Inhibition Of Sympathetic Nervous System Research Articles

Peripheral Sympathectomy Alters Neuroinflammatory and Microglial Responses to Sleep Fragmentation in Female Mice

Sleep loss, either induced by obstructive sleep apnea or other forms of sleep dysfunction, induces an inflammatory response, as commonly measured by increased circulating levels of pro-inflammatory cytokines. Increased catecholamines from sympathetic nervous system (SNS) activation regulates this peripheral inflammation. However, the role that catecholamines play in mediating neuroinflammation from sleep perturbations is undescribed. The aims of this study were to determine (i) the effect of peripheral SNS inhibition upon neuroinflammatory responses to sleep fragmentation (SF) and (ii) whether homeostasis can be restored after 1 week of recovery sleep. We measured gene expression levels of pro- and anti-inflammatory cytokines and microglial activity in brain (prefrontal cortex, hippocampus and hypothalamus) of female mice that were subjected to acute SF for 24 hours, chronic SF for 8 weeks, or 7 days of recovery after chronic SF. In each experiment, SF and control mice were peripherally sympathectomized with 6-hydroxydopamine (6-OHDA) or injected with vehicle. SF elevated cytokine mRNA expression in brain and increased microglial density and cell area in some regions. In addition, chronic SF promoted hyper-ramification in resting microglia upon exposure to chronic, but not acute, SF. Effects of chronic SF were more pronounced than acute SF, and 1 week of recovery was not sufficient to alleviate neuroinflammation. Importantly, 6-OHDA treatment significantly alleviated SF-induced inflammation and microglial responses. This study provides evidence of SNS regulation of neural inflammation from SF, suggesting a potential role for therapeutics that could mitigate neuroinflammatory responses to sleep dysfunction.

INDY as a Therapeutic Target for Cardio-Metabolic Disease

Decreased expression of the plasma membrane citrate transporter INDY (acronym I’m Not Dead, Yet) promotes longevity and protects from high-fat diet- and aging-induced metabolic derangements. Preventing citrate import into hepatocytes by different strategies can reduce hepatic triglyceride accumulation and improve hepatic insulin sensitivity, even in the absence of effects on body composition. These beneficial effects likely derive from decreased hepatic de novo fatty acid biosynthesis as a result of reduced cytoplasmic citrate levels. While in vivo and in vitro studies show that inhibition of INDY prevents intracellular lipid accumulation, body weight is not affected by organ-specific INDY inhibition. Besides these beneficial metabolic effects, INDY inhibition may also improve blood pressure control through sympathetic nervous system inhibition, partly via reduced peripheral catecholamine synthesis. These effects make INDY a promising candidate with bidirectional benefits for improving both metabolic disease and blood pressure control.

Chemical sympathectomy reduces peripheral inflammatory responses to acute and chronic sleep fragmentation.

Sleep loss contributes to the development of cardiovascular, metabolic, and neurological disorders by promoting a systemic proinflammatory phenotype. The neuroendocrine-immune mechanisms contributing to such pathologies are poorly understood. The sympathetic nervous system (SNS) regulates immunity and is often activated following sleep disturbances. The aims of this study were to determine 1) the effect of SNS inhibition on inflammatory responses to sleep fragmentation (SF) and 2) whether homeostasis can be restored after 1 wk of recovery sleep. We measured stress responses (norepinephrine and corticosterone), gene expression levels of pro- and anti-inflammatory cytokines in peripheral (heart, liver, and spleen) tissues, and protein levels of cytokines and chemokines in serum of female mice that were subjected to acute SF for 24 h, chronic SF for 8 wk, or 7 days of recovery after chronic SF. In each experiment, SF and control mice were chemically sympathectomized with 6-hydroxydopamine (6-OHDA) or injected with vehicle. Both acute and chronic SF elevated mRNA and protein levels of cytokines in peripheral tissues. Changes in inflammatory responses mirrored stress-axes activation, with increased corticosterone and norepinephrine in SF mice. 6-OHDA treatment significantly alleviated SF-induced inflammation, thus providing evidence of SNS regulation of peripheral inflammation from SF. Effects of chronic SF were more severe than acute SF, and 1 wk of recovery from SF sufficiently alleviated peripheral inflammatory responses but not NE responses.

β-Adrenergic Blocker, Carvedilol, Abolishes Ameliorating Actions of Adipose-Derived Stem Cell Sheets on Cardiac Dysfunction and Remodeling After Myocardial Infarction.

