Chronic Sympathetic Nervous System Research Articles

Genetic ablation of Lmp2 increases the susceptibility for impaired cardiac function.

Proteasome degradation is an integral part of cellular growth and function. Proteasomal intervention may mitigate adverse myocardial remodeling, but is associated with the onset of heart failure. Previously, we have demonstrated that increasing abundance of cardiac Lmp2 and its incorporation into proteasome complexes is an endogenous mechanism for proteasome regulation during hypertrophic remodeling of the heart induced by chronic ß-adrenoreceptor stimulation. Here, we investigated whether Lmp2 is required for myocardial remodeling not driven by inflammation and show that Lmp2 is a tipping element for growth and function in the heart but not for proteasome insufficiency. While it has no apparent impact under unchallenged conditions, myocardial remodeling without Lmp2 exacerbates hypertrophy and restricts cardiac function. Under chronic ß-adrenoreceptor stimulation, as seen in the development of cardiovascular disease and the manifestation of heart failure, genetic ablation of Lmp2 in mice caused augmented concentric hypertrophy of the left ventricle. While the heart rate was similarly elevated as in wildtype, myocardial contractility was not maintained without Lmp2, and apparently uncoupled of the ß-adrenergic response. Normalized to the exacerbated myocardial mass, contractility was reduced by 41% of the pretreatment level, but would appear preserved at absolute level. The lack of Lmp2 interfered with elevated 26S proteasome activities during early cardiac remodeling reported previously, but did not cause bulk proteasome insufficiency, suggesting the Lmp2 containing proteasome subpopulation is required for a selected group of proteins to be degraded. In the myocardial interstitium, augmented collagen deposition suggested matrix stiffening in the absence of Lmp2. Indeed, echocardiography of left ventricular peak relaxation velocity (circumferential strain rate) was reduced in this treatment group. Overall, targeting Lmp2 in a condition mimicking chronic ß-adrenoreceptor stimulation exhibited the onset of heart failure. Anticancer therapy inhibiting proteasome activity, including Lmp2, is associated with adverse cardiac events, in particular heart failure. Sparing Lmp2 may be an avenue to reduce adverse cardiac events when chronic sympathetic nervous system activation cannot be excluded.

Abstract 3007: Psychosocial stressors and breast cancer gene expression in the Black Women's Health Study

Abstract Introduction: Chronic sympathetic nervous system (SNS) activation following exposure to psychosocial stressors may influence cancer risk through dysregulation of immune function or adrenergic signaling pathways. Prior research out of the Black Women’s Health Study (BWHS) reported associations between psychosocial stressors and breast cancer risk. We hypothesized that women with greater exposure to psychosocial stressors before their breast cancer diagnosis have higher tumor gene expression of immune-related and adrenergic signaling pathways. Methods: The BWHS is a large, prospective cohort study that has collected health and lifestyle information biennially since 1995. We included data from 417 BWHS breast cancer cases with RNA sequencing data and information on early-life trauma and neighborhood disadvantage. We used the R package DESeq2 to conduct age-adjusted differential gene expression analyses by levels of each stress exposure and described the top differentially expressed pathways using the Molecular Signature Database REACTOME subset of canonical pathways. Targeted analyses of immune-related pathways used CIBERSORT to quantify the proportions of infiltrating immune cells and the R package GSVA for single-sample gene set enrichment analysis (ssGSEA) of genes comprising a T cell exhaustion signature. We also used ssGSEA to evaluate a set of genes involved in adrenergic signaling. Given the variability in gene expression for ER+ versus ER- breast cancers, all analyses were run separately for ER+ (n=299) and ER- (n=118) tumors. Results: Pathways related to nervous system development and the metabolism of RNA were differentially expressed by levels of stress exposures among ER+ and ER- cases, while pathways related to immune function and adrenergic signaling were differentially expressed only among ER- cases, and only when evaluating differential gene expression by levels of neighborhood disadvantage. Targeted analyses of tumor immune infiltration showed significantly higher B cell fractions among ER+ cases without exposure to early trauma compared to those with early trauma. The relative fractions of other immune cells did not differ by stress exposure for ER+ or ER- tumors. Findings from ssGSEA gene set analyses indicated similar expression of genes involved in T cell exhaustion and adrenergic signaling pathways by stress exposure levels for both ER+ and ER- breast cancers. Conclusions: Our findings provide evidence of differential gene expression by levels of stress exposure; however, the differential expression may be driven by multiple pathways and not just the hypothesized immune-related and adrenergic signaling pathways. Additional studies are needed to describe mechanisms by which psychosocial stressors may influence breast cancer risk, both overall and by gene expression profile. Citation Format: Mollie E. Barnard, Xutao Wang, Jessica L. Petrick, W. Evan Johnson, Julie R. Palmer. Psychosocial stressors and breast cancer gene expression in the Black Women's Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3007.

