Sympathetic Nervous System Activity Research Articles

Skin conductance responses to oral stimuli: The role of taste quality and intensity, and personality traits

Measuring emotional responses to tastes and foods, using both self-reports and also implicit and physiological measurements is gaining attention. Among physiological measurements, skin conductance response (SCR) is one the most commonly used indicators of emotional activation but it has been rarely applied to taste and other oral stimuli and its interpretation is not yet clear. Furthermore, the effect of individual differences in SCR to tastes has been rarely taken into account. To address these issues, SCR to bitter, astringent, and sweet samples presented both at weak/moderate and moderate/strong intensity was recorded while eighty Italians, selected based on PROP (6-n-propylthiouracil) status (only Medium-Tasters), performed an implicit affective test. Samples were presented blind in aqueous solutions monadically in triplicate. Subjects (Ss) were asked to taste a sample, then a neutral face was briefly presented on a screen, and Ss were asked to indicate if they trusted the face (yes/no) and how much (on a 9-point Scale). Data on Ss’ psychological traits (anxiety, sensation seeking, food neophobia, emotional stability) was also collected. Two clusters were identified based individual SCR. These clusters differed in their SCR mainly to strong bitterness, and partially to astringency, while they did not differ for their response to the sweet samples. The High bitter responders were more anxious and neurotic than Low bitter responders. For this cluster higher intensities induced higher SCR, but this was not found in the Low bitter responders cluster that tended to have higher SCR to the least intense samples. No differences in the implicit affective responses to samples were found between clusters. These results indicate that SCR to tastes reflect mainly different sources of arousal, such as novelty/surprisingness, quality and intensity of the stimuli, and this may change at an individual level. This suggests that measurement of SC can contribute to a better understanding of individual differences in taste and oral experience and could provide a link between taste responsiveness and sympathetic nervous system activity.

SIESTA DIPPING AND CIRCADIAN BLOOD PRESSURE PATTERNS IN ACUTE ISCHEMIC STROKE

Objective: The purpose of this study was to investigate the alterations of blood pressure (BP) during the midday (siesta time) and the changes of circadian BP patterns in acute phase of ischemic stroke (AIS) with the severity of stroke and their predictive role for the 3 months outcome. Design and method: A total of 228 AIS patients (prospective multicenter follow-up study, NCT01915862) underwent 24-hour ambulatory blood pressure monitoring (ABPM) every 20 minutes within 48 hours from stroke onset using an automated oscillometric device. Clinical and laboratory findings were recorded. Mean BP parameters during day (7:00-22:59), midday (13:00-16:59) and night (23:00-6:59) and siesta and nocturnal dipping were calculated. Endpoints were death and disability/death at 3 months. Results: Siesta SBP dippers had less severe stroke, lower incidence of hypertension and SBP/DBP on admission, lower levels of serum glucose and WBC and delayed initiation of ABPM compared to risers. There was a reverse relation of siesta SBP dipping with both nocturnal dipping (r = -0.27, p<0.001) and the severity of stroke (r = -0.13, p = 0.049). The “double dippers” (siesta and nocturnal dipping) had the least severe stroke, the lowest SBP/DBP on admission and heart rate from ABPM and lower risk of an unfavorable outcome, while the “double risers” had the opposite results, by an approximately 5-fold risk of death/disability at 3 months. Conclusions: These findings indicate different circadian BP patterns according to stroke severity during the acute phase of AIS, potentially driven by patient's physical stress and maybe alterations of the sympathetic nervous system activity, which should be considered as markers of patient's state and prognosis.

CORRELATION BETWEEN BLOOD PRESSURE RESPONSE TO SUB MAXIMAL EXERCISE AND LEFT VENTRICULAR HYPERTROPHY

Objective: Currently, there is no common consent on what constitutes a normal increase in blood pressure (BP) during physical activity and, consequently, what constitutes an exaggerated increase in BP response to exercise. At this stage, the processes, and clinical consequences of hypertensive response to exercise (HRE) remain unknown. Even in those who do not have hypertension or other cardiovascular disorders, a hypertensive response to exercise (HRE) is common. An increased blood pressure response to exercise is a legitimate risk marker for future hypertension, as previous research has demonstrated. HRE has among its contributors the endothelial dysfunction and an increase in afterload. in terms of neurohormonal aspects Excess sympathetic nervous system activation and an increase in angiotensin II appear to be crucial mechanisms in HRE, according to studies. Design and method: Of the 84 eligible participants, men (n 46) women (n 38) with I and II degree hypertension (n 32) and pre hypertension (n 22). The study analysis included the subjects with an age range of 18-64 years (mean age 42.1±12.7 years) With or without left ventricular hypertrophy (LVH) described as normal, Concentric hypertrophy, Eccentric hypertrophy, concentric remodeling. Results: For most of the subjects on the initial evaluation, we discovered echocardiographic evidence of concentric hypertrophy. Among the resting and exercise BP indices, submaximal SBP was the strongest correlate of LV mass (r = 0.40, P<0.04). In multivariate analysis, maximal SBP was independently associated with LV mass and concentric LV hypertrophy, after adjustment for lean body mass and gender. Submaximal exercise SBP is a modest but still independent predictor of LV remodeling (grade and type of LV geometry) in population with prehypertension, I and II grade hypertension. Conclusions: More frequent clinical control of resting BP, an echocardiogram, a 24-hour BP ambulatory monitoring as a more dynamic test, and at least annual repetition of the exercise test, to follow up the same abnormal response, as more studies are needed and a consensus regarding the abnormal response of the BP during exercise. Our study can be of clinical importance to prevent future adverse events linked to hypertension induced organ damage.