Treatment of myocardial infarction (MI) includes inhibition of the sympathetic nervous system (SNS). Cell-based therapy using adipose-derived stem cells (ASCs) has emerged as a novel therapeutic approach to treat heart failure in MI. The purpose of this study was to determine whether a combination of ASC transplantation and SNS inhibition synergistically improves cardiac functions after MI.Methods and Results:ASCs were isolated from fat tissues of Lewis rats. In in vitro studies using cultured ASC cells, mRNA levels of angiogenic factors under normoxia or hypoxia, and the effects of norepinephrine and a β-blocker, carvedilol, on the mRNA levels were determined. Hypoxia increased vascular endothelial growth factor (VEGF) mRNA in ASCs. Norepinephrine further increased VEGF mRNA; this effect was unaffected by carvedilol. VEGF promoted VEGF receptor phosphorylation and tube formation of human umbilical vein endothelial cells, which were inhibited by carvedilol. In in vivo studies using a rat MI model, transplanted ASC sheets improved contractile functions of MI hearts; they also facilitated neovascularization and suppressed fibrosis after MI. These beneficial effects of ASC sheets were abolished by carvedilol. The effects of ASC sheets and carvedilol on MI heart functions were confirmed by Langendorff perfusion experiments using isolated hearts. ASC sheets prevented cardiac dysfunctions and remodeling after MI in a rat model via VEGF secretion. Inhibition of VEGF effects by carvedilol abolished their beneficial effects.

The application of dexmedetomidine in local anesthesia

Background Dexmedetomidine(Dex) is a highly selective agonist of α2 adrenergic receptors. It provides multifacet actions, including sedation, analgesia, anxiolysis, and inhibition of sympathetic nervous system, through activating α2 adrenergic receptors. Because of its ourstanding pharmacological properties, it has been widely used in both general and local anesthesia. Objective To review the applition of Dex for local anesthesia. Content In comparison to general anesthesia, local anesthesia, including intrathecal anesthesia and nerve blocking, has advantages in both costs and feasibility. As patients are awake during local anesthesia and operation, sedatives and tranquilizers become necessary to mitigate fear and anxiety. As a sedative, Dex relieves anxiety, but has minor inhibition of respiration, leading to minimal alterations in hemodynamic parameters. As a tranquilizer, Dex does not directly affect GABAergic synaptic transmission, and promotes wakefulness during anesthesia, facilitating cooperation of patients with surgeons. The application of ultrasound-assisted imaging techniques in nerve blocking with anesthetics improves the localization and simplifies the procedures. Local administration of Dex with anesthetics for nerve blocking and intrathecal anesthesia prolongs the effects of anesthetics through various mechanisms. Because the above-mentioned advantages, Dex has also been used in pediatric anesthesia. Trend Dex is an ideal adjuvant drug for local anesthesia which provides adequate sedation and anxiolysis, and prolongs effects of anesthetics, but with minor adverse effects on hemodynamics and respiration during operations. Key words: Dexmedetomidine; Regional anesthesia; Nerve block

The metabolic syndrome in mice overexpressing neuropeptide Y in noradrenergic neurons.

A gain-of-function polymorphism in human neuropeptide Y (NPY) gene (rs16139) associates with metabolic disorders and earlier onset of type 2 diabetes (T2D). Similarly, mice overexpressing NPY in noradrenergic neurons (OE-NPYDBH) display obesity and impaired glucose metabolism. In this study, the metabolic syndrome-like phenotype was characterized and mechanisms of impaired hepatic fatty acid, cholesterol and glucose metabolism in pre-obese (2-month-old) and obese (4-7-month-old) OE-NPYDBH mice were elucidated. Susceptibility to T2D was assessed by subjecting mice to high caloric diet combined with low-dose streptozotocin. Contribution of hepatic Y1-receptor to the phenotype was studied using chronic treatment with an Y1-receptor antagonist, BIBO3304. Obese OE-NPYDBH mice displayed hepatosteatosis and hypercholesterolemia preceded by decreased fatty acid oxidation and accelerated cholesterol synthesis. Hyperinsulinemia in early obese state inhibited pyruvate- and glucose-induced hyperglycemia, and deterioration of glucose metabolism of OE-NPYDBH mice developed with aging. Furthermore, streptozotocin induced T2D only in OE-NPYDBH mice. Hepatic inflammation was not morphologically visible, but upregulated hepatic anti-inflammatory pathways and increased 8-isoprostane combined with increased serum resistin and decreased interleukin 10 pointed to increased NPY-induced oxidative stress that may predispose OE-NPYDBH mice to insulin resistance. Chronic treatment with BIBO3304 did not improve the metabolic status of OE-NPYDBH mice. Instead, downregulation of beta-1-adrenoceptors suggests indirect actions of NPY via inhibition of sympathetic nervous system. In conclusion, changes in hepatic fatty acid, cholesterol and glucose metabolism favoring energy storage contribute to the development of NPY-induced metabolic syndrome, and the effect is likely mediated by changes in sympathetic nervous system activity.