Chronic adrenergic stress and generation of myeloid-derived suppressor cells: Implications for cancer immunotherapy in dogs.

Recent studies have highlighted a key role played by the sympathetic nervous system (SNS) and adrenergic stress in mediating immune suppression associated with chronic inflammation in cancer and other diseases. The connection between chronic SNS activation, adrenergic stress and immune suppression is linked in part to the ability of catecholamines to stimulate the bone marrow release and differentiation of myeloid-derived suppressor cells (MDSC). Rodent model studies have revealed an important role for β-adrenergic receptor signalling in suppression of cancer immunity in mice subjected to chronic stresses, including thermal stress. Importantly, therapeutic blockade of beta-adrenergic responses by drugs such as propranolol can partially reverse the generation and differentiation of MDSC, and partly restore tumour immunity. Clinical trials in both humans and dogs with cancer have demonstrated that propranolol blockade can improve responses to radiation therapy, cancer vaccines and immune checkpoint inhibitors. Thus, the SNS stress response has become an important new target to relieve immune suppression in cancer and other chronic inflammatory conditions.

Posttraumatic Stress Disorder (PTSD): Level 4 – Efficacious

Posttraumatic stress disorder (PTSD) is a psychophysiological disorder characterized by chronic sympathetic nervous system activation, persisting perceptual/sensory vigilance for threats, and recurrent distressing memories of a traumatic event. Persons with PTSD frequently experience intrusive memories, nightmares, and flashbacks lived as if in the present moment. Many also exhibit a persisting negative emotional state, including fear, anger, guilt, and shame (Badour et al., 2017; Moss, 2017). PTSD often produces significant disability, lowered quality of life, and functional impairment (Alonso et al., 2004). The syndrome and symptoms of PTSD have been reported since the early 1800s and described under various diagnostic labels as exhaustion, irritable heart, Da Costa syndrome, and shell shock. Kardiner (1941) described the condition as a physioneurosis, a disorder that is both physiological and psychological. The psychophysiological basis of PTSD calls for psychophysiologically based interventions. Bessel van der Kolk has highlighted the problems in PTSD with affect regulation and called for mind–body interventions such as yoga and neurofeedback (NF) to enhance affective self-regulation (van der Kolk, 2014; van der Kolk et al., 2014, 2016). The purpose of this article is to review the published research on applications of biofeedback (BFB) and NF treatment of PTSD. Much of the research on this topic is still exploratory; several studies were conducted to show the viability of specific protocols. Accordingly, the review will include pilot studies, quasi-experimental studies, and randomized controlled studies. There is an emerging body of research on whether BFB or NF training before combat deployment or before childbirth can prevent the development of PTSD (Hourani et al., 2016; Pyne et al., 2019; Schlesinger et al., 2020). This important research will not be reviewed here.

Sympathoinhibitory effect of sacubitril-valsartan in heart failure with reduced ejection fraction: A pilot study.

Chronic sympathetic nervous system (SNS) overactivity, characteristic of heart failure (HF) with reduced ejection fraction (HFrEF), is associated with poor prognosis and contributes to increased mortality risk. Sacubitril-valsartan is a recently approved, first-in-class, angiotensin receptor neprilysin inhibitor (ARNI) drug that markedly reduces the risks of death from cardiovascular causes and hospitalization for HF in patients with HFrEF, but the physiological mechanisms underlying these benefits are not fully understood. This single-arm, open-label, prospective study sought to test the hypothesis that short-term treatment with sacubitril-valsartan reduces SNS activity, measured directly via muscle sympathetic nerve activity (MSNA), in patients with HFrEF. MSNA, heart rate (HR), and arterial blood pressure (BP) were assessed in stable Class II and III patients with HFrEF (n=9, 69±8yrs.; 28.6±3.6kg/m2) on contemporary, guideline-directed medical treatment who were subsequently started on sacubitril-valsartan. These measurements were repeated after two months of treatment with sacubitril-valsartan. Sacubitril-valsartan reduced MSNA burst frequency (baseline: 43±10 bursts/min; 2-month: 36±10 bursts/min, p=0.05) and burst incidence (baseline: 68±16 bursts/100 heartbeats; 2-month: 55±16 bursts/100 heartbeats, p=0.02), while HR and BP were unchanged following the treatment (p>0.05). These preliminary findings provide new evidence regarding the ability of sacubitril-valsartan to rapidly reduce SNS activity in patients with HFrEF, suggesting the presence of a novel sympathoinhibitory effect of this new drug class.

In Vivo Stimulation of α- and β-Adrenoceptors in Mice Differentially Alters Small RNA Content of Circulating Extracellular Vesicles.

When myocardial function is compromised as in heart failure (HF), there is activation of the sympathetic nervous system with elevated circulating catecholamine levels. These catecholamines activate cardiac and extra-cardiac adrenergic receptors (ARs). Interest in secreted extracellular vesicles (EVs) from the heart is growing and in HF, it is not known whether excessive activation of α- or β-adrenergic receptors (ARs) could induce specific changes in EV content. In this study, we have evaluated, by next generation sequencing, the small RNA content, including micro-RNAs (miRs), of circulating EVs of mice exposed to chronic selective α- or β- AR stimulation. EVs from mouse blood were purified by differential ultracentrifugation resulting in EVs with an average size of 116.6 ± 4.8 nm that by immunoblotting included protein markers of EVs. We identified the presence of miRs in blood EVs using miR-21-5p and -16-5p real-time PCR as known constituents of blood exosomes that make up a portion of EVs. We next performed next generation sequencing (NGS) of small non-coding RNAs found in blood EVs from mice following 7 days of chronic treatment with isoproterenol (ISO) or phenylephrine (PE) to stimulate α- or β-ARs, respectively. PE increased the percent of genomic repeat region reads and decreased the percent of miR reads. In miR expression analysis, PE and ISO displayed specific patterns of miR expression that suggests differential pathway regulation. The top 20 KEGG pathways predicted by differential expressed miRs show that PE and ISO share 11 of 20 pathways analyzed and reveal also key differences including three synapse relative pathways induced by ISO relative to PE treatment. Both α-and β-AR agonists can alter small RNA content of circulating blood EVs/exosomes including differential expression and loading of miRs that indicate regulation of distinct pathways. This study provides novel insight into chronic sympathetic nervous system activation in HF where excessive catecholamines may not only participate in pathological remodeling of the heart but alter other organs due to secretion of EVs with altered miR content.

11C]meta-hydroxyephedrine PET evaluation in experimental pulmonary arterial hypertension: Effects of carvedilol of right ventricular sympathetic function

BackgroundLittle is known about the sequelae of chronic sympathetic nervous system (SNS) activation in patients with pulmonary arterial hypertension (PAH) and right heart failure (RHF). We aimed to, (1) validate the use of [11C]-meta-hydroxyephedrine (HED) for assessing right ventricular (RV) SNS integrity, and (2) determine the effects of β-receptor blockade on ventricular function and myocardial SNS activity in a PAH rat model. MethodsPAH was induced in male Sprague-Dawley rats (N = 36) using the Sugen+chronic hypoxia model. At week 5 post-injection, PAH rats were randomized to carvedilol (15 mg·kg−1·day−1 oral; N = 16) or vehicle (N = 16) for 4 weeks. Myocardial SNS function was assessed with HED positron emission tomography(PET). ResultsWith increasing PAH disease severity, immunohistochemistry confirmed selective sympathetic denervation within the RV and sparing of parasympathetic nerves. These findings were confirmed on PET with a significant negative relationship between HED volume of distribution(DV) and right ventricular systolic pressure (RVSP) in the RV (r = −0.90, p = 0.0003). Carvedilol did not reduce hemodynamic severity compared to vehicle. RV ejection fraction (EF) was lower in both PAH groups compared to control (p < 0.05), and was not further reduced by carvedilol. Carvedilol improved SNS function in the LV with significant increases in the HED DV, and decreased tracer washout in the LV (p < 0.05) but not RV. ConclusionsPAH disease severity correlated with a reduction in HED DV in the RV. This was associated with selective sympathetic denervation. Late carvedilol treatment did not lead to recovery of RV function. These results support the role of HED imaging in assessing SNS innervation in a failing right ventricle.

Sympathetic nervous system as a target for aging and obesity-related cardiovascular diseases.

Chronic sympathetic nervous system overactivity is a hallmark of aging and obesity and contributes to the development of cardiovascular diseases including hypertension and heart failure. The cause of this chronic sympathoexcitation in aging and obesity is multifactorial and centrally mediated. In this mini-review, we have provided an overview of the key and emerging central mechanisms contributing to the pathogenesis of sympathoexcitation in obesity and healthy aging, specifically focusing on hypertension. A clear understanding of these mechanisms will pave way for targeting the sympathetic nervous system for the treatment of cardiovascular diseases in obesity and aging.

In This Issue

HomeCirculation ResearchVol. 118, No. 7In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Originally published1 Apr 2016https://doi.org/10.1161/RES.0000000000000102Circulation Research. 2016;118:1041Glut1, Myelopoiesis, and Atherosclerosis (p 1062)Download figureDownload PowerPointInhibiting extramedullary hematopoietic activity may halt progression of atherosclerosis, say Sarrazy et al.To proliferate and differentiate hematopoietic stem and progenitor cells (HSPCs) in the bone marrow increase their glucose uptake to meet the rising metabolic demand. Indeed PET-CT imaging can identify increased metabolic activity in HSPCs by the uptake of glucose (or rather its radiolabeled analogue) during bone marrow and extramedullary hematopoietic activity. Cell proliferation dependent glucose uptake has been observed in atherosclerotic plaques as well as the spleen. Overproduction of hematopoietic cells, including neutrophils and monocytes, could both contribute to atherosclerosis onset and exacerbate plaque growth. To study extramedullary hematopoiesis more closely, Sarrazy and colleagues examined atherosclerosis-prone mice. They found that glucose uptake was increased in the aortic arch, spleens and bone marrow of these animals, which correlated with increased expression of the glucose transporter Glut1 in their HSPCs. Furthermore, suppression of Glut1 activity reduced not only HSPC proliferation and differentiation—specifically myelopoiesis—but also the progression of atherosclerosis. The authors propose that preventing glucose uptake by HSPCs with an appropriately targeted Glut1 inhibitor could be a potential treatment strategy for atherosclerosis.Long-Term Effects of Cardiac Progenitor Cells (p 1091)Download figureDownload PowerPointThe benefits of cardiac progenitor cell therapy lasts at least a year in rats, report Tang et al.Several studies show that the therapeutic use of cardiac progenitor cells (CPCs) can promote repair and improve function of damaged hearts in animals after myocardial infarction. However, long-term effects of CPC therapy remain unknown as most studies have examined the potential benefits for only four-to-six weeks. Therefore, Tang and colleagues studied the outcome of CPC therapy for myocardial infarction in rats, one year after CPC transplant. They found that while the overall survival rate was no different between control and CPC-treated animals, the treated group exhibited less hypertrophy, smaller scars, increased left ventricle wall thickness, and evidence of less fibrosis. Significantly, CPC treatment did not result in tumor formation. The team used male CPCs and female recipients to enable identification of the cells—by the Y chromosome—and this approach revealed that while a small number of the cells were still present even after 1 year, the transplanted cells had not differentiated into mature cardiomyocytes, although increased proliferation of endogenous CPCs was observed. Together these results indicate that CPC therapy is safe, and that it provides long-term benefits, and induces endogenous CPCs to proliferate and promote repair. The study paves the way for long-term studies evaluating the clinical efficacy of stem cells, say the authors.GRK2 and Prognosis in Heart Failure (p 1116)Download figureDownload PowerPointRengo et al assess the usefulness of a possible new biomarker for heart failure.Heart failure (HF) is a leading cause of death worldwide, and about five million people in the United States suffer from the condition. A major characteristic of HF is chronic sympathetic nervous system (SNS) hyperactivity, which while compensatory in the initial stages of disease becomes deleterious in the long run. Indeed, chronic SNS hyperactivity boosts cardiac levels of G-protein coupled receptor (GPCR) kinase 2 (GRK2), which in turn leads to dysfunctional β-adrenergic signaling—a key factor contributing to the progress of HF pathology. Importantly, the levels of GRK2 in peripheral lymphocytes correlate with those in the failing heart. Rengo and colleagues studied levels of lymphocyte GRK2 in 257 HF patients and found that they accurately reflect disease severity. Patients at low risk of death has lower levels of GRK2, while high levels of protein were identified in high risk individuals. Currently, left ventricle ejection fraction and levels of NT-proBNP are used as biomarkers for HF; however, the team suggests that GRK2 could offer independent and additional prognostic value over and above current approaches. The authors therefore suggest that further larger-scale clinical investigations are warranted to assess the value of the prognostic value of GRK2 in heart failure patients. Previous Back to top Next FiguresReferencesRelatedDetails April 1, 2016Vol 118, Issue 7 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000102 Originally publishedApril 1, 2016 PDF download Advertisement

Abstract B73: Adrenergic signaling promotes pancreatic tumor initiation and progression

Abstract Background/Aims: There is increasing evidence that chronic sympathetic nervous system activation can lead to increased noradrenaline levels in the tumor microenvironment. This process has been associated with proliferative signals largely mediated by beta-adrenergic signaling. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. In this study we aimed to investigate the role of locally and systemically delivered catecholamines to the tumor microenvironment in a well-established genetically engineered pancreatic cancer mouse model (PDx1-Cre/KRasG12D (KC) and PDx1-Cre/KRasG12D/Trp53R172H (KPC)). Methods: Adrenergic signaling was induced or inhibited in KC or KPC mice or 3D pancreatic spheres in culture using specific non-selective and selective agonists or antagonists. Adrenergic receptor expression was assessed by RT-PCR, Western blot and immunohistochemistry. Adrenergic signaling was also modeled in vivo applying restraint stress. To elucidate the crosstalk between nerve and cancer cells, pancreatic spheres and pancreatic cancer cells were co-cultured with dorsal root ganglia and neuronal plasticity was quantified by evaluating neurite outgrowth and number of branches. Denervation of the pancreas was performed using surgical or chemical neural ablation. Results: Adrenergic signaling receptors, in particular ADRB2, is upregulated during pancreatic cancer development. Furthermore, in vitro stimulation of cells harboring an oncogenic KRas mutation displayed a significantly increased sphere forming efficiency. This effect was blocked by the non-specific beta-blocker propranolol and the selective beta2-blocker ICI 188,551. Stimulation of pancreatic sphere formation from KC mice induced by adrenergic signaling from dorsal root ganglia in vitro was also prevented by selective blockage of the beta2-adrenergic signaling pathway. While surgical or chemical (Botulinum toxin A) denervation of the pancreas appeared not to retard the development precancerous lesions in KC mice, denervation significantly increased the survival when performed in mice after a tumor (3-5mm) was detected by high–resolution ultrasound imaging. In contrast, stress accelerated pancreatic cancer development in KC mice. The effects of stress were prevented by treatment with the selective ADRB2 antagonist ICI 188,551. Conclusions: Taken together, our data suggests that an increased level of stress and an increased level of systemic catecholamines may promote pancreatic carcinogenesis in its early stages. During this phase, patients might benefit from pharmacological inhibition of stress-induced signaling. The progression of pancreatic cancer seems to depend on the local delivery of catecholamines to the microenvironment, and thus patients might also benefit by additional targeting of the ADRB2 signaling pathway. Citation Format: Bernhard W. Renz, Christoph B. Westphalen, Xiaowei Chen, Yoku Hayakawa, Yoshihiro Takemoto, Marina Macchini, Daniel L. Worthley, Samuel Asfaha, Axel Kleespies, Helen Remotti, Kenneth P. Olive, Timothy C. Wang. Adrenergic signaling promotes pancreatic tumor initiation and progression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B73.

