Sympathetic Activity Research Articles

The impact of inflammatory and oxidative stress biomarkers on the sympathetic nervous system in severe coronary atherosclerosis.

The present study aimed at evaluating the association between sympathetic nervous system activation (SNS) and the severity of coronary artery disease (CAD). In addition, we tested the hypothesis that inflammation and oxidative stress influence the SNS activation. Adult patients with severe CAD scheduled for coronary artery bypass graft (CABG) surgery were enrolled. SYNTAX I score was calculated based on coronary angiography. Systemic activation of the SNS was estimated through circulating levels of norepinephrine (NE). Plasma levels of pro-inflammatory cytokines (IL 1β, IL 6 and HIF 1α) and oxidative stress molecules (SOD-1 and LOX-1) were obtained prior to surgery. Circulating NE levels were significantly correlated with the severity of CAD, as assessed by the SYNTAX I score (p 0.002; r 0.329). Elevated levels of circulating pro-inflammatory markers were significantly correlated with increased NE concentrations (for IL-1β: p < 0.001, r = 0.49; for IL-6 and NE: p = 0.003, r = 0.32; for HIF-1α and NE: p = 0.049, r = 0.21). Additionally, oxidative stress molecules were associated with circulating NE levels (for SOD-1 and NE: p = 0.016, r = 0.26; for LOX-1 and NE: p = 0.004, r = 0.31). In patients with CAD referred for CABG, SNS activation, indicated by plasma NE levels, was correlated with disease severity as assessed by the SYNTAX I score, as well as with markers of inflammation and oxidative stress. This suggests that inflammation, oxidative stress, and SNS activation form an interconnected network, with each component influencing the others. It might be of interest to develop a scoring system including inflammation and oxidative stress markers to identify patients that require a more aggressive approach to lower inflammation, oxidative stress and modulate the sympathetic nervous system. This could be of use especially in the setting of a scheduled intervention -such as CABG surgery.

Resistant Hypertension: A Brief Review of Pathophysiology.

A 52-year-old male comes to the internal medicine clinic for a follow-up for the management of hypertension. He was initially diagnosed with hypertension 5 years ago. His other past medical history includes obesity and hyperlipidemia. His current medications currently include losartan 100 mg daily, hydrochlorothiazide 25 mg, and amlodipine 10 mg. His physical exam is significant for an elevated in-office blood pressure of 160/105 mmHg, BMI 38, and neck circumference >40 cm. He also reports snoring at night and having significant daytime sleepiness despite getting over 8 hours of sleep each night. This patient meets the most recent diagnostic criteria per the American Heart Association for resistant hypertension. Resistant hypertension is an increasingly prevalent phenotype encountered in both primary care and subspecialty clinics. Multiple comorbidities, including obesity, sleep apnea, chronic kidney disease, heart failure, and diabetes mellitus, are associated with resistant hypertension. Our understanding of the potential etiologies for this condition continues to evolve rapidly. We used a narrative review to explore four research areas in the pathophysiology of resistant hypertension (the sympathetic nervous system, aldosterone excess, endothelial dysfunction, and inflammation) and explore the novel therapies currently in development.

Cellular mechanisms of synchronized rhythmic burst generation in the ventromedial hypothalamus.

The ventromedial hypothalamus (VMH) plays an important role in feeding behavior and control of the sympathetic nervous system (SNS). The VMH includes a group of neurons that exhibit strong synchronized rhythmic burst firing (so-called VMH oscillation). This VMH oscillation is glucose inhibited, responsive to feeding-related peptides, and is functionally coupled to outputs of the SNS. However, the details of its rhythm generation and synchronization mechanisms are unknown. In the present study, we investigated cellular mechanisms of VMH oscillation by means of electrophysiological recordings and calcium imaging in juvenile rat slice preparations including the VMH. In the electrophysiological study, we performed membrane potential recording from neurons in the vicinity of pipettes for field potential recording. We found that the rhythmic bursts in the VMH were preserved in low Ca2+/high Mg2+ synaptic transmission blockade solution. During membrane hyperpolarization by current injection, the action potential was largely inhibited, but fluctuation of the membrane potential remained with a frequency similar to that at resting potential level. The electric VMH oscillation disappeared after application of either a gap junction blocker, carbenoxolone (100µM), or a persistent sodium channel blocker, riluzole (20µM). Membrane potentials and input resistances of rhythmic burst neurons in the VMH were not significantly changed during these manipulations. A calcium imaging study revealed that all VMH cells exhibiting synchronized rhythmic activity detected by intracellular calcium increases were silenced following the application of carbenoxolone. These results suggest that VMH oscillation arises from the activation of persistent sodium channels and coupling via gap junctions.

Acute cardiovascular responses of postmenopausal women to resistance training sessions differing in set configuration: A study protocol for a crossover trial.

Resistance training is hardly recommended for postmenopausal women to counteract negative effects of hormonal changes. However, some concern exists about the marked hemodynamic responses caused by high-load resistance exercises. In this regard, studies on young, healthy, physically active individuals suggest that set configuration can modulate acute cardiovascular, metabolic, and cardiac autonomic responses caused by resistance training sessions, but this has not yet been explored in postmenopausal women. A sample of 60 physically active postmenopausal women (30 normotensive, 30 hypertensive) will participate in this crossover study. After a medical exam, ergometry, familiarization session, and two testing sessions, participants will complete three experimental sessions and one control session in a randomized order. Each experimental session includes 36 repetitions of four exercises (horizontal leg press, bench press, prone leg curl, and lat pull-down) differing in set configuration: 9 sets of 4 repetitions (i.e., 33% intensity of effort) with 45 s of inter-set recovery, 6 sets of 6 repetitions (50% intensity of effort) with 72 s, and 4 sets of 9 repetitions (75% intensity of effort) with 120 s; with 4 min rest between exercises. Before and immediately after each session, arterial stiffness, hemodynamic variables, cardiac autonomic modulation, baroreflex sensitivity, sympathetic vasomotor tone, and resting oxygen uptake will be evaluated. Furthermore, perceived effort, mechanical performance (e.g., power, velocity), heart rate, and lactatemia will be collected throughout sessions. The impact of set configuration on these variables will be analyzed, along with comparisons between normotensive and hypertensive women. Cardiovascular responses to resistance exercise have been scarcely studied in females, particularly postmenopausal women. The results of this study will provide information about the modulating role of set structure on metabolic and cardiovascular responses of normotensive and hypertensive postmenopausal women to resistance training. NCT05544357 on 7 December 2022.

Molecular Insight into Obesity-Associated Nephropathy: Clinical Implications and Possible Strategies for its Management.

Obesity is a significant health concern due to its rapid increase worldwide. It has been linked to the pathogenic factors of renal diseases, cancer, cardiovascular diseases, hypertension, dyslipidemia, and type 2 diabetes. Notably, obesity raises the likelihood of developing chronic kidney disease (CKD), leading to higher adult mortality and morbidity rates. This study explores the molecular mechanisms that underlie obesity-associated nephropathy and its clinical implications. Obesity-Associated Nephropathy (OAN) develops and worsens due to insulin resistance and hyperinsulinemia, which promote renal sodium reabsorption, glomerular hyperfiltration, and hypertension, leading to progressive kidney damage. Renal damage is further aggravated by persistent inflammation and redox damage, mediated by adipokines and proinflammatory cytokines, such as TNF-α and IL-6. Furthermore, stimulation of the sympathetic nervous system and the renin-angiotensin- aldosterone system (RAAS) intensifies glomerular hypertension and fibrosis. These elements cause glomerular hyperfiltration, renal hypertrophy, and progressive kidney damage. Clinical manifestations of obesity-associated nephropathy include proteinuria, reduced glomerular filtration rate (GFR), and ultimately, CKD. Management strategies currently focus on lifestyle modifications, such as weight loss through diet and exercise, which have been effective in reducing proteinuria and improving GFR. Pharmacological treatments targeting metabolic pathways, including GLP-1 receptor agonists and SGLT2 inhibitors, have shown renoprotective properties. Additionally, traditional RAAS inhibitors offer therapeutic benefits. Early detection and comprehensive management of OAN are essential to prevent its progression and lessen the burden of CKD.