Therapeutic options of Angiotensin Receptor Neprilysin inhibitors (ARNis) in chronic heart failure with reduced ejection fraction: Beyond RAAS and sympathetic nervous system inhibition

In heart failure, in addition to the renin–angiotensin–aldosterone system and sympathetic nervous system, the natriuretic peptide (NP) system plays a fundamental role among compensating mechanisms. The NPs undergo rapid enzymatic degradation that limits their vasorelaxant, natriuretic, and diuretic actions. Degradation of NPs is partially due to the action of neprilysin, which is a membrane-bound endopeptidase found in many tissues. This article summarizes recent findings on a new natriuretic peptide-enhancing drug and their implication for future pharmacological treatment of patients suffering from heart failure with reduced ejection fraction.

Blocking Sympathetic Nervous System Reverses Partially Stroke-Induced Immunosuppression but does not Aggravate Functional Outcome After Experimental Stroke in Rats.

Stoke results in activation of the sympathetic nervous system (SNS), inducing systemic immunosuppression. However, the potential mechanisms underlying stroke-induced immunosuppression remain unclear. Here, we determined the SNS effects on functional outcome and explored the interactions among SNS, β-arrestin2 and nuclear factor-κB (NF-κB) after experimental stroke in rats. In the current study, stroke was induced by a transient middle cerebral artery occlusion (MCAO) in rats, and SNS activity was inhibited by intraperitoneal injection of 6-hydroxydopamine HBr (6-OHDA). 7.0T Micro-MRI and Longa score were employed to assess the functional outcome after stroke. Flow cytometry and ELISA assay were used to measure the expression of MHC class II, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Western blot was conducted to analyze β-arrestin2 and NF-κB protein expression levels after experimental stroke. We found significantly increased infarct volumes and functional impairment after MCAO at different post-surgery time points, which were not aggravated by 6-OHDA treatment. SNS blockade partially reversed the expression of MHC class II after stroke over time, as well as TNF-α and IFN-γ levels in lipopolysaccharide-stimulated macrophages in vitro. Treatment of MCAO rats with SNS-inhibitor significantly diminished NF-κB activation and enhanced β-arrestin2 expression after stroke. This study suggests that pharmacological SNS inhibition dose not aggravate functional outcome after stroke. Stroke-induced immunosuppression may be involved in the SNS-β-arrestin2-NF-κB pathway.

Effects of transcutaneous electrical nerve stimulation (TENS) on arterial stiffness and blood pressure in resistant hypertensive individuals: study protocol for a randomized controlled trial.

BackgroundResistant hypertension (RH) treatment requires an adequate and intense therapeutic approach. However, the results are not always satisfactory despite intensive treatment. Of the different pathophysiological mechanisms involved in the pathogenesis of RH, sympathetic overstimulation and therapies that block the sympathetic system have been widely studied. These approaches, however, are invasive and expensive. Another possible approach is by transcutaneous electrical nerve stimulation (TENS), a noninvasive method that modulates activity by using low-frequency transcutaneous electrical stimulation to inhibit primary afferent pathways. Thus, the current study will evaluate the effect of applying TENS in the cervicothoracic region of subjects with RH and will seek to develop a new low-cost and readily available therapy to treat this group of hypertensive individuals.Methods/designThis is a randomized, single blind (subject), parallel-assignment study controlled with a sham group and including participants aged 40 to 70 years with resistant hypertension. The trial has two arms: the treatment and control (sham group). The treatment group will be submitted to the stimulation procedure (TENS). The sham group will not be submitted to stimulation. The primary outcomes will be a reduction in the peripheral blood pressure and adverse events. The secondary outcomes will be a reduction the central blood pressure. The study will last 30 days. The sample size was calculated assuming an alpha error of 5 % to reject the null hypothesis with a statistical power of 80 %, thereby resulting in 28 participants per group (intervention versus sham).DiscussionIn recent decades, RH has become very common and costly. Adequate control requires several drugs, and in many cases, treatment is not successful. Sympathetic nervous system inhibition by renal denervation and central inhibition have significant effects in reducing BP; however, these treatments are costly and invasive. Another type of sympathetic nervous system inhibition can also be noninvasively achieved by electric current. Therefore, the application of TENS may be a new therapeutic option for treating resistant hypertensive individuals.Trial RegistrationClinical Trials NCT02365974Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1302-8) contains supplementary material, which is available to authorized users.