Nitric Oxide as a Target for Hypertension Management : a Review

High blood pressure is well-established as a leading cause of stroke, ischemic heart disease, and cardiovascular disease. Globally cardiovascular disease accounts for approximately 17 million deaths a year, nearly one third of the total. A number of pharmaceutical agents are available for initial treatment of high BP. These include older molecules such as diuretics and beta-blocking agents, and newer molecules such as dihydropyridine calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and direct acting vasodilators. Comprehensive hypertension management focuses on reducing overall cardiovascular risk and should be the preferred approach for initial management of hypertension. Nitric oxide is a gaseous signaling molecule that regulates various physiological and pathophysiological responses in the human body. Nitric oxide is a gaseous lipophilic free radical which reacts with various molecules to cause pleiotropic effects and it is generated by three distinct isoforms of nitric oxide synthase. The physiologic effects include circulation and blood pressure, platelet function, host defense, and neurotransmission in central nervous system and in peripheral nerves. The etiology of the association between impaired nitric oxide bioactivity and hypertension is complex, however, and has not been fully elucidated. Important mechanisms of hypertension and cardiovascular disease, in which impaired nitric oxide bioactivity plays a major role, include arterial stiffness and increased systolic pulse wave velocity, and possibly chronic sympathetic nervous system activation to be investigated in-depth. NO plays a vital role in a wide variety of pathophysiological and biochemical reactions. Nitric oxide is a critically important mediator in the pathophysiology of different cardiac diseases. Nitric oxide has been identied as one of the key targets for novel therapeutic interventions to minimize irreversible tissue damage associated with complications of hypertension and other cardiovascular disorders.

Effects of intermittent standing bouts during the workday on energy expenditure in desk-bound office workers

Background: Chronic sympathetic nervous system overactivity is a characteristic of the metabolic syndrome that contributes to insulin resistance, target organ damage and a worse clinical prognosis. Plasma noradrenaline (NE) levels reflect the dynamic interplay of synthesis, release and disposition. Objectives: This study was conducted to examine (1) the effects of dietary weight loss on indices of noradrenaline turnover and (2) whether baseline hyperinsulinemia modulates sympathetic neural adaptations. Subjects and methods: Obese individuals aged 56± 1 yr, body mass index 32.5± 0.4 kg/m2, with metabolic syndrome, underwent a 12-week hypocaloric diet (HCD, n = 39) or no treatment (n = 26). Neurochemical measurements comprised arterial dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenylglycol (DHPG) concentrations, intraneuronal precursor and metabolite respectively of NE, arterial NE, the steady-state ratio of [3H]-DHPG to [3H]-NE, as an index of neuronal uptake, and calculated whole-body plasma NE clearance and spillover rates. Hyperinsulinemia was defined as an insulin AUC0—120 during oral glucose tolerance test > 10,000mU/Lmin. Results: Body weight decreased by −7.4± 0.5% in HCD group (P < 0.001) and was accompanied by reductions in DOPA, NE and DHPG averaging −14± 5% (P = 0.001), −23± 4% (P < 0.001) and −5± 4% (P = 0.03), respectively. NE spillover rate decreased by −88± 39 ng/min (P = 0.01), whereas neuronal uptake and NE plasma clearance were unchanged. Despite similar weight loss, hyperinsulinemic subjects exhibited greater reductions in NE, NE spillover rate and diastolic blood pressure, compared to normoinsulinemic subjects (group by time interaction P < 0.05). Change in insulin AUC0—120 during weight loss, independently predicted the reduction in NE level. Conclusions: Weight loss is associated with down regulation of NE production and reduced spillover rate into plasma, but no overall alteration in disposition indices. Hyperinsulinemic subjects derive a greater sympathoinhibitory benefit during weight loss.