Decreases in Sympathetic Activity Due to Low-Intensity Extremely Low-Frequency Electric Field Treatment Revealed by Measurement of Spontaneous Fluctuations in Skin Conductance in Healthy Subjects

Decreases in Sympathetic Activity Due to Low-Intensity Extremely Low-Frequency Electric Field Treatment Revealed by Measurement of Spontaneous Fluctuations in Skin Conductance in Healthy Subjects

Superior cervical ganglionectomy attenuates vascular remodeling in spontaneously hypertensive rats.

Sympathetic hyperactivity contributes to the pathogenesis of hypertension. However, it is unclear whether the excessive sympathetic activity is an independent and crucial factor for vascular remodeling in hypertension. This study focused on the effect of local sympathetic denervation with superior cervical ganglionectomy (SCGx) on vascular remodeling. Surgical bilateral SCGx was performed in 9-week-old male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Control rats received sham-operation without SCGx. All measurements were made 4 weeks after the surgery. The effectiveness of SCGx was confirmed by the eye features of Horner syndrome, greatly reduced tyrosine hydroxylase (TH) contents in the superior cervical ganglion (SCG)-innervated arteries in the head. Although SCGx had no significant effects on blood pressure and heart rate in WKY and SHR, it attenuated vascular remodeling of facial artery and superficial temporal artery in SHR, two representative SCG-innervated extracranial arteries, without significant effects on non-SCG-innervated thoracic aorta and mesenteric artery. SCGx-treated SHR had more auricular blood flow and retina microvasculature than sham-operated SHR. However, SCGx had only a mild effect in attenuating the vascular remodeling of basilar artery and middle cerebral artery, two representative SCG-innervated intracranial arteries, in SHR. SCGx-treated SHR exhibited upregulation of α-smooth muscle actin, downregulation of proliferating cell nuclear antigen, and attenuation of oxidative stress and inflammation in facial artery and superficial temporal artery. Sympathetic denervation by SCGx in SHR attenuated local vascular remodeling, suggesting that sympathetic overactivity is a crucial pathogenic factor of vascular remodeling in SHR.

Childhood Maltreatment and Electrodermal Reactivity to Stress Among Pregnant Women.

There are competing theoretical hypotheses regarding the consequences of early adversity, such as childhood maltreatment, for individuals' autonomic nervous system activity. Research examining potential implications of child maltreatment for sympathetic nervous system activity, specifically, is scarce. In this preregistered study, we examined whether childhood maltreatment history is associated with pregnant adults' sympathetic responses to different stressors. This population is particularly relevant, given potential intergenerational consequences of pregnant individuals' physiological responses to stress. Pregnant women's (N=162) electrodermal levels were recorded while completing the Trier Social Stress Test (TSST), which elicits social-evaluative threat, and while watching a video of an unfamiliar infant crying, which was intended to activate the attachment system. Pregnant women's retrospective reports of childhood maltreatment were negatively associated with their electrodermal reactivity to the TSST and to the video of the infant crying. Follow-up analyses indicated that these associations were specific to reported experiences of childhood abuse and not childhood neglect. Altogether, these findings indicate that self-reported childhood maltreatment experiences, and childhood abuse in particular, may result in blunted activity of the sympathetic nervous system in response to multiple types of stressors.

Light modulates glucose and lipid homeostasis via the sympathetic nervous system.

Light is an important environmental factor for vision, and for diverse physiological and psychological functions. Light can also modulate glucose metabolism. Here, we show that in mice, light is critical for glucose and lipid homeostasis by regulating the sympathetic nervous system, independent of circadian disruption. Light deprivation from birth elicits insulin hypersecretion, glucagon hyposecretion, lower gluconeogenesis, and reduced lipolysis by 6-8 weeks, in male, but not, female mice. These metabolic defects are consistent with blunted sympathetic activity, and indeed, sympathetic responses to a cold stimulus are significantly attenuated in dark-reared mice. Further, long-term dark rearing leads to body weight gain, insulin resistance, and glucose intolerance. Notably, metabolic dysfunction can be partially alleviated by 5 weeks exposure to a regular light-dark cycle. These studies provide insight into circadian-independent mechanisms by which light directly influences whole-body physiology and inform new approaches for understanding metabolic disorders linked to aberrant environmental light conditions.

Human iPSC-derived mesenchymal stem cells relieve high blood pressure in spontaneously hypertensive rats via splenic nerve activated choline acetyltransferase-positive cells.

Despite substantial advancements in modern medicine, the management of hypertension remains a major challenge. Stem cell-based therapies have recently demonstrated remarkable efficacy in treating cardiovascular diseases, including hypertension. However, the antihypertensive mechanism of mesenchymal stem cells (MSCs) has not been extensively explored. This study aimed to investigate the role of injected MSCs in regulating blood pressure homeostasis. Our previous study demonstrated that human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) are functional and homogeneous sources for MSC-based therapy. After the injection of hiPSC-MSCs, a significant reduction in blood pressure and end target organ inflammation were observed in spontaneously hypertensive rats (SHRs). Cell tracking assays demonstrated that the injected hiPSC-MSCs accumulated in the spleens of the SHRs. The injected hiPSC-MSCs accumulated adjacent to the splenic nerve, potentially contributing to the antihypertensive effects. Furthermore, the hiPSC-MSCs released abundant glutamate, which acts as a neuromodulator to activate the splenic sympathetic nerve. After inhibition of glutamate synthesis by siRNA, the ability of hiPSC-MSCs to activate sympathetic nerves was significantly diminished. In addition, the antihypertensive effects of hiPSC-MSCs were eliminated after splenic nerve denervation (SND), underscoring the critical role of the splenic nerve. Moreover, activation of the splenic nerve resulted in increased release of norepinephrine (NE), which increased the number of choline acetyltransferase-positive (ChAT+) cells in the spleen and peripheral blood. Consequently, the acetylcholine (ACh) produced by elevated ChAT+ cells could act as a vasodilator, lowering blood pressure and mitigating inflammation in end target organs. In summary, our findings indicate that hiPSC-MSCs effectively lower blood pressure in hypertension by influencing the splenic nerves and regulating ChAT+ cells. The connection between blood pressure regulation and the splenic nerve may offer new insights into the treatment of hypertension.

Exposure to nicotine and withdrawal in Wistar rats: an electrophysiological study.

Throughout the world, smoking is one of the principal causes of preventable death. Nicotine, the primary active component of tabacco, acts as a psychostimulant and modulates the electrical activity of a number of the areas of the brain involved in addiction. Abstinence from nicotine will also impact the functional state of the brain, which is reflected in symptoms of craving and susceptibility to relapse. In addition, given the increase in the sympathetic tone of the heart and pulse rate promoted by nicotine, its consumption can contribute to tachyarrhythmia. The present study investigated the electroencephalographic (EEG) and electrocardiographic (ECG) patterns of Wistar rats submitted to acute or chronic exposure to nicotine, followed by withdrawal for 24 or 48 hours, and the re-administration (or not) of nicotine, to simulate episodes of relapse. The EEG data revealed an increase in all types of brainwaves, with emphasis on high-frequency (alpha, beta, and gamma) brain oscillations following both acute and chronic exposure to nicotine (14 days), whereas in withdrawal, there was a predominancy of delta waves. When exposure to nicotine was reinstated after withdrawal, the observed EEG profile was similar to that found in chronic exposure. The electrocardiogram reads showed that both acute and chronic exposure to nicotine caused abnormalities in the atrioventricular conduction and that, while these changes improve with substance withdrawal, relapse can worsen these parameters. The results of this study indicate that high-frequency brainwaves are correlated with nicotine dependence, while slow brain oscillations are consistent with drug craving, and episodes of nicotine relapse can reproduce brain activity patterns linked to dependence. Finally, exposure to nicotine predisposes the individual to heart rhythm abnormalities, which are attenuated by withdrawal, but may nevertheless be restored rapidly with re-exposure to the substance. This study demonstrated that nicotine increases high-frequency brain oscillations, which is associated with addiction, whereas withdrawal elevates the delta wave power, suggesting craving. Re-exposure to nicotine following withdrawal restores rapidly the EEG profile of chronic dependence. In addition, nicotine has deleterious impacts on cardiac activity, which are linked to fatal arrhythmias. This implies that stopping smoking is beneficial for the amelioration of the alterations in heart rhythm caused by nicotine addiction. This study elucidates the functional states of the brain and heart during both sporadic and chronic nicotine use, and the electrophysiological explanation for substance dependence and drug relapse after craving episodes.

Energy Expenditure in Critically Ill Patients with Aneurysmal Subarachnoid Hemorrhage, Intracerebral Hemorrhage, and Traumatic Brain Injury-A Prospective Observational Study.

Energy expenditure (EE) in patients with aneurysmal subarachnoid hemorrhage (SAH) may differ from other intracranial pathologies, such as intracerebral hemorrhage (ICH) or traumatic brain injury (TBI), due to an activation of the sympathetic nervous system. Indirect calorimetry (IC) is recommended, but is not always available. We study EE, catabolism, and metabolic stress in patients with SAH, TBI, ICH, and sepsis as controls. A prospective observational study was conducted in the intensive care units of the University Medical Center Hamburg-Eppendorf, Germany. IC was used to measure EE on days 2-3, 5-7, and 10-15 post-admission. Urinary catecholamines, metabolites, and urine urea were also measured. Statistical analysis included t-tests, Chi-square tests, and generalized mixed models. We included 110 patients-43 SAH patients (13 with the surgical securing of the aneurysm and 30 with coil embolization of the aneurysm), 22 TBI patients, 23 ICH patients, and 22 controls. The generalized linear mixed model analysis for groups and timepoints including age, height, and weight as covariates revealed a significantly lower EE at timepoint 1 for ICH versus SAH-interventional (p = 0.003) and versus the control (p = 0.004), as well as at timepoint 2 for ICH versus SAH-interventional (p = 0.002) and versus SAH-surgical (p = 0.013) with a lower EE in ICH patients. No significant differences between groups were found for EE at the other timepoints, or concerning urine urea and measurements of catecholamines in urine. In patients with SAH, ICH, and TBI, no meaningful differences in EE were detected compared to septic critically ill patients, except for a lower EE in ICH patients in the early phase.

Weight Loss Therapies and Hypertension Benefits.

Obesity and hypertension have become an international health issue, with detrimental consequences on patients. Obesity and hypertension share common pathophysiological mechanisms, such as overactivity of the renin-angiotensin-aldosterone and the sympathetic nervous systems, insulin resistance, and disruption of the leptin pathway. Approved therapies for obesity and overweight include phentermine/topiramate, orlistat, naltrexone/bupropion, the glucagon-like peptide-1 receptor agonists liraglutide and semaglutide, tirzepatide, and bariatric surgery. This review gives the clinical data in a thorough manner and explains in detail how each of the previously mentioned therapies affects blood pressure levels.

Beta-adrenergic reactivity of erythrocyte membranes in adolescents with supraventricular and ventricular arrhythmias before and after radiofrequency ablation

Aim. To evaluate β-adrenergic reactivity of erythrocyte membranes (β-ARM) in adolescents with ventricular and supraventricular arrhythmias before and after radiofrequency ablation (RFA) of heart rhythm disturbances.Materials and methods. The study included 49 adolescents aged 11–17 years, of which 15 had Wolff – Parkinson – White pattern (WPW), 13 – WPW syndrome, 10 – atrioventricular nodal reentry tachycardia (AVNRT), and 11 – ventricular arrhythmia (VA). The control group consisted of 11 adolescents without cardiovascular pathology. All patients received surgical treatment for heart rhythm disturbances (HRD) using RFA. In patients with HRD, β-ARM was determined by a set of reagents BETA-ARM AGAT (AGAT LLC, Russia) before RFA and 3 days after it. In the control group, the parameter was determined at the stage of inclusion in the study.Results. In adolescents with supraventricular arrhythmias, median values of β-ARM did not differ significantly from the control group. RFA in adolescents in these groups did not affect the value of β-ARM on day 3 after the surgery. In adolescents with VA, the median value of β-ARM was initially higher than in the control group (p = 0.026). On day 3 after RFA, an increase in β-ARM was noted in this group (p = 0.028) compared to baseline values.Conclusion. Activation of the sympathetic nervous system plays a significant role in the pathogenesis of VA in adolescence. The study showed the possibility of using β-ARM to assess the state of the sympathetic nervous system in patients with methodological limitations in analyzing heart rate variability.

Insight of autonomic dysfunction in CLN3 disease: a study on episodes resembling paroxysmal sympathetic hyperactivity (PSH)

BackgroundRecurrent non-epileptic episodes resembling paroxysmal sympathetic hyperactivity (PSH) have been observed in adolescents with Juvenile Ceroid Lipofuscinosis (CLN3-disease) and a possible association to an autonomic dysfunction has been suggested. The objective of the present study was to investigate the dynamics of the autonomic activity up to, during, and in the time after individual attacks. We include all seven suitable CLN3 patients in Denmark ≥ 15 years of age. HRV parameters were assessed from continuous heart rate monitoring during seven consecutive days and a particular focus of HRV parameters was obtained in close temporal context to clinically recurrent PSH-like episodes. In addition, the likelihood of PSH was assessed by caregiver’s description and by video documentation.ResultsRespectively eight and five episodes were recorded in two patients (18 and 20 years of age). The episodes were all safely superior to the cut off values of the clinical assessment score to be considered PSH-like episodes. During all 13 episodes, HRV revealed a statistically significant decrease in root mean square of successive differences (RMSSD) and standard deviation of the Poincaré-Plot interval (SD1) in the minutes prior to the clinical onset of the episodes, both indicating a sudden decrease in parasympathetic activity in advance of the onset. The reduced activity remained low during the episodes, and 15–30 min following the attack cessation, the parasympathetic activity had returned to pre-attacks levels. The sympathetic HRV parameters were unchanged resulting in a sympathetic overactivity during the episodes. In a third participant (32 years of age), in whom severity of PSH-like episodes had been gradually reduced during the last years, five episodes were registered. A similar temporally related reduction of the parasympathetic activity was found, but because the sympathetic activity decreased as well, no sympathetic dominance developed, which most reasonable is the reason to the clinically reduced expression of the episodes.ConclusionThe documented transient withdrawal of parasympathetic activity leading to a paroxysmal unbalanced sympathetic hyperactivity most probably accounts for the PSH-like episodes occurring in post-adolescent CLN3 patients. The findings shed new light on both aetiology and possible preventative and therapeutic measures.

Higher skin sympathetic nerve activity as a potential predictor of overactive bladder in females refractory to oral monotherapy.

