LI) activity (an indicator of chronic neuronal activation), NOX-4 (subunits of NAD(P)H oxidase), NLRP3 and IL-1ß, and lower levels of IL-10 in the PVN than normal diet rats. Bilateral PVN infusions of PDTC attenuated these high-salt-induced changes. These findings suggest that high-salt-induced NF-κB activation in the PVN caused hypertension via sympathoexcitation, which are associated with the increases of NLRP3, IL-1ß and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates NLRP3, IL-1ß and oxidative stress in the PVN and thereby attenuates hypertension.

Blockade of Salusin-ß in Hypothalamic Paraventricular Nucleus Attenuates Hypertension and Cardiac Hypertrophy in Salt-induced Hypertensive Rats.

Salusin-ß, a multifunctional bioactive peptide, is considered as a promising candidate biomarker for predicting cardiovascular diseases. This study was designed to determine whether inhibition of salusin-ß in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by restoring neurotransmitters and cytokines. Male Sprague Dawley rats were fed with a normal salt diet (NS, 0.3%) or a high salt diet (HS, 8%) for 8 weeks to induce hypertension. Then, these rats received bilateral PVN infusion of a specific salusin-ß blocker, antisalusin-ß IgG (SIgG), or control IgG (CIgG) for 2 weeks. HS rats exhibited higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/bodyweight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and messenger RNA levels of cardiac atrial natriuretic peptide (ANP), and ß-myosin heavy chain. Compared with NS rats, HS rats had higher levels of glutamate, norepinephrine, tyrosine hydroxylase, proinflammatory cytokines, and lower levels of gamma-aminobutyric acid, interleukin 10, and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN, and higher plasma levels of proinflammatory cytokines. Chronic PVN infusion of SIgG attenuated all these changes in HS rats. Our findings suggest that HS rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between proinflammatory and anti-inflammatory cytokines in the PVN; and chronic inhibition of salusin-ß in the PVN restores neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive responses and cardiac hypertrophy.

Interaction between AT1 receptor and NF-κB in hypothalamic paraventricular nucleus contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure.

Angiotensin II type 1 receptor (AT1-R) and nuclear factor-kappaB (NF-κB) in the paraventricular nucleus (PVN) play important roles in heart failure (HF); however, the central mechanisms by which AT1-R and NF-κB contribute to sympathoexcitation in HF are yet unclear. In this study, we determined whether interaction between AT1-R and NF-κB in the PVN modulates neurotransmitters and contributes to NAD(P)H oxidase-dependent oxidative stress and sympathoexcitation in HF. Rats were implanted with bilateral PVN cannulae and subjected to coronary artery ligation or sham surgery (SHAM). Subsequently, animals were treated for 4 weeks through bilateral PVN infusion with either vehicle or losartan (LOS, 10 µg/h), an AT1-R antagonist; or pyrrolidine dithiocarbamate (PDTC, 5 µg/h), a NF-κB inhibitor via osmotic minipump. Myocardial infarction (MI) rats had higher levels of glutamate (Glu), norepinephrine (NE) and NF-κB p65 activity, lower levels of gamma-aminobutyric acid (GABA), and more positive neurons for phosphorylated IKKß and gp91(phox) (a subunit of NAD(P)H oxidase) in the PVN when compared to SHAM rats. MI rats also had higher levels of renal sympathetic nerve activity (RSNA) and plasma proinflammatory cytokines (PICs), NE and epinephrine. PVN infusions of LOS or PDTC attenuated the decreases in GABA and the increases in gp91(phox), NF-κB activity, Glu and NE, in the PVN of HF rats. PVN infusions of LOS or PDTC also attenuated the increases in RSNA and plasma PICs, NE and epinephrine in MI rats. These findings suggest that interaction between AT1 receptor and NF-κB in the PVN contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure.