The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study.

BACKGROUND: Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival. METHODS: In this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20). RESULTS: Ex vivo cytokine production capacity of TNF, IL-6 and IL-1ß was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1ß after BCS (p = .041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p = .045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p = .003 and p = .041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p = .038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1ß and TNF on POD3 (r = .408; p = .011 and r = .500; p = .001, respectively). CONCLUSIONS: This pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation.

Impact of maternal obesity on resting muscle sympathetic nerve activity during uncomplicated pregnancy: a longitudinal assessment.

Maternal obesity increases the risk of adverse pregnancy outcomes. The mechanisms that contribute to this elevated risk are unclear but may be related to greater activity of the sympathetic nervous system, which is associated with hypertensive disorders of pregnancy. We hypothesized that resting muscle sympathetic nerve activity (MSNA) would be greater in women with obesity during pregnancy when compared with normal-weight women. Blood pressure, heart rate, and MSNA were recorded during 5 min of supine rest in 14 normal-weight women [body mass index (BMI) 22.1 ± 2.1 (SD) kg/m2] and 14 women with obesity (BMI 33.9 ± 3.5 kg/m2) during (early and late) pregnancy and postpartum. All women had uncomplicated pregnancies. Resting MSNA burst frequency was not different between groups during early (normal weight 17 ± 10 vs. obesity 22 ± 15 bursts/min, P = 0.35) but was significantly greater in the obesity group during late pregnancy (23 ± 13 vs. 35 ± 15 bursts/min, P = 0.031) and not different postpartum (10 ± 6 vs. 9 ± 7 bursts/min, P = 0.74). These findings were also apparent when comparing burst incidence and total activity. Although still within the normotensive range, systolic blood pressure was greater in the obesity group across all time points (P = 0.002). Diastolic blood pressure was lower during pregnancy compared with postpartum (P < 0.001) and not different between groups (P = 0.488). Heart rate increased throughout pregnancy in both groups (P < 0.001). Our findings suggest that maternal obesity is associated with greater increases in sympathetic activity even during uncomplicated pregnancy. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy.NEW & NOTEWORTHY The impact of maternal obesity on resting muscle sympathetic nerve activity was examined during (early and late) and after uncomplicated pregnancy. Resting muscle sympathetic nerve activity is not different during early pregnancy or postpartum but is significantly elevated in women with obesity during late pregnancy when compared with normal-weight women. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy.

Circadian and sex differences in post-ischemic vasodilation and reactive hyperemia in young individuals and elderly with and without type 2 diabetes.

OBJECTIVE: Cardiovascular events show morning preference and sex differences, and are related to aging and type 2 diabetes. We assessed circadian variations and sex differences in vascular conductance (VC) and blood flow (BF) regulations following a brief bout of forearm ischemia. METHODS: Young healthy individuals (H18-30) and elderly without (H50-80) and with type 2 diabetes (T2DM50-80) of both sexes were included. Forearm VC and BF, and mean arterial pressure (MAP) at baseline and following circulatory reperfusion were measured at 6 a.m. and 9 p.m. RESULTS: In the morning compared to evening, following reperfusion, the VC and BF increments were similar in H18-30 (p>.71), but lower in H50-80 (p<.001) and T2DM50-80 (p<.01). VC and BF following circulatory reperfusion were higher in men than women in H18-30 (p<.001), but similar between sexes in the older groups (p>.23). CONCLUSIONS: Forearm vasodilation following reperfusion is attenuated in the morning in the elderly, impairing BF towards an ischemic area. Diabetes does not affect the circadian regulation of VC and BF, but that of MAP. There are sex differences in VC and BF at baseline and after circulatory reperfusion at a young age, being greater in men, which disappear with aging without being affected by diabetes.

The Adult Carotid Body: A Germinal Niche at the Service of Physiology.

The carotid body is the most relevant oxygen sensor in mammalian organisms. This organ helps to detect acute changes in PO2, but it is also crucial for the organismal adaptation to a maintained hypoxemia. Profound angiogenic and neurogenic processes take place in the carotid body to facilitate this adaptation process. We have described a plethora of multipotent stem cells and restricted progenitors, from both vascular and neuronal lineages, existing in the quiescent normoxic carotid body, ready to contribute to organ growth and adaptation upon the arrival of the hypoxic stimulus. Our deep understanding of the functioning of this stunning germinal niche will very likely facilitate the management and treatment of an important group of diseases that course with carotid body over-activation and malfunction.

Neuromuscular and gene signaling responses to passive whole-body heat stress in young adults.

This study aimed to investigate whether acute passive heat stress 1) decreases muscle Maximal Voluntary Contraction (MVC); 2) increases peripheral muscle fatigue; 3) increases spinal cord excitability, and 4) increases key skeletal muscle gene signaling pathways in skeletal muscle. Examining the biological and physiological markers underlying passive heat stress will assist us in understanding the potential therapeutic benefits. MVCs, muscle fatigue, spinal cord excitability, and gene signaling were examined after control or whole body heat stress in an environmental chamber (heat; 82 °C, 10% humidity for 30 min). Heart Rate (HR), an indicator of stress response, was correlated to muscle fatigue in the heat group (R = 0.59; p < 0.05) but was not correlated to MVC, twitch potentiation, and H reflex suppression. Sixty-one genes were differentially expressed after heat (41 genes >1.5-fold induced; 20 < 0.667 fold repressed). A strong correlation emerged between the session type (control or heat) and principal components (PC1) (R = 0.82; p < 0.005). Cell Signal Transduction, Metabolism, Gene Expression and Transcription, Immune System, DNA Repair, and Metabolism of Proteins were pathway domains with the largest number of genes regulated after acute whole body heat stress. Acute whole-body heat stress may offer a physiological stimulus for people with a limited capacity to exercise.

Sympathetic activation leads to Schlemm's canal expansion via increasing vasoactive intestinal polypeptide secretion from trabecular meshwork.

We previously demonstrated vasoactive intestinal polypeptide (VIP) eyedrops reduce intraocular pressure (IOP) and stabilize cytoskeleton of the Schlemm's canal (SC) endothelium in a chronic ocular hypertension rat model. Here we determine if the trabecular meshwork (TM) releases endogenous VIP and affect SC in paracrine manner, and whether this cellular interaction via VIP is strengthened under stimulated sympathetic activity. A rat model of moderate-intensity exercise was established to stimulate sympathetic activation. IOP post exercise was measured by a rebound tonometer. Sympathetic nerve activity at the TM was immunofluorescence-stained with DßH and PGP9.5. Morphological changes of TM and SC were quantitatively measured by hematoxylin-eosin (HE) staining. Further, epinephrine was applied to mimic sympathetic excitation on primary rat TM cells, and ELISA to measure VIP levels in the medium. The cytoskeleton protective effect of VIP in the epinephrine-stimulated conditioned medium (Epi-CM) was evaluated in oxidative stressed human umbilical vein endothelial cells (HUVECs). Elevated sympathetic nerve activity was found at TM post exercise. Changes accompanying the sympathetic excitation included thinned TM, expanded SC and decreased IOP, which were consistent with epinephrine treatment. Epinephrine decreased TM cell size, enhanced VIP expression and release in the medium in vitro. Epi-CM restored linear F-actin and cell junction integrity in H2O2 treated HUVECs. Blockage of VIP receptor by PG99-465 attenuated the protective capability of Epi-CM. VIP expression was upregulated at TM and the inner wall of SC post exercise in vivo. PG99-465 significantly attenuated exercise-induced SC expansion and IOP reduction. Thus, the sympathetic activation promoted VIP release from TM cells and subsequently expanded SC via stabilizing cytoskeleton, which resulted in IOP reduction.

Chronic ethanol consumption plus an atherogenic diet cause metabolic steatohepatitis with advanced liver fibrosis in apolipoprotein E/low-density lipoprotein receptor double-knockout mice.