Physiology's Impact: Exploring the Mysteries of Life

The discipline of physiology explores the mysteries of life. How is it possible that the same organism can live in a dangerous environment, where extreme ambient temperatures, gravitational forces, oxygen availability, or other abiotic factors impose serious challenges to the maintenance of

Biologic Effects of Dopamine on Tumor Vasculature in Ovarian Carcinoma

Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA), an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2), our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP) levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth.

Sympathetic Nervous System Function and Dysfunction in Chronic Hemodialysis Patients

Adequate sympathetic nervous system activation is essential for the compensatory mechanisms of blood pressure maintenance during the hemodialysis (HD) procedure. Chronic sympathetic nervous system overactivity, however, may lead to the development of hypertension and cardiovascular disease in HD patients. The present review focuses on recent findings on the sympathetic nervous system activity in these patients. Sympathetic overactivity has been demonstrated directly by muscle sympathetic nerve activity recordings (MSNA) in chronic renal disease, but only rarely in HD patients. In the latter, sympathetic activity has mostly been assessed using indirect methodology. Decreased heart rate variability, increased blood pressure variability (BPV), and suppressed baroreflex function are believed to represent chronic sympathetic overactivity in HD patients. The HD procedure and ultrafiltration are associated with enhanced sympathetic activity and baroreflex activation. During most episodes of intradialytic hypotension, the baroreflex is adequately activated; sympathetic withdrawal with bradycardia, however, has been reported during excessive hypovolemia. Sympathetic overactivity is also believed to be a mechanism associated with intradialytic hypertensive episodes and refractory hypertension. While successful renal transplantation is associated with improvement of heart rate variability (HRV), improvement and restoration of baroreflex function, persistent sympathetic overactivity has been documented in transplanted patients using MSNA recordings. Decreased HRV and baroreflex function have been reported to be associated with increased mortality and morbidity in HD patients. The predictive value of sympathetic outflow assessed by MSNA has yet to be determined. Optimization of HD treatment, pharmacological interventions, and renal sympathetic denervation are several approaches targeting sympathetic overactivity to improve cardiovascular morbidity and mortality.

Mindfulness meditation lowers blood pressure and sympathetic activity in hypertensive patients with chronic kidney disease

Chronic kidney disease (CKD) is characterized by chronic sympathetic nervous system (SNS) overactivation that contributes to hypertension and mortality. Previous reports suggest that mindfulness meditation may have beneficial effects on blood pressure (BP), but the mechanisms are unknown. We hypothesized that mindfulness meditation lowers BP in hypertensive CKD patients by lowering central SNS output. We measured continuous arterial BP and muscle sympathetic nerve activity (MSNA) in 16 male, hypertensive patients with Stage III CKD at baseline, and during 14 minutes of either: a) mindfulness‐based meditation (N=10); or b) health education on hypertension (control intervention, N=6). The meditation group compared to controls had a significantly greater reduction in systolic BP (− 13.2±1.8 vs. −2.3±1.3 mm Hg, p&lt;0.001), diastolic BP (−5.5±1.3 vs. −1.5±0.9, p=0.046), mean arterial pressure (−1.7±0.8 vs. −8.1±1.2 mm Hg, p=0.002), and a trend towards greater reduction in heart rate (−3.3±1.3 vs. +0.2±1.0 beats/min, p=0.071). Concomitantly, there was a significantly greater reduction in MSNA during mindfulness meditation compared to the control intervention (− 6.1±1.3 vs. +1.5±1.3 bursts/min, p=0.002). These findings suggest that mindfulness meditation may lower arterial BP and heart rate by decreasing SNS output in hypertensive patients with CKD. Supported by K grant HL098744.