Long-term safety and efficacy of renal sympathetic denervation in atrial fibrillation: 3-year results of the AFFORD study

BackgroundAtrial fibrillation (AF) is the most common sustained arrhythmia which has been associated with increased sympathetic nervous system activity and hypertension. Recent evidence indicated that renal sympathetic denervation (RDN) could safely contribute to an improvement in AF burden.ObjectiveTo investigate the long-term safety and efficacy of radiofrequency RDN in hypertensive patients with symptomatic AF.MethodsThis pilot study included patients with symptomatic paroxysmal or persistent AF (European Hearth Rhythm Association class ≥ II) despite optimal medical therapy, office systolic blood pressure (BP) ≥ 140 mmHg and ≥ 2 antihypertensive drugs. AF burden was measured using an implantable cardiac monitor (ICM), implanted 3 months prior to RDN. ICM interrogation and 24-h ambulatory BP monitoring were performed at baseline and at 3/6/12/24/36 months post RDN. The primary efficacy outcome was daily AF burden. Statistical analyses were performed using Poisson and negative binomial models.ResultsA total of 20 patients with a median age [25th–75th percentiles] of 66.2 [61.2–70.8] years (55% female) were included. At baseline, office BP ± standard deviation (SD) was 153.8/87.5 ± 15.2/10.4 mmHg, while mean 24-h ambulatory BP was 129.5/77.3 ± 15.5/9.3 mmHg. Baseline daily AF burden was 1.4 [0.0–10.9] minutes/day and throughout a 3-year follow-up period, no significant change was observed (− 15.4%/year; 95% confidence interval (CI) − 50.2%, + 43.7%; p = 0.54). The number of defined daily doses of antiarrhythmic drugs and antihypertensive drugs remained stable over time, while mean 24-h ambulatory systolic BP decreased with − 2.2 (95% CI − 3.9, − 0.6; p = 0.01) mmHg/year.ConclusionsIn patients with hypertension and symptomatic AF, stand-alone RDN reduced BP but did not significantly reduce AF burden up until 3 years of follow-up.Graphical abstract

(023) The Acute Effect of Caffeine on Genital Arousal in Women: A Pilot Study

Abstract Introduction Genital sexual arousal, a process characterized by increased vaginal lubrication and vasocongestion in females, is facilitated by moderate activation of the sympathetic nervous system (SNS) (for review, see Stanton, Handy, & Meston, 2018). Among the range of factors that impede the female genital arousal response (e.g., disrupted endocrine functioning and vascular and neurological problems), antidepressants have strikingly deleterious effects on genital arousal function that hinder quality of life (Nappi et al., 2016) and jeopardize medication adherence. When patients present with antidepressant-induced sexual side effects, physicians may switch their antidepressant or tack on an additional medication (e.g., bupropion) to counter them. While sometimes effective, this increases patients’ financial burden and often introduces a host of new side effects. Moderate activation of the SNS through exercise has shown promising results for ameliorating antidepressant-induced genital arousal dysfunction (Lorenz & Meston, 2012; 2014). Given that SNS activation prior to sex counteracts the inhibitory effect of antidepressants on genital blood flow, it is feasible that caffeine – an SNS stimulant (Biaggioni et al., 1991; Zahn et al., 1987) – could improve antidepressant-induced genital arousal difficulties if ingested prior to sex. Caffeine could serve as a low-cost, widely accessible intervention with minimal side effects if efficacy is shown. Objective The goal of the present pilot study is to examine whether the acute administration of 300mg of caffeine increases genital arousal (i.e., vaginal pulse amplitude) in women experiencing antidepressant-induced genital arousal difficulties. Methods Women attended two counterbalanced in-laboratory sessions in which they ingested either 300mg caffeine or placebo. Fifteen minutes post-ingestion, they viewed an erotic film while their heart rate and genital sexual arousal were measured. Caffeine consumption was controlled for. Results Preliminary data analyses suggest that compared to placebo, 300mg of caffeine increases vaginal pulse amplitude fifteen minutes post-ingestion among women experiencing antidepressant-induced genital arousal difficulties. Additional pilot subjects are currently being tested; results will be updated with an addendum upon completion. Conclusions If efficacy is demonstrated in our sample, caffeine may serve as a low-cost, widely accessible treatment for women experiencing antidepressant-induced genital arousal dysfunction. While we aim to target genital arousal concerns with caffeine, improvements in genital arousal are likely to positively impact other stages of women’s sexual response given the high degree of overlap between these stages. Disclosure No