BACKGROUND: Nonalcoholic steatohepatitis is the inflammatory subtype of nonalcoholic fatty liver disease with a high risk of progression to liver fibrosis. We investigated metabolic steatohepatitis with advanced liver fibrosis in apolipoprotein E/low-density lipoprotein receptor double-knockout (AL) mice fed a co-diet of ethanol with a low-carbohydrate-high-protein-high-fat atherogenic diet (AD) for 16 weeks. We also examined the underlying mechanisms, especially hepatic sympathetic activation, involved in the effects. METHODS: We maintained 12-week-old male AL mice on AD and a standard chow diet (SCD) with or without ethanol treatment for 16 weeks. Age-matched male C57BL/6J mice on SCD without ethanol treatment served as controls. We conducted blood biochemical, histopathological, and fluorescence immunohistochemical, and reverse transcriptase polymerase chain reaction studies. RESULTS: AL mice showed significant hyperlipidemia. AD induced increased body weight, hepatic steatosis, and hepatic damage; ethanol and the AD co-diet resulted in hepatic sympathetic activation accompanied by hepatic steatosis, lobular inflammation, bridging fibrosis, and hepatic damage. Hepatic Kupffer cells (KCs) and hepatic stellate cells (HSCs), which showed sympathetic activation, produced 4.4- to 9.4-fold more inflammatory factors (KC and KC-derived tumor necrosis factor-α, and chemokine [C-C motif] ligand 2) and 2.0- to 32.0-fold more fibrosis factors (HSC and HSC-derived transforming growth factor ß1 and collagen 1a1); all p < 0.05 vs. controls. CONCLUSIONS: We created a model of metabolic steatohepatitis with advanced liver fibrosis from coexisting hyperlipidemia and hepatic sympathetic activation in AL mice on a co-diet of ethanol and AD. KCs and HSCs became the cellular targets of hepatic sympathetic activation, which could play a role in the initiation and progression of metabolic steatohepatitis with advanced liver fibrosis.

An Update on Refractory Hypertension.

PURPOSE OF REVIEW: To update on definition, diagnosis, prevalence, patient characteristics, pathophysiology, and treatment of refractory hypertension (RfHTN). RECENT FINDINGS: Refractory hypertension (RfHTN) is defined as blood pressure (BP) that is uncontrolled despite using ≥ 5 antihypertensive medications of different classes, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist (MRA) at maximal or maximally tolerated doses. This new phenotype is different from resistant hypertension (RHTN), defined as BP that is uncontrolled despite using ≥ 3 medications, commonly a long-acting calcium channel blocker (CCB), a blocker of the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]), and a diuretic. The RHTN phenotype includes controlled RHTN, BP that is controlled on 4 or more medications. RfHTN is largely attributable to increased sympathetic activity, unlike RHTN, which is mainly due to increased intravascular fluid volume frequently caused by hyperaldosteronism and chronic excessive sodium ingestion. Compared to those with controlled RHTN, patients with RfHTN have a higher prevalence of target organ damage and do not have elevated aldosterone levels. Ongoing clinical trials are assessing the safety and efficacy of using devices to aid with BP control in patients with RfHTN. RfHTN is a separate entity from RHTN and is generally attributable to increased sympathetic activity.

Anger recall mental stress decreases 123I-metaiodobenzylguanidine (123I-MIBG) uptake and increases heterogeneity of cardiac sympathetic activity in the myocardium in patients with ischemic cardiomyopathy.