This study investigates predictors of unsatisfactory outcomes in female overactive bladder (OAB) patients treated with oral monotherapy by analyzing skin sympathetic nerve activity (SKNA) using a novel "neuECG" method. The study included 55 newly diagnosed female patients with idiopathic OAB, autonomic function was evaluated using neuECG before treatment initiation, and validated OAB questionnaires and urodynamic studies were administered. Initial monotherapy was administered for the first 4 weeks, with non-responders defined as patients not achieving satisfactory symptom relief and requiring further treatment. Responders (n = 32) and non-responders (n = 23) had no significant differences in baseline characteristics or urodynamic parameters; however, non-responders exhibited significantly higher baseline average SKNA (aSKNA) (1.36 ± 0.49 vs. 0.97 ± 0.29 μV, p = 0.001), higher recovery aSKNA (1.28 ± 0.46 vs. 0.97 ± 0.35 μV, p = 0.007), and a lower stress/baseline ratio of aSKNA (1.05 ± 0.42 vs. 1.26 ± 0.26, p = 0.029). Baseline aSKNA had the highest predictive value for monotherapy refractoriness in OAB (AUROC = 0.759, p = 0.001), with an optimal cut-off point of >1.032 μV. These findings suggest that elevated pre-treatment aSKNA can predict resistance to oral monotherapy in OAB, warranting close monitoring and proactive treatment strategies for patients with high aSKNA.

Rapid assessment of cardiac autonomic modulation and adaptive stress responses: Automatic calculation of time-varying parasympathetic, sympathetic, and Baevsky stress indexes

Cardiac autonomic modulation (CAM), which is regulated by the balance between the sympathetic and parasympathetic nervous systems, is involved in various physiological and pathological conditions. Heart rate variability (HRV) analysis has been used to explore the complex relationship between the brain and heart, as described by Porges&amp;rsquo; polyvagal theory and Thayer&amp;rsquo;s neurovisceral integration model. Recently, an automated calculation of new parasympathetic, sympathetic, and Baevsky stress indexes based on HRV parameters has been introduced for faster and more comprehensive CAM assessment, though their normal ranges remain undefined. This study aimed to determine the average values of these indexes in a healthy population of different ages during rest, daily activities, non-rapid eye movement sleep, graded physical effort, and acute psychophysiological stress. At rest, the parasympathetic and sympathetic indexes were consistently within the proposed normal range and inversely related. However, Baevsky stress index values from Kubios were higher than expected, conflicting with the assumption that they are simply the square root of those calculated using the original formula. Despite this, time-varying assessment of all indexes can provide valuable insights into CAM adaptation during physical effort and acute psychophysiological stress in real-world critical situations. Notably, our novel finding shows that the inverse correlation between parasympathetic and sympathetic/stress indexes under stress is better explained by non-linear functions, offering a potential new measure of brain&amp;ndash;heart interaction during real-life critical events.

The β2-adrenergic biased agonist nebivolol inhibits the development of Th17 and the response of memory Th17 cells in an NF-κB-dependent manner.

Adrenergic receptors regulate metabolic, cardiovascular, and immunological functions in response to the sympathetic nervous system. The effect of β2-adrenergic receptor (AR) as a high expression receptor on different subpopulations of T cells is complex and varies depending on the type of ligand and context. While traditional β2-AR agonists generally suppress T cells, they potentially enhance IL-17A production by Th17 cells. The effects of pharmacological drugs that count as biased agonists of AR like nebivolol are not completely understood. We investigated the impact of nebivolol on human memory CD4+ T (Th1, Th2, Th17) cells and polarized naive Th17 cells, highlighting its potential for IL-17A suppression via a non-canonical β2-AR cell signaling pathway. The effects of nebivolol were tested on healthy human peripheral blood mononuclear cells, purified memory Th cells, and polarized naive Th17 cells activated with anti-CD3/anti-CD28/anti-CD2 ImmunoCult reagent. IFN-γ, IL-4, and IL-17A, which are primarily derived from Th1, Th2, and Th17 cells, respectively, were quantified by ELISA and flow cytometry. IL-10 was measured by ELISA. Gene expression of RORC, ADRB1, ADRB2, and ADRB3 was evaluated by qPCR. The ADRB2 gene was knocked out in memory Th cells using CRISPR/Cas9. Protein expression of phosphorylated serine133-CREB and phosphorylated NF-κB p65 was assessed by Western blot. Proliferation was assessed by fluorescent dye loading and flow cytometry. Nebivolol treatment decreased IL-17A and IFN-γ secretion by activated memory Th cells and elevated IL-4 levels. Nebivolol reduced the proportion of IL-17A+ Th cells and downregulated RORC expression. Unlike the β2-AR agonist terbutaline, nebivolol inhibited the shift of naive CD4+ T cells toward the Th17 phenotype. IL-10 and the proliferation index remained unchanged. Nebivolol-treated β2-knockout memory Th cells showed significant inhibition of β2-AR-mediated signaling, evidenced by the absence of IL-17A suppression compared to controls. Phosphorylation of the NF-κB p65 subunit was inhibited by nebivolol, but CREB phosphorylation was not changed, suggesting a selective transcriptional control. The findings demonstrate that nebivolol acts through a β2-AR-mediated signaling pathway, as a distinctive anti-inflammatory agent capable of selectively shifting Th17 cells and suppressing the phosphorylation of NF-κB. This highlights nebivolol's potential for therapeutic interventions in chronic autoimmune conditions with elevated IL-17A levels.