Effects of whole-body cryotherapy and static stretching are maintained 4 weeks after treatment in most patients with chronic fatigue syndrome

In the previous study, whole-body cryotherapy (WBC)+static stretching (SS) has been shown to reduce the severity of some symptoms in Chronic Fatigue Syndrome (CFS) noted just after the therapy. Here we consider the effects of treatment and explore the sustainability of symptom improvements at four weeks (one-month) follow-up. Twenty-two CFS patients were assessed one month after WBC + SS programme. Parameters related to fatigue (Chalder Fatigue Questionnaire (CFQ), Fatigue Impact Scale (FIS), Fatigue Severity Scale (FSS)), cognitive function (Trial Making test part A and B (TMT A and TMT B and its difference (TMT B-A)), Coding) hemodynamic, aortic stiffness (aortic systolic blood pressure (sBP aortic)) and autonomic nervous system functioning were measured. TMT A, TMT B, TMT B-A and Coding improved at one month after the WBC + SS programme. WBC + SS had a significant effect on the increase in sympathetic nervous system activity in rest. WBC + SS had a significant, positive chronotropic effect on the cardiac muscle. Peripheral and aortic systolic blood pressure decreased one month after WBC + SS in comparison to before. Effects of WBC + SS on reduction of fatigue, indicators of aortic stiffness and symptoms severity related to autonomic nervous system disturbance and improvement in cognitive function were maintained at one month. However, improvement in all three fatigue scales (CFQ, FIS and FSS) was noted in 17 of 22 patients. In addition, ten patients were treated initially but they were not assessed at 4 weeks, and are thus not included in the 22 patients who were examined on follow-up. The overall effects of WBC + SS noted at one month post-treatment should be interpreted with caution.

Oral CBD-rich hemp extract modulates sterile inflammation in female and male rats.

Introduction: Cannabidiol (CBD) extract from the cannabis plant has biomedical and nutraceutical potential. Unlike tetrahydrocannabinol (THC), CBD products produce few psychoactive effects and pose little risk for abuse. There is emerging preclinical and clinical evidence that CBD is stress modulatory and may have anti-inflammatory properties. People across the United States legally ingest CBD-rich hemp extracts to manage mental and physical health problems, including stress and inflammation. Preclinical studies have revealed potential mechanisms for these effects; however, the impact of this prior work is diminished because many studies: 1) tested synthetic CBD rather than CBD-rich hemp extracts containing terpenes and/or other cannabinoids thought to enhance therapeutic benefits; 2) administered CBD via injection into the peritoneal cavity or the brain instead of oral ingestion; and 3) failed to examine potential sex differences. To address these gaps in the literature, the following study tested the hypothesis that the voluntary oral ingestion of CBD-rich hemp extract will attenuate the impact of stressor exposure on plasma and tissue inflammatory and stress proteins in females and males. Methods: Adult male and female Sprague Dawley rats (10-15/group) were randomly assigned to be given cereal coated with either vehicle (coconut oil) or CBD-rich hemp extract (L-M0717, CBDrx/Functional Remedies, 20.0mg/kg). After 7days, rats were exposed to a well-established acute model of stress (100, 1.5mA, 5-s, intermittent tail shocks, 90min total duration) or remained in home cages as non-stressed controls. Results: Stressor exposure induced a robust stress response, i.e., increased plasma corticosterone and blood glucose, and decreased spleen weight (a surrogate measure of sympathetic nervous system activation). Overall, stress-induced increases in inflammatory and stress proteins were lower in females than males, and oral CBD-rich hemp extract constrained these responses in adipose tissue (AT) and mesenteric lymph nodes (MLN). Consistent with previous reports, females had higher levels of stress-evoked corticosterone compared to males, which may have contributed to the constrained inflammatory response measured in females. Discussion: Results from this study suggest that features of the acute stress response are impacted by oral ingestion of CBD-rich hemp extract in female and male rats, and the pattern of changes may be sex and tissue dependent.

Positron Emission Tomography in Heart Failure: From Pathophysiology to Clinical Application.

Imaging modalities are increasingly being used to evaluate the underlying pathophysiology of heart failure. Positron emission tomography (PET) is a non-invasive imaging technique that uses radioactive tracers to visualize and measure biological processes in vivo. PET imaging of the heart uses different radiopharmaceuticals to provide information on myocardial metabolism, perfusion, inflammation, fibrosis, and sympathetic nervous system activity, which are all important contributors to the development and progression of heart failure. This narrative review provides an overview of the use of PET imaging in heart failure, highlighting the different PET tracers and modalities, and discussing fields of present and future clinical application.

Deviations in continuously monitored electrodermal activity before severe clinical complications: a clinical prospective observational explorative cohort study

Monitoring of high-risk patients in hospital wards is crucial in identifying and preventing clinical deterioration. Sympathetic nervous system activity measured continuously and non-invasively by Electrodermal activity (EDA) may relate to complications, but the clinical use remains untested. The aim of this study was to explore associations between deviations of EDA and subsequent serious adverse events (SAE). Patients admitted to general wards after major abdominal cancer surgery or with acute exacerbation of chronic obstructive pulmonary disease were continuously EDA-monitored for up to 5 days. We used time-perspectives consisting of 1, 3, 6, and 12 h of data prior to first SAE or from start of monitoring. We constructed 648 different EDA-derived features to assess EDA. The primary outcome was any SAE and secondary outcomes were respiratory, infectious, and cardiovascular SAEs. Associations were evaluated using logistic regressions with adjustment for relevant confounders. We included 714 patients and found a total of 192 statistically significant associations between EDA-derived features and clinical outcomes. 79% of these associations were EDA-derived features of absolute and relative increases in EDA and 14% were EDA-derived features with normalized EDA above a threshold. The highest F1-scores for primary outcome with the four time-perspectives were 20.7–32.8%, with precision ranging 34.9–38.6%, recall 14.7–29.4%, and specificity 83.1–91.4%. We identified statistically significant associations between specific deviations of EDA and subsequent SAE, and patterns of EDA may be developed to be considered indicators of upcoming clinical deterioration in high-risk patients.

Neighborhood socioeconomic deprivation and individual-level socioeconomic status are associated with dopamine-mediated changes to monocyte subset CCR2 expression via a cAMP-dependent pathway

Social determinants of health (SDoH) include socioeconomic, environmental, and psychological factors that impact health. Neighborhood socioeconomic deprivation (NSD) and low individual-level socioeconomic status (SES) are SDoH that associate with incident heart failure, stroke, and cardiovascular mortality, but the underlying biological mechanisms are not well understood. Previous research has demonstrated an association between NSD, in particular, and key components of the neural-hematopoietic-axis including amygdala activity as a marker of chronic stress, bone marrow activity, and arterial inflammation. Our study further characterizes the role of NSD and SES as potential sources of chronic stress related to downstream immunological factors in this stress-associated biologic pathway. We investigated how NSD, SES, and catecholamine levels (as proxy for sympathetic nervous system activation) may influence monocytes which are known to play a significant role in atherogenesis. First, in an ex vivo approach, we treated healthy donor monocytes with biobanked serum from a community cohort of African Americans at risk for CVD. Subsequently, the treated monocytes were subjected to flow cytometry for characterization of monocyte subsets and receptor expression. We determined that NSD and serum catecholamines (namely dopamine [DA] and norepinephrine [NE]) associated with monocyte C–C chemokine receptor type 2 (CCR2) expression (p < 0.05), a receptor known to facilitate recruitment of monocytes towards arterial plaques. Additionally, NSD associated with catecholamine levels, especially DA in individuals of low SES. To further explore the potential role of NSD and the effects of catecholamines on monocytes, monocytes were treated in vitro with epinephrine [EPI], NE, or DA. Only DA increased CCR2 expression in a dose-dependent manner (p < 0.01), especially on non-classical monocytes (NCM). Furthermore, linear regression analysis between D2-like receptor surface expression and surface CCR2 expression suggested D2-like receptor signaling in NCM. Indicative of D2-signaling, cAMP levels were found to be lower in DA-treated monocytes compared to untreated controls (control 29.78 pmol/ml vs DA 22.97 pmol/ml; p = 0.038) and the impact of DA on NCM CCR2 expression was abrogated by co-treatment with 8-CPT, a cAMP analog. Furthermore, Filamin A (FLNA), a prominent actin-crosslinking protein, that is known to regulate CCR2 recycling, significantly decreased in DA-treated NCM (p < 0.05), indicating a reduction of CCR2 recycling. Overall, we provide a novel immunological mechanism, driven by DA signaling and CCR2, for how NSD may contribute to atherogenesis. Future studies should investigate the importance of DA in CVD development and progression in populations disproportionately experiencing chronic stress due to SDoH.

Specific xenon-based gas mixtures used for stress correction therapy in patients exposed to lethal force scenarios

Introduction. Stress reaction in deadly scenarios is a systemic response of human body to the impact of extreme and acute psychotraumatic factors. The condition is associated with complete or partial loss of ability to perform tasks and can lead to the development of post-traumatic stress disorder. Therefore, new effective means and methods of stress correction in lethal force scenarios is a most urgent challenge for catastrophe medicine.The objective is to estimate the therapeutic efficacy of xenon gas mixtures in the treatment of different categories of employees exposed to occupational hazards, including acute stress.Methodology. A randomized controlled experimental study was conducted, involving 48 employees of law enforcement bodies and rescue operations professionals. Acute stress disorders were treated using a course of oxygen-xenon gas mixture inhalations (oxygen – 75 %, xenon – 25 %). Comprehensive medical and psychological examination allowed to monitor treatment efficiency.Results and discussion. Oxygen-xenon gas mixture inhalations contributed to normalization of systemic hemodynamics, improved parasympathetic activity and reduced sympathetic nervous system activity, leading to a significant reduction in the level of anxiety and improvement of psychopathological symptoms.Conclusion. The obtained findings provide extra evidence showing that xenon-based gas mixtures are a promise as a stress correction tool in patients exposed to lethal force scenarios and acute occupational hazard.

Orexin receptors in paraventricular nucleus influence sexual behavior via regulating the sympathetic outflow in males.

Orexins are hypothalamic neuropeptides associated with various neurophysiological activities such as sleep, arousal, and reward. However, there are few studies investigating the relationships between orexin receptors in the paraventricular nucleus and sexual behaviors. To explore the roles of orexin receptors in the paraventricular nucleus on sexual behaviors and uncover its potential mechanisms in males. Orexin A, orexin 1 receptor antagonist SB334867, and orexin 2 receptor antagonist TCS-OX2-29 were microinjected into the paraventricular nucleus to investigate the effects of orexin receptors on copulatory behavior testing of C57BL/6 mice. To explore if ejaculation could activate orexin 1 receptor-expressing neurons in the paraventricular nucleus, fluorescence immunohistochemical double staining was utilized. The levels of serum norepinephrine were measured and the lumbar sympathetic nerve activity was recorded to reflect the sympathetic nervous system activity. Moreover, the bulbospongiosus muscle-electromyogram was recorded and analyzed. To test whether perifornical/lateral hypothalamic area orexinergic neurons directly projected to the paraventricular nucleus, virus retrograde tracing technology was utilized. Orexin A significantly enhanced sexual performance by shortening the intromission and ejaculation latencies, and increasing the mount and intromission frequencies, while the opposite outcomes appeared with SB334867. However, TCS-OX2-29 had no significant effects on sexual behaviors. Moreover, orexin A increased lumbar sympathetic nerve activity and the levels of serum norepinephrine, while SB334867 decreased lumbar sympathetic nerve activity and norepinephrine, which caused a significant decrease in sympathetic nervous system outflow. Meanwhile, a robust increase in the bulbospongiosus muscle-electromyogram activity was identified after microinjecting orexin A. Furthermore, cFos immunopositive cells were increased and double stained with orexin 1 receptor-expressing neurons in the mating group. Additionally, the retrograde tracing results demonstrated that orexinergic neurons in the perifornical/lateral hypothalamic area directly projected to the paraventricular nucleus. Orexin 1 receptor in the paraventricular nucleus could influence the ejaculatory reflex via mediating the sympathetic nervous system activity, which might be of great importance in the treatment of premature ejaculation in the future.

Beta-Adrenergic stimulation is necessary but not sufficient to promote CIH-induced Multiple Myeloma progression

Multiple myeloma (MM), a terminal cancer of bone marrow plasma cells, affects about 35,000 people yearly, and kills 13,000. The KaLwRij mouse model spontaneously develops pre-malignant myeloma disease (MGUS) and is receptive to myeloma development. In the C57BL/6 mouse model, chronic intermittent hypoxia allows lethal engraftment of malignant myeloma cells. Our central hypothesis is that myeloma susceptibility in both models is modulated by the sympathetic nervous system and beta-adrenergic receptor activation. 8 - week old C57BL/6 female mice were exposed to either propranolol, isoproterenol, or saline for 6 weeks. At week 2, mice were injected with either 5TGM1/GFP+ (MM) cells or saline. Heart rate and heart rate variability were collected using MouseOx and LabChart Pro to monitor expected drug effects. All animals were monitored for terminal paralysis. Bone marrow and spleen cells were harvested for qPCR analysis to quantify 5TGM1 cell proliferation. C57BL/6 mice did not have decreased survival when treated with isoproterenol, but propranolol was protective against CIH-induced MM susceptibility. Propranolol did not increase survival in KalwRij mice. In order for Multiple Myeloma to progress in the CIH mouse model, β2-adrenergic receptor activation is required but is not sufficient. This experiment can be used to understand the role of sympathetic nervous system stimulation and its contribution to MM engraftment and growth. Supported by NIH 1R56HL152365. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The stress of losing sleep: Sex-specific neurobiological outcomes