BACKGROUND: Acute psychological stressors such as anger can precipitate ventricular arrhythmias, but the mechanism is incompletely understood. Quantification of regional myocardial sympathetic activity with 123I-metaiodobenzylguanidine (123I-mIBG) SPECT imaging in conjunction with perfusion imaging during mental stress may identify a mismatch between perfusion and sympathetic activity that may exacerbate a mismatch between perfusion and sympathetic activity that could create a milieu of increased vulnerability to ventricular arrhythmia. METHODS: Five men with ischemic cardiomyopathy (ICM), and five age-matched healthy male controls underwent serial 123I-mIBG and 99mTc-Tetrofosmin SPECT/CT imaging during an anger recall mental stress task and dual isotope imaging was repeated approximately 1 week later during rest. Images were reconstructed using an iterative reconstruction algorithm with CT-based attenuation correction. The mismatch of left ventricular myocardial 123I-mIBG and 99mTc-Tetrofosmin was assessed along with radiotracer heterogeneity and the 123I-mIBG heart-to-mediastinal ratios (HMR) were calculated using custom software developed at Yale. RESULTS: The hemodynamic response to mental stress was similar in both groups. The resting-HMR was greater in healthy control subjects (3.67 ± 0.95) than those with ICM (3.18 ± 0.68, P = .04). Anger recall significantly decreased the HMR in ICM patients (2.62 ± 0.3, P = .04), but not in normal subjects. The heterogeneity of 123I-mIBG uptake in the myocardium was significantly increased in ICM patients during mental stress (26% ± 8.23% vs. rest: 19.62% ± 9.56%; P = .01), whereas the 99mTc-Tetrofosmin uptake pattern was unchanged. CONCLUSION: Mental stress decreased the 123I-mIBG HMR, increased mismatch between sympathetic activity and myocardial perfusion, and increased the heterogeneity of 123I-mIBG uptake in ICM patients, while there was no significant change in myocardial defect size or the heterogeneity of 99mTc-Tetrofosmin perfusion. The changes observed in this proof-of-concept study may provide valuable information about the trigger-substrate interaction and the potential vulnerability for ventricular arrhythmias.

Obesity and Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is characterized by upper airway collapse during sleep. Chronic intermittent hypoxia, sleep fragmentation, and inflammatory activation are the main pathophysiological mechanisms of OSA. OSA is highly prevalent in obese patients and may contribute to cardiometabolic risk by exerting detrimental effects on adipose tissue metabolism and potentiating the adipose tissue dysfunction typically found in obesity. This chapter will provide an update on: (a) the epidemiological studies linking obesity and OSA; (b) the studies exploring the effects of intermittent hypoxia and sleep fragmentation on the adipose tissue; (c) the effects of OSA treatment with continuous positive airway pressure (CPAP) on metabolic derangements; and (d) current research on new anti-diabetic drugs that could be useful in the treatment of obese OSA patients.

Stellate Ganglia and Cardiac Sympathetic Overactivation in Heart Failure.

Heart failure (HF) is a major public health problem worldwide, especially coronary heart disease (myocardial infarction)-induced HF with reduced ejection fraction (HFrEF), which accounts for over 50% of all HF cases. An estimated 6 million American adults have HF. As a major feature of HF, cardiac sympathetic overactivation triggers arrhythmias and sudden cardiac death, which accounts for nearly 50-60% of mortality in HF patients. Regulation of cardiac sympathetic activation is highly integrated by the regulatory circuitry at multiple levels, including afferent, central, and efferent components of the sympathetic nervous system. Much evidence, from other investigators and us, has confirmed the afferent and central neural mechanisms causing sympathoexcitation in HF. The stellate ganglion is a peripheral sympathetic ganglion formed by the fusion of the 7th cervical and 1st thoracic sympathetic ganglion. As the efferent component of the sympathetic nervous system, cardiac postganglionic sympathetic neurons located in stellate ganglia provide local neural coordination independent of higher brain centers. Structural and functional impairments of cardiac postganglionic sympathetic neurons can be involved in cardiac sympathetic overactivation in HF because normally, many effects of the cardiac sympathetic nervous system on cardiac function are mediated via neurotransmitters (e.g., norepinephrine) released from cardiac postganglionic sympathetic neurons innervating the heart. This review provides an overview of cardiac sympathetic remodeling in stellate ganglia and potential mechanisms and the role of cardiac sympathetic remodeling in cardiac sympathetic overactivation and arrhythmias in HF. Targeting cardiac sympathetic remodeling in stellate ganglia could be a therapeutic strategy against malignant cardiac arrhythmias in HF.

Stress and working memory in children and adolescents: Insights from a multisystem approach.