Obesity-Related Metabolic Syndrome: Mechanisms of Sympathetic Overactivity

The prevalence of the metabolic syndrome has increased worldwide over the past few years. Sympathetic nervous system overactivity is a key mechanism leading to hypertension in patients with the metabolic syndrome. Sympathetic activation can be triggered by reflex mechanisms as arterial baroreceptor impairment, by metabolic factors as insulin resistance, and by dysregulated adipokine production and secretion from visceral fat with a mainly permissive role of leptin and antagonist role of adiponectin. Chronic sympathetic nervous system overactivity contributes to a further decline of insulin sensitivity and creates a vicious circle that may contribute to the development of hypertension and of the metabolic syndrome and favor cardiovascular and kidney disease. Selective renal denervation is an emerging area of interest in the clinical management of obesity-related hypertension. This review focuses on current understanding of some mechanisms through which sympathetic overactivity may be interlaced to the metabolic syndrome, with particular regard to the role of insulin resistance and of some adipokines.

Targeting cardiac β-adrenergic signaling via GRK2 inhibition for heart failure therapy

Cardiac cells, like those of the other tissues, undergo regulation through membrane-bound proteins known as G protein-coupled receptors (GPCRs). β-adrenergic receptors (βARs) are key GPCRs expressed on cardiomyocytes and their role is crucial in cardiac physiology since they regulate inotropic and chronotropic responses of the sympathetic nervous system (SNS). In compromised conditions such as heart failure (HF), chronic βAR hyperstimulation occurs via SNS activation resulting in receptor dysregulation and down-regulation and consequently there is a marked reduction of myocardial inotropic reserve and continued loss of pump function. Data accumulated over the last two decades indicates that a primary culprit in initiating and maintain βAR dysfunction in the injured and stressed heart is GPCR kinase 2 (GRK2), which was originally known as βARK1 (for βAR kinase). GRK2 is up-regulated in the failing heart due to chronic SNS activity and targeting this kinase has emerged as a novel therapeutic strategy in HF. Indeed, its inhibition or genetic deletion in several disparate animal models of HF including a pre-clinical pig model has shown that GRK2 targeting improves functional and morphological parameters of the failing heart. Moreover, non-βAR properties of GRK2 appear to also contribute to its pathological effects and thus, its inhibition will likely complement existing therapies such as βAR blockade. This review will explore recent research regarding GRK2 inhibition; in particular it will focus on the GRK2 inhibitor peptide known as βARKct, which represents new hope in the treatment against HF progression.

Resistant hypertension and obstructive sleep apnea in end-stage renal disease

Resistant hypertension and obstructive sleep apnea in end-stage renal disease

Obesity and adipokines: effects on sympathetic overactivity

Excess body weight is a major risk factor for cardiovascular disease, increasing the risk of hypertension, hyperglycaemia and dyslipidaemia, recognized as the metabolic syndrome. Adipose tissue acts as an endocrine organ by producing various signalling cytokines called adipokines (including leptin, free fatty acids, tumour necrosis factor-α, interleukin-6, C-reactive protein, angiotensinogen and adiponectin). A chronic dysregulation of certain adipokines can have deleterious effects on insulin signalling. Chronic sympathetic overactivity is also known to be present in central obesity, and recent findings demonstrate the consequence of an elevated sympathetic outflow to organs such as the heart, kidneys and blood vessels. Chronic sympathetic nervous system overactivity can also contribute to a further decline of insulin sensitivity, creating a vicious cycle that may contribute to the development of the metabolic syndrome and hypertension. The cause of this overactivity is not clear, but may be driven by certain adipokines. The purpose of this review is to summarize how obesity, notably central or visceral as observed in the metabolic syndrome, leads to adipokine expression contributing to changes in insulin sensitivity and overactivity of the sympathetic nervous system.