Alzheimer's Disease: An Attempt of Total Recall.

This review is an attempt to compile existing hypotheses on the mechanisms underlying the initiation and progression of Alzheimer's disease (AD), starting from sensory impairments observed in AD and concluding with molecular events that are typically associated with the disease. These events include spreading of amyloid plaques and tangles of hyperphosphorylated tau and formation of Hirano and Biondi bodies as well as the development of oxidative stress. We have detailed the degenerative changes that occur in several neuronal populations, including the cholinergic neurons in the nucleus basalis of Meynert, the histaminergic neurons in the tuberomammillary nucleus, the serotonergic neurons in the raphe nuclei, and the noradrenergic neurons in the locus coeruleus. Furthermore, we discuss the potential role of iron accumulation in the brains of subjects with AD in the disease progression which served as a basis for the idea that iron chelation in the brain may mitigate oxidative stress and decelerate disease development. We also draw attention to possible role of sympathetic system and, more specifically, noradrenergic neurons of the superior cervical ganglion in triggering of the disease. We also explore the alternative possibility of compensatory protective changes that may occur in these neurons to support cholinergic function in the forebrain of subjects with AD.

Relationship between regional sympathetic vascular transduction and sympathetic transduction of blood pressure in young adults at rest.

A burst of muscle sympathetic nerve activity (MSNA) induces vasoconstriction that transiently reduces regional vascular conductance and increases systemic blood pressure (BP) over the subsequent 4-8 cardiac cycles. These responses are termed sympathetic neurovascular transduction and sympathetic transduction of BP, respectively. Sympathetic transduction of BP is commonly calculated and interpreted as a proxy measure for regional sympathetic neurovascular transduction, despite the systemic nature of BP regulation. The present analysis tested whether the peak change in signal-averaged sympathetic transduction of BP was correlated to the change in regional sympathetic vascular transduction at rest. Fourteen adults (5 females, 23±3 years) arrived at the laboratory, ate a standardized meal, and rested for 90-120 minutes. MSNA (fibular nerve microneurography), heart rate (electrocardiography), beat-to-beat BP (finger photoplethysmography), and superficial femoral artery blood flow (Doppler ultrasound) were obtained continuously for 10 minutes in the supine position. Femoral vascular conductance was calculated as blood flow divided by mean arterial BP. The peak change in diastolic BP following a burst of MSNA was correlated to the corresponding nadir change in femoral vascular conductance (r=-0.58 [-0.07 to -0.85], P=0.03) and superficial femoral artery blood flow (r=-0.54 [-0.17 to -0.83], P=0.04). The nadir change in diastolic BP in cardiac cycles not following a MSNA burst was correlated to the peak change in femoral vascular conductance (r=-0.42 [-0.83 to 0.00], p=0.05) but not superficial femoral artery blood flow (r=0.41 [-0.77 to 0.15], p=0.14). In conclusion, more commonly assessed sympathetic transduction of BP provides moderate insight into regional sympathetic neurovascular transduction.