Despite considerable research with adults suggesting that acute stress negatively affects working memory (WM), a core cognitive function, few studies have assessed these effects in youths. Studies that have been conducted have produced null findings, although these studies did not measure stress via multiple systems (e.g., hypothalamic-pituitary-adrenal [HPA] axis and sympathetic nervous system [SNS]) or include wide developmental age ranges. In the current study, we examined the links between acute stress and WM in 8- to 15-year-olds. Youths completed the Trier Social Stress Test-Modified, during which repeated saliva samples were collected to measure responses of the HPA axis (cortisol) and SNS (salivary alpha-amylase). Immediately afterward, youths completed the n-back task, an established measure of WM. Accuracy and false alarm (FA) scores were computed to explore whether associations between arousal and WM differed when WM versus only the inhibitory control facet of WM processes were considered. Relations varied as a function of age, physiological system, and type of WM process. Accuracy improved and FA scores deceased as age and SNS reactivity increased, particularly in combination. Moreover, when arousal was higher according to only one physiological system (HPA axis or SNS), FA scores were lower, but when arousal was driven by both systems or low in both systems, FA scores were higher. Together, results highlight the need for more complex investigations of stress and WM across development that take into account system-specific responses and multiple facets of WM.

Sensory signals mediating high blood pressure via sympathetic activation: role of adipose afferent reflex.

Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Although there are numerous reviews focused on the role of sympathetic nerves in different models of hypertension, few have revised the contribution of afferent nerves innervating adipose tissue and their role in the development of obesity-induced hypertension. Both clinical and basic research support the beneficial effects of bilateral renal denervation in lowering blood pressure. However, recent studies revealed that afferent signals from adipose tissue, in an adipose-brain-peripheral pathway, could contribute to the increased sympathetic activation and blood pressure during obesity. This review focuses on the role of adipose tissue afferent reflexes and briefly describes a number of other afferent reflexes modulating blood pressure. A comprehensive understanding of how multiple afferent reflexes contribute to the pathophysiology of essential and/or obesity-induced hypertension may provide significant insights into improving antihypertensive therapeutic approaches.

Reproducibility of Heart Rate Variability Revealed by Repeated Measurements during and after Hemodialysis.

BACKGROUND/AIMS: Trajectory of heart rate variability (HRV) represents a noninvasive real-time measure of autonomous nervous system (ANS) and carries the capability of providing new insights into the hemodynamic compensation reserve during hemodialysis (HD). However, studies on HRV reproducibility during HD are scarce and did not refer to different reading periods. In this observational study, we aimed to establish the best suited and most reliable and reproducible HRV index in routine HD treatments including different reading rates. METHODS: HRV was characterized by standardized mathematical variation expressions of R/R' intervals: SD of all R/R' intervals (ms), square root of the root mean square of the sum of all differences between adjacent R/R' intervals (ms), percentage of consecutive R/R' intervals that differ by >50 ms (%), low-frequency spectral analysis HRV (LF, expressing sympathetic activity), and high-frequency HRV (HF, expressing parasympathetic activity). To compare robustness of these HRV indices during HD procedures, we compared HRV indices means between different HD sessions and controlled for association with clinical parameters. RESULTS: In 72 HD treatments of 34 patients, we detected the highest reproducibility (89%) of HRV measures when analyzing the low-frequency to high-frequency (LF/HF) ratio in long-term (3 h) readings. Long-term LF/HF was able to discriminate -between patients with and without heart failure NYHA classes ≥3 (p = 0.009) and type 2 diabetes (p = 0.023). We were unable to study relationships between ANS and intradialytic complications because they did not appear in our cohort. Short-term readings of HRV indices did not show any significance of pattern change during HD. CONCLUSION: In summary, our data provide evidence for high robustness of long-term LF/HF in analyzing HRV in HD patients using future automated monitoring systems. For short-term analysis, mathematical real-time analysis must evolve.

Elevated Heart Rate in Combination with Elevated Blood Pressure Predicts Lower Cardiovascular Mortality in Acute Decompensated Heart Failure.