Sleep is a vital and evolutionarily conserved process, critical to daily functioning and homeostatic balance. Losing sleep is inherently stressful and leads to numerous detrimental physiological outcomes. Despite sleep disturbances affecting everyone, women and female rodents are often excluded or underrepresented in clinical and pre-clinical studies. Advancing our understanding of the role of biological sex in the responses to sleep loss stands to greatly improve our ability to understand and treat health consequences of insufficient sleep. As such, this review discusses sex differences in response to sleep deprivation, with a focus on the sympathetic nervous system stress response and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We review sex differences in several stress-related consequences of sleep loss, including inflammation, learning and memory deficits, and mood related changes. Focusing on women's health, we discuss the effects of sleep deprivation during the peripartum period. In closing, we present neurobiological mechanisms, including the contribution of sex hormones, orexins, circadian timing systems, and astrocytic neuromodulation, that may underlie potential sex differences in sleep deprivation responses.

Regulator Of G Protein Signaling-4 Modulates Short-Chain Fatty Acid-induced Cardiac Inflammation And Norepinephrine Release from Sympathetic Neurons

Free fatty acid receptor (FFAR)-3 (also known as GPR41) is a Gi/o protein-coupled receptor (GPCR) mediating many cellular effects of short-chain fatty acids (SCFAs) like propionate and butyrate. It inhibits cyclic 3’,5’-adenosine monophosphate (cAMP) synthesis and promotes sympathetic nervous system (SNS) activity and norepinephrine (NE) release. It is also blocked by ketone bodies, such as beta-hydroxybutyrate. Regulator of G protein Signaling (RGS)-4 deactivates (terminates) Gi/o- and Gq-protein signaling. Cardiac RGS4 protects the heart against arrhythmogenesis via calcium signaling attenuation and against pressure overload-induced hypertrophy. In the present study, we examined whether RGS4 regulates SCFA signaling and function (through FFAR3) in cardiac myocytes and sympathetic neurons in vitro, as well as in mice post-pressure overload in vivo. We found that siRNA-mediated RGS4 depletion in H9c2 cardiomyocytes enhances propionate-induced cAMP lowering, Giα protein subunit activation, and upregulation of pro-inflammatory mediators [p38 mitogen activated protein kinase (MAPK), interleukin (IL)-6 &amp; IL-1β, transforming growth factor (TGF)-β]. On the other hand, RGS4 overexpression in sympathetic neuron-like Neuro-2A cells significantly reduces propionate/FFAR3-mediated NE release. In vivo, in C57/B6 mice undergoing transverse aortic constriction (TAC) to induce pressure overload, cardiac RGS4 was found upregulated, at both the mRNA and protein levels, in post-TAC mice compared to sham-operated controls. This was accompanied by markedly reduced propionic acid-dependent FFAR3 signaling in isolated membranes from the post-TAC hearts. 3-hydroxybutyrate exerts the same effect in vitro in HEK293T cells overexpressing human FFAR3, i.e., inhibits Gi/o protein signaling by FFAR3. Finally, although initially (24 hours post-TAC) elevated, compared to sham (6.6+0.4 nmol/g of tissue vs. 4.1+0.7 nmol/g of tissue, respectively; n=5), cardiac NE levels were markedly suppressed at 7 days post-TAC (5.4+0.3 nmol/g of heart tissue, n=5). In conclusion, RGS4 inhibits SCFA/FFAR3 pro-inflammatory signaling in the myocardium, and neuronal SCFA/FFAR3 signaling that promotes NE release. Pressure overload upregulates cardiac RGS4 in vivo to protect the heart against FFAR3-mediated inflammation and elevated catecholamine toxicity. Thus, RGS4 actions on FFAR3 or pharmacological blockade of this receptor with a ketone body may protect the heart against pathological stimuli (e.g., hypertension) that precipitate heart disease via increased sympathetic activity and elevated catecholaminergic toxicity. 1) NIH (NHLBI); 2) NSU‘s President‘s Faculty Research &amp; Development Grant (PFRDG). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Electronic cigarettes exposures modulate Heart Rate and Heart Rate Variability