Aortic remodelling following the treatment and regression of hypertensive left ventricular hypertrophy: a cardiovascular magnetic resonance study

Background: Increased arterial stiffness independently predicts adverse prognosis. While different antihypertensive strategies produce different magnitudes of left ventricular hypertrophy (LVH) regression, there are no comparative data on how these strategies affect arterial stiffness. The aim was to determine the longitudinal change in aortic stiffness following the treatment of essential hypertension with two mechanistically different antihypertensive treatment strategies. Methods and results: Forty-two patients with essential hypertension and CMR confirmed with LVH were randomly assigned to antihypertensive regimes for 6 months. Treatment strategies were designed either to inhibit the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system (SNS) (valsartan and moxonidine, group VM) or to have neutral effect on these systems (bendroflumethiazide and amlodipine, group BA). Both treatment groups underwent identical baseline and a 6-month follow-up CMR and were compared with a healthy age-matched control group. Baseline aortic distensibility (AD) was lower in both hypertensive groups compared with controls (2.8 × 10−3 mmHg−1 in group VM (p = 0.001) and 3.3 × 10−3 mmHg−1 group BA (p = 0.039) compared with 4.5 × 10−3 mmHg−1 in the control group). AD increased after antihypertensive therapy (VM: 2.8 × 10−3 mmHg−1–4.2 × 10−3 mmHg−1 (p = 0.001); BA 3.3 × 10−3 mmHg−1–4.6 × 10−3 mmHg−1 (p < 0.01)). In both treatment groups AD returned to a level comparable with the normal control group (p = 0.81) after 6 months. Conclusions: In patients with essential hypertension and LVH, AD was lower than in matched normal controls. Despite the opposing pharmacological mechanisms utilised across the treatment groups, the improvement in AD was similar, suggesting that blood pressure reduction per se may be more important than RAAS and SNS inhibition for the improvement of aortic remodelling.

Sympathetic inhibition attenuates hypoxia induced insulin resistance

Acute exposure to hypoxia decreases insulin sensitivity in healthy humans. The mechanism is unclear but increased activation of the sympathetic nervous system (SNS) may be involved. We hypothesized that SNS inhibition would attenuate hypoxia induced insulin resistance. Insulin sensitivity (hyperinsulinemic euglycemic clamp) was determined in 10 men (23±1 years, body mass index 24.2±0.8 kg/m2 (mean±SE)) during normoxia (FIO2=0.21), hypoxia (FIO2=0.11), normoxia and SNS inhibition (48‐hour transdermal clonidine), and hypoxia and SNS inhibition. Oxyhemoglobin saturation was decreased (P&lt;0.01) in hypoxia (63±2%) compared with normoxia (96±0%), and was unaffected by SNS inhibition (P&gt;0.25). The area under the norepinephrine curve (relative to the normoxia response) was increased in hypoxia (137±13%; P=0.02); clonidine prevented the hypoxia induced increase under the norepinephrine curve (94±14%; P=0.43). Compared with normoxia (225±23 nmol/kg fat free mass/pmol/L/min) the glucose infusion rate (adjusted for fat free mass and circulating insulin), required to maintain blood glucose at 5 mmol/Lduring administration of insulin, was decreased in hypoxia (128±30; P=0.03), and unchanged during normoxia and SNS inhibition (219±19; P=0.86), and hypoxia and SNS inhibition (169±23; P=0.23). We conclude that short‐term SNS inhibition attenuates hypoxia induced insulin resistance.Support: DARPA N66001‐10‐c‐2134

Clonidine therapy in patients with heart failure improves exercise efficiency, functional class and symptoms

Chronic heart failure (HF) is associated with activation of the sympathetic nervous system (SNS) [1–3].Inhibition of the peripheral SNS using beta-blockers is standard therapy, but there remains interest in central SNS inhibition. In an animal model of HF clonidine has been shown to prolong survival [4], but the only mortality study of central SNS inhibition in humans used moxonidine rather than clonidine and demonstrated increased mortality [5].The effect of chronic clonidine therapy on ejection fraction (EF), exercise capacity and biomechanical efficiency is largely unknown.