Despite its clinical relevance, a subclass of acute decompensated heart failure (ADHF) with elevated blood pressure, known as hypertensive ADHF (HT-ADHF), has been less intensively evaluated. This study aimed to characterize the prognostic nature and pathophysiology of HT-ADHF. A total of 509 consecutive patients with first-time ADHF hospitalization were subjects of the study. Participants were divided into two groups: an HT-ADHF group (systolic blood pressure, SBP > 140 mmHg at presentation) and a non-HT-ADHF group (SBP ≤ 140 mmHg). Median follow-up duration measured 253 days. Unadjusted Kaplan-Meier analysis demonstrated both a lower cardiovascular mortality rate in the HT-ADHF group and similar incidences of heart failure rehospitalization in both groups. Adjusted Cox hazard analysis showed an association of elevated SBP at presentation with significantly lower cardiovascular mortality, though no such association was observed with heart failure rehospitalization. Moreover, elevated heart rate in combination with elevated SBP at presentation predicted a significantly lower risk of cardiovascular mortality (Hazard Ratio: 0.32, 95% CI: 0.14-0.77, P = 0.01). Also, significantly lower cardiovascular mortality was observed in this subtype, compared with other types of ADHF.

Different paths, same destination: divergent action potential responses produce conserved cardiac fight-or-flight response in mouse and rabbit hearts.

KEY POINTS: Cardiac electrophysiology and Ca2+ handling change rapidly during the fight-or-flight response to meet physiological demands. Despite dramatic differences in cardiac electrophysiology, the cardiac fight-or-flight response is highly conserved across species. In this study, we performed physiological sympathetic nerve stimulation (SNS) while optically mapping cardiac action potentials and intracellular Ca2+ transients in innervated mouse and rabbit hearts. Despite similar heart rate and Ca2+ handling responses between mouse and rabbit hearts, we found notable species differences in spatio-temporal repolarization dynamics during SNS. Species-specific computational models revealed that these electrophysiological differences allowed for enhanced Ca2+ handling (i.e. enhanced inotropy) in each species, suggesting that electrophysiological responses are fine-tuned across species to produce optimal cardiac fight-or-flight responses. ABSTRACT: Sympathetic activation of the heart results in positive chronotropy and inotropy, which together rapidly increase cardiac output. The precise mechanisms that produce the electrophysiological and Ca2+ handling changes underlying chronotropic and inotropic responses have been studied in detail in isolated cardiac myocytes. However, few studies have examined the dynamic effects of physiological sympathetic nerve activation on cardiac action potentials (APs) and intracellular Ca2+ transients (CaTs) in the intact heart. Here, we performed bilateral sympathetic nerve stimulation (SNS) in fully innervated, Langendorff-perfused rabbit and mouse hearts. Dual optical mapping with voltage- and Ca2+ -sensitive dyes allowed for analysis of spatio-temporal AP and CaT dynamics. The rabbit heart responded to SNS with a monotonic increase in heart rate (HR), monotonic decreases in AP and CaT duration (APD, CaTD), and a monotonic increase in CaT amplitude. The mouse heart had similar HR and CaT responses; however, a pronounced biphasic APD response occurred, with initial prolongation (50.9 ± 5.1 ms at t = 0 s vs. 60.6 ± 4.1 ms at t = 15 s, P < 0.05) followed by shortening (46.5 ± 9.1 ms at t = 60 s, P = NS vs. t = 0). We determined the biphasic APD response in mouse was partly due to dynamic changes in HR during SNS and was exacerbated by ß-adrenergic activation. Simulations with species-specific cardiac models revealed that transient APD prolongation in mouse allowed for greater and more rapid CaT responses, suggesting more rapid increases in contractility; conversely, the rabbit heart requires APD shortening to produce optimal inotropic responses. Thus, while the cardiac fight-or-flight response is highly conserved between species, the underlying mechanisms orchestrating these effects differ significantly.