Background: Despite a lack of empirical data, an unprecedented rise in electronic cigarettes (ECs) has been widely perceived as safe. Multiple studies support a causal link between tobacco cigarette (TC) use and cardiovascular (CV) diseases; however, there is a lack of data with EC use. We have previously shown that chronic and acute EC use decreases heart rate variability (HRV) in humans, likely via increased sympathetic nervous system activation. Objective: We aimed to evaluate HRV effects induced by brief EC exposures utilizing an in-vivo model for freely moving C57BL/6 mice. Methods and Results: Telemetry devices were implanted in the abdomen of six 10-week-old C57BL/6 male mice to monitor electrocardiographic activity continuously. Mice underwent an exposure protocol designed to reflect human vaping topography with two EC exposures, each lasting 15-minutes (4-sec puff/ 26-sec Air) followed by 45-min post-exposure periods. Air (primary control) and PBS (secondary control) were also included, each with their own post-exposure events. During EC exposures, we observed bradycardic effects in heart rate (HR) with the standard deviation of NN intervals (SDNN), root mean square of successive differences (RMSSD), and the proportion of adjacent normalized RR intervals that differed by more than 6 ms (pNN 6 ) significantly (p&lt; 0.05) altered as compared to Air exposures. After EC exposures, SDNN, RMSSD and pNN 6 parameters significantly decreased compared to Air. No significant differences between Air and PBS were observed in these parameters. Frequency domain parameters also indicated significant changes in HRV; the low frequency (LF) and high frequency (HF) bands showed marked increases during and after the EC exposures, while the log (LF/HF) ratio remained relatively unchanged, suggesting a possible coactivation of both parasympathetic and sympathetic branches of the autonomic nervous system. Conclusion: Short-term EC exposures lower heart rate and altered HRV in mice in an acute manner, suggesting that ECs may not be safe as previously assumed. This work was funded by the Tobacco-Related Disease Research Program (TRDRP) which included the High Impact Pilot Research Award [28IP-0036], the Cornelius Hopper Diversity Award Supplement and the Student Research Award Supplement, the UCLA Center for Occupational and Environmental Health (COEH) Student Project Award, and in part by the National Institute of Environmental Health Sciences (NIEHS) via the Student-to-Scientist Bridge program at California State University, Northridge [5R25ES025507]. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Corticotropin-releasing hormone and oxytocin receptors tonically influence nTS activity in rats subjected to chronic intermittent hypoxia

Chronic intermittent hypoxia (CIH) elevates basal sympathetic nervous system activity, blood pressure, respiration and augments their responses to an acute hypoxic challenge. These physiological effects are due, in part, to the integration of several central nuclei. The nucleus tractus solitarii (nTS) is the initial site of peripheral chemoafferent integration and receives input from the paraventricular nucleus of the hypothalamus (PVN) to modulate nTS activity. PVN-to-nTS projections contain oxytocin (OT) and/or corticotropin-releasing hormone (CRH), yet their contribution to nTS activity after CIH is not well understood. We sought to determine the influence of these neuropeptides on nTS synaptic and neuronal activity, hypothesizing they individually increase nTS activity, which is magnified by their co-application, and such responses are enhanced by CIH. Male Sprague-Dawley rats (~3 wks) were exposed to 10d normoxia (21% O2) or CIH (~30s of 6% O2, 10x/hr, 8 h/day). In nTS slices, spontaneous (s) and TS-evoked excitatory postsynaptic currents (EPSCs), membrane potential and action potential discharge (APD) were recorded (n=7,9). Events were examined during OT and CRH or their receptor block (OTR-x, CRHR2-x). Overall, aCSF vehicle did not alter events over the 40-min recording, confirming their stability. Network-driven sEPSCs were enhanced in normoxic slices by only CRH, whereas CRHR2-x did not alter currents. After CIH, the elevation of sEPSCs by CRH was lost and block of OTR and CRHR2-x reduced sEPSC amplitude, indicating a greater tonic activation of these receptors on the nTS neurocircuitry. Afferent (TS)- EPSCs evoked at 0.5 and 20 Hz were not altered by OT or CRH alone nor their receptor block in normoxia. However, CIH elevated TS-EPSCs in response to CRH and CRH+OT, and this effect was greater than normoxia. Block of OTR and CRHR2 after CIH did not alter TS-EPSC amplitude, indicating their minimal tonic influence on sensory integration. Membrane potential was not altered in either group in response to OT and/or CRH application, or their receptor blockade. APD was induced in both groups by current injection. The co-application of OT and CRH increased the APD in normoxic but not CIH neurons. Within the nTS, CIH decreased the expression of OT and CRH (via immunohistochemistry, n = 3-4) and increased OTR and CRHR2 mRNA (via RNA Scope, n=3-4). In agreement with the increased OTR and CRHR2 mRNA expression, calcium imaging in primary dissociated nTS neurons demonstrated enhanced responses to OT+ CRH following CIH vs normoxia (n= 15, 17). Taken together, these data suggest that following CIH, OT and CRH have modality specific effects on nTS activity. NIH R01 HL098602 &amp; R01 HL128454 (DDK). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ratio of visceral fat area to body fat mass (VBR) is a superior predictor of coronary heart disease.

Ratio of visceral fat area to body fat mass (VBR) is a superior predictor of coronary heart disease.