A lesson from polycystic ovarian syndrome: untangling the role of renal sympathetic nervous system on hypertension and insulin resistance

A lesson from polycystic ovarian syndrome: untangling the role of renal sympathetic nervous system on hypertension and insulin resistance

Interaction between sympathetic nervous system and renin angiotensin system on MMPs expression in juvenile rat aorta

The aim of our present study is to investigate the interaction between angiotensin II (ANG II) and sympathetic nervous system (SNS) on matrix metalloproteinase MMP-2 and MMP-9 expression and activity in juvenile rat aorta under normal conditions. Sympathectomy with guanethidine and blockade of the ANG II receptors (AT1R) by losartan were performed alone or in combination on new-born rats. mRNA, protein expression and activity of MMP-2 and MMP-9 were examined by Q-RT-PCR, immunoblotting and zymography, respectively. MMP-2 mRNA and protein amount were decreased after sympathectomy or AT1R blockade and an additive effect was observed after combined treatment. However, MMP-9 expression was reduced to the same level in the three treated groups. There were some detectable gelatinolytic activity of the MMPs in both control and treated rats. We concluded that ANG II stimulates directly and indirectly (via sympathostimulator pathway) the MMP-2 expression but seems unable to affect MMP-9 expression through direct pathway. Combined inhibition of SNS and ANG II were more efficient than a single inhibition in reducing MMP amounts in rat vessels.

Evidence for a Predominant Intrinsic Sympathetic Control of Cerebral Blood Flow Alterations in an Animal Model of Cerebral Arteriovenous Malformation

In terms of neurogenic cerebral blood flow (CBF) control, the activity of the sympathetic nervous system (SNS) has a regulating effect. The impact of a manipulation of both the peripheral (via the perivascular sympathetic net) and central components (via the intracortical noradrenergic terminals originating from the locus coeruleus) on CBF-and especially on hyperperfusion syndromes-is unclear. To test the specific patterns following such alterations, cortical oxygen saturation (rSO2), regional CBF (rCBF), and cortical interstitial norepinephrine (NE) concentrations were measured. Twelve weeks after either the creation of an extracranial AV fistula or sham operation, 80 male Sprague-Dawley rats underwent one of the following procedures: (1) no SNS manipulation, (2) peripheral SNS inhibition via bilateral sympathectomy, (3) central SNS inhibition via the neurotoxin DSP-4, or (4) complete SNS inhibition. Norepinephrine concentrations were lowest after complete inhibition (NE [nmol]: pre, 1.8 ± 1.2; post, 2.4 ± 1.8) and highest following peripheral inhibition (NE [nmol]: pre, 3.6 ± 1.9; post, 6.6 ± 4.4). Following fistula occlusion, rCBF (laser Doppler unit [LDU]) and rSO2 (%SO2) increases were highest after complete inhibition (pre: 204 ± 14LDU, 34 ± 3%SO2; post: 228 ± 18LDU, 39 ± 3%SO2) and lowest after peripheral inhibition (pre: 221 ± 18LDU, 41 ± 2%SO2; post: 226 ± 14LDU, 47 ± 2%SO2). Thus, a complete inhibition down-regulates SNS activity and provokes a cortical hyperperfusion condition. With this, the hitherto unknown predominant role of the intrinsic component could be demonstrated for the first time in vivo.

Persistence of muscle sympathetic nerve activity during vasovagal syncope

To determine whether sympathetic nerve firing to skeletal muscle vasculature is withdrawn during vasovagal syncope (VVS) precipitated by passive graded head-up tilt (HUT) table testing. We performed passive graded HUT table testing in 18 patients with a history of recurrent postural VVS whom we evaluated during the syncopal event. All patients developed typical VVS during testing. Blood pressure was measured continuously via intra-brachial arterial line. Muscle sympathetic nerve activity (MSNA) was measured using an electrode in the peroneal nerve. Passive graded HUT was then applied. No pharmacological agents were used to provoke syncope. The recording site was maintained through the syncopal event in 10 of 18 patients and we were able to demonstrate persistence of MSNA during syncope in 9. The predominant haemodynamic pattern of syncope in this cohort was mixed--hypotension and bradycardia, with heart rate not falling <40 b.p.m. (n = 10). Our data challenge the established view that the final trigger for human orthostatic vasovagal reactions is sympathetic nervous system inhibition. Efferent sympathetic nerve traffic to the skeletal muscle vasculature was nearly always maintained through the faint. This finding supports an alternative viewpoint, that vasodilator mechanisms underlie the blood pressure fall in VVS.