Intermittent restraint-induced sympathetic activation attenuates hepatic steatosis and inflammation in a high-fat diet-fed mouse model.

Nonalcoholic fatty liver disease (NAFLD) is very prevalent worldwide and is associated with insulin resistance and metabolic syndrome. Stress is a physiological and biological response to maintain homeostasis of the body against stressors while severe stress response is an important contributor to various illnesses, including metabolic syndrome and brain disorders. We have evaluated the effects of intermittent restraint stress on NAFLD in a high-fat diet (HFD)-fed mouse model. C57/BL6 mice had free access to a 60% HFD for 8 wk, with or without intermittent restraint stress (3 h) conducted three times a week. HFD administration increased fat accumulation in liver tissues. Unlike the stressed standard diet group, the levels of hepatic total cholesterol and triglycerides were significantly ameliorated in the HFD with stress group compared with the HFD alone group. These beneficial results were in accordance with serum levels of liver enzymes (aspartate transaminase, alanine transaminase) and hepatic levels of TNF-α and oxidative stress parameters (reactive oxygen species, nitric oxide, and malondialdehyde). The intermittent restraint stress significantly attenuated the HFD-derived alterations in serum insulin levels, hepatic protein kinase B activity, and gene expression, especially related to lipogenesis. This intermittent restraint stress also elevated the serum epinephrine concentration and activated the adrenergic receptor ß2 or ß3 in livers or white adipose tissue (WAT). Activation of energy expenditure markers (uncoupling protein 1, peroxisome proliferator-activated receptor-γ coactivator-1α) in brown adipose tissue and the browning of WAT were also observed in the HFD with stress group. Taken together, our findings showed the beneficial effects of sympathetic activation by intermittent restraint stress on HFD-induced hepatic steatosis and partial inflammation.NEW & NOTEWORTHY In modern society, stress is a part of daily life, and a certain level of stress is inevitable to most of the general population. Uncontrolled severe stress is obviously harmful; however, certain kind/level of stress could be beneficial on lipid metabolism via sympathetic activation. Our data suggest that a sympathetic activation by intermittent restraint stress could play a positive role in maintaining the balance of hepatic lipid metabolism, especially under high-fat diet conditions.

Prevention of Intradialytic Hypotension with Intermittent Back-Filtrate Infusion Haemodiafiltration: Insights into the Underlying Mechanism.

BACKGROUND: Intradialytic hypotension (IDH) is a major challenge to safely performing haemodialysis. Blood volume depletion due to fluid removal is a major cause of hypotension, so more emphasis should be placed on finding alternative modalities to traditional constant rate ultrafiltration. SUMMARY: Intermittent back-filtrate infusion haemodiafiltration (I-HDF) utilises purified online quality dialysate with an automated dialysis machine. A bolus of 200 mL of dialysate is repetitively infused at 30-min intervals. A pilot study with 68 hypotension-prone patients revealed that I-HDF can reduce the frequency of IDH interventions, particularly in elderly patients and patients with large interdialytic weight gain (IDWG). This was typically accompanied by an increase in intradialytic blood pressure and decreased tachycardia in the latter half of the session, suggesting reduced sympathetic stimulation during I-HDF. Protective mechanisms involved in the pathophysiology of IDH could be explained in part by the findings obtained in this pilot study. Intermittent increases in blood pressure during I-HDF may prevent venous pooling (i.e., the DeJager-Krogh phenomenon), and reduced sympathetic stimulation may maintain a physiological state less likely to induce the cardio-vagal reflex (i.e., the Bezold-Jarisch reflex). The plasma refilling rate (PRR), evaluated as the refilling fraction (RF), is unexpectedly smaller in I-HDF. However, in patients who respond, the RF is well achieved, which suggests that adequate PRR is the central physiology for preventing IDH. Patients for whom I-HDF is effective are characteristically relatively elderly and show increased IDWG. Blood pressure increment and reduced sympathetic activation in I-HDF may be a mechanism for prevention of IDH. Key Messages: Evaluating relative changes in blood volume during I-HDF will provide a new perspective for exploring appropriate ultrafiltration modification that circumvents IDH.

Vascular endothelial function masks increased sympathetic vasopressor activity in rats with metabolic syndrome.

Sympathetic hyperactivation, a common feature of obesity and metabolic syndrome, is a key trigger of hypertension. However, some obese subjects with autonomic imbalance present a dissociation between sympathetic activity-mediated vasoconstriction and increased blood pressure. Here, we aimed to determine in a rat model of metabolic syndrome whether the endothelium endothelial nitric oxide (NO) synthase (eNOS)-NO pathway contributes to counteract the vasopressor effect of the sympathetic system. Rats were fed a high-fat and high-sucrose (HFS) diet for 15 wk. Sympathovagal balance was evaluated by spectral analysis of heart rate variability and plasmatic catecholamine measurements. Blood pressure was measured in the presence or absence of N-nitro-l-arginine methyl ester (l-NAME) to inhibit the contribution of eNOS. Vascular reactivity was assessed on isolated aortic rings in response to α1-adrenergic agonist. The HFS diet increased sympathetic tone, which is characterized by a higher low on the high-frequency spectral power ratio and a higher plasmatic concentration of epinephrine. Despite this, no change in blood pressure was observed. Interestingly, HFS rats exhibited vascular hyporeactivity (-23.6%) to α1-adrenergic receptor stimulation that was abolished by endothelial removal or eNOS inhibition (l-NAME). In addition, eNOS phosphorylation (Ser1177) was increased in response to phenylephrine in HFS rats only. Accordingly, eNOS inhibition in vivo revealed higher blood pressure in HFS rats compared with control rats (147 vs. 126 mmHg for mean blood pressure, respectively). Restrain of adrenergic vasopressor action by endothelium eNOS is increased in HFS rats and contributes to maintained blood pressure in the physiological range. NEW & NOTEWORTHY Despite the fact that prohypertensive sympathetic nervous system activity is markedly increased in rats with early metabolic syndrome, they present with normal blood pressure. These observations appear to be explained by increased endothelial nitric oxide synthase response to adrenergic stimulation, which results in vascular hyporeactivity to α-adrenergic stimulation, and therefore blood pressure is preserved in the physiological range. Listen to this article's corresponding podcast at http://www.physiology.org/doi/10.1152/ajpheart.00217.2017 .

Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis by possible reduction of NLRP3 activation and up-regulation of NET expression.

OBJECTIVE: Previous studies have shown that acute inflammation is associated with increased sympathetic activity, which in turn increases the inflammatory response and leads to organ damage. The present study aimed to investigate whether dexmedetomidine administration during acute pancreatitis (AP) lessens pancreatic pathological and functional injury and the inflammatory response, and to explore the underlying mechanisms. METHODS: Mild pancreatitis was induced in mice with caerulein, and severe pancreatitis was induced with caerulein plus lipopolysaccharide (LPS). After pancreatitis induction, dexmedetomidine at 10 or 20 µg/kg was injected via the tail vein. Pancreatic pathological and functional injury was assessed by histology and serum levels of amylase and lipase, respectively. The inflammatory response was evaluated by determining serum levels of inflammatory factors. The expression of myeloperoxidase (MPO) was examined by immunohistochemistry. The expression of norepinephrine transporter (NET), NLRP3, pro-IL-1ß, and interleukin (IL)-1ß in pancreatic tissue was detected by Western blot and real-time PCR. RESULTS: Dexmedetomidine at 20 µg/kg significantly attenuated pancreatic pathological injury, reduced serum levels of amylase, lipase, IL-1ß, IL-6, and tumor necrosis factor (TNF)-α, and decreased the expression of MPO in pancreatic tissue in both mouse models of pancreatitis. In addition, dexmedetomidine at 20 µg/kg significantly down-regulated the expression of NLRP3, pro-IL-1ß, and IL-1ß in pancreatic tissue, but up-regulated the expression of NET in both mouse models. CONCLUSION: Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis possibly by reducing NLRP3 activation and up-regulating NET expression.