328 Sympathetic nervous system inhibition, in acute and chronic CCL4 intoxication, results in inhibition of hepatic stellate cells/myofibroblasts and stimulation of hepatic progenitor cells

328 Sympathetic nervous system inhibition, in acute and chronic CCL4 intoxication, results in inhibition of hepatic stellate cells/myofibroblasts and stimulation of hepatic progenitor cells

Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury

Recovery from liver damage might be enhanced by encouraging repopulation of the liver by endogenous hepatic progenitor cells. Oval cells are resident hepatic stem cells that promote liver regeneration and repair. Little is known about the mediators that regulate the accumulation of these cells in the liver. Parasympathetic nervous system inhibition reduces the number of oval cells in injured livers. The effect of sympathetic nervous system (SNS) inhibition on oval cell number is not known. Adrenergic inhibition mobilizes hematopoietic precursors into the circulation and has also been shown to promote liver regeneration. Thus, we hypothesized that SNS inhibition would promote hepatic accumulation of oval cells and reduce liver damage in mice fed antioxidant-depleted diets to induce liver injury. Our results confirm this hypothesis. Compared with control mice that were fed only the antioxidant-depleted diets, mice fed the same diets with prazosin (PRZ, an α-1 adrenoceptor antagonist) or 6-hydroxydopamine (6-OHDA, an agent that induces chemical sympathectomy) had significantly increased numbers of oval cells. Increased oval cell accumulation was accompanied by less hepatic necrosis and steatosis, lower serum aminotransferases, and greater liver and whole body weights. Neither PRZ nor 6-OHDA affected the expression of cytokines, growth factors, or growth factor receptors that are known to regulate progenitor cells. In conclusion, stress-related sympathetic activity modulates progenitor cell accumulation in damaged livers and SNS blockade with α-adrenoceptor antagonists enhances hepatic progenitor cell accumulation. (H epatology 2003;38:664-673.)

265 Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury

265 Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury

Losartan reduces central and peripheral sympathetic nerve activity in a rat model of neurogenic hypertension.

We have developed a new model of neurogenic hypertension in the rat, in which hypertension is caused by injecting 50 microL of 10% phenol in the lower pole of one kidney. Administration of phenol in the kidney causes an immediate and persistent rise in blood pressure (BP), norepinephrine (NE) secretion from the posterior hypothalamic nuclei (PH), and renal sympathetic nerve activity (RSNA). Because angiotensin II (Ang II) is known to stimulate central and peripheral sympathetic nervous system (SNS) activity, we have tested the hypothesis that losartan, a specific Ang II AT1 receptor antagonist, may lower BP, at least in part, by SNS inhibition. To this end, we studied the effects of losartan on BP and SNS activity following intrarenal phenol injection. Central SNS activity was measured by NE secretion from the PH using a microdialysis technique, and peripheral SNS activity was measured by direct recording of renal nerve activity. At the end of the experiments, brains were isolated and interleukin (IL)-1beta and nitric oxide synthase (NOS) mRNA gene expression was measured by RT-PCR in the PH, paraventricular nuclei (PVN), and locus ceruleus (LC). The intrarenal injection of phenol raised BP, as well as central and renal SNS activity, but reduced the abundance of IL-1beta and neuronal NOS (nNOS) mRNA in the PH, PVN, and LC. Whether injected intravenously or in the lateral ventricle, losartan caused a significant (P<0.01) and dose-dependent inhibition of the effects of phenol on BP, NE secretion from the PH, and RSNA. Losartan also caused a significant (P<0.01) and dose-dependent rise in IL-1beta and nNOS-mRNA gene expression in the PH, PVN, and LC of phenol-injected rats. In conclusion, these studies have shown that the intrarenal injection of phenol causes a rise in central and renal SNS activity and a decrease in IL-1beta and nNOS-mRNA in the PH, PVN, and LC. Losartan prevented the rise in BP and SNS activity, as well as the decrease in IL-1beta and nNOS mRNA abundance caused by phenol. These studies have demonstrated that the antihypertensive action of losartan in the phenol renal injury model is largely mediated by inhibition of central and peripheral SNS activity and suggest that activation of IL-1beta and nNOS, 2 important modulators of central SNS activity, mediates the inhibitory action of losartan on SNS activity.