Evidence of Sympathetic Overactivity in Subjects with REM Behavior Disorder at Risk for Parkinson’s Disease (P6-13.002)

<h3>Objective:</h3> To evaluate sympathetic nervous system (SNS) activity in subjects with REM sleep behavior disorder (RBD) at risk of Parkinson’s disease, using imaging and autonomic functions markers. <h3>Background:</h3> While the nature of RBD is not completely understood, there is evidence that enhancement of noradrenergic activity may play a causative role, as suggested by evidence of persistent tonic discharge of locus coeruleus (LC) and RBD-triggering action of selective norepinephrine reuptake inhibitors. <h3>Design/Methods:</h3> Subjects &gt;50 years old with RBD with at least one pre-motor PD symptom (hyposmia, constipation, depression) were tested with a battery of autonomic evaluations including SCOPA-AUT questionnaire, cardiac MIBG scintigraphy, Heart Rate Variability (HRV) and neuromelanin sensitive MRI (NSMRI) of LC and substantia nigra (SN). Analyzed variables included: 1) for MIBG, late heart/mediastinum (H/M) ratio and washout ratio (WR); 2) for HRV, time and frequency domain measures; 3) for NSMRI, contrast-to-noise ratio (CNR) between LC and pons and between substantia nigra (SN) and cerebral peduncles. Results were compared with available normative ranges. <h3>Results:</h3> 14 subjects (11M, age 66.2±8.2) were enrolled. Average total SCOPA-AUT score was increased (12.1±6.7 vs 8.8±5.4), with gastrointestinal (2.4±2.1 vs 1.4±1.6), urinary (5.4±2.7 vs 3.9±2.4) and cardiovascular (0.86±1.10 vs 0.3±0.6) scores above normal ranges. MIBG late H/M ratio was reduced (1.45±0.31) with increased WR (33.0±14.8). HRV results showed enhanced sympathetic and low parasympathetic activity both in time (SDNN 106.8±73.2ms; RMSSD 21.9±10.9ms; PNN50% 6.7±8.4%) and frequency domain (LF/HF 3.4±1.8). NMSMRI showed high LC CNR (right 3.26±1.9 vs 2.08±0.5; left 2.95±0.9 vs 2.79±0.5). SN CNR was high (Medial 6.24±1.9 vs 4.57±0.8; Central 6.26±1.6 vs 3.43±0.6; Lateral 3.44±2.1 vs 3.05±0.5) and MDS-UPDRS motor scores were low (2.9±3.3). <h3>Conclusions:</h3> RBD subjects at risk for PD show abnormal autonomic scores, which appears to be driven by SNS overactivity, as suggested by increased MIBG WR, elevated LF/HF HRV ratios and increased LC and SN NSMRI signal. <b>Disclosure:</b> Dr. Tagliati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbott. Dr. Tagliati has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Boston Scientific. Dr. Tagliati has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Supernus. Dr. Tagliati has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuroDerm. Dr. Tagliati has received publishing royalties from a publication relating to health care. Dr. Gregorio has nothing to disclose. Dr. Maghzi has nothing to disclose. Gloria Obialisi has nothing to disclose. Dr. Hogg has nothing to disclose. Dr. Malatt has nothing to disclose. Dr. Tan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Allergan. Dr. Artal has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Jazz Pharmaceuticals. Dr. Artal has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Private Parties. The institution of Dr. Artal has received research support from Jazz Pharma. The institution of Dr. Artal has received research support from Axsome. The institution of Dr. Artal has received research support from Suven. Dr. Shehata has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott. Brian Renner has nothing to disclose. The institution of Dr. Sati has received research support from National Multiple Sclerosis Society. The institution of Dr. Sati has received research support from National Institutes of Health. Dr. Sati has received publishing royalties from a publication relating to health care.

Thoracic Spinal Cord Neuroinflammation as a Novel Therapeutic Target in Pulmonary Hypertension.

Pulmonary hypertension (PH) is associated with aberrant sympathoexcitation leading to right ventricular failure (RVF), arrhythmias, and death. Microglial activation and neuroinflammation have been implicated in sympathoexcitation in experimental PH. We recently reported the first evidence of thoracic spinal cord (TSC) neuroinflammation in PH rats. Here, we hypothesize that PH is associated with increased cardiopulmonary afferent signaling leading to TSC-specific neuroinflammation and sympathoexcitation. Furthermore, inhibition of TSC neuroinflammation rescues experimental PH and RVF. We performed transcriptomic analysis and its validation on the TSC of monocrotaline (n=8) and Sugen hypoxia (n=8) rat models of severe PH-RVF. A group of monocrotaline rats received either daily intrathecal microglial activation inhibitor minocycline (200 μg/kg per day, n=5) or PBS (n=5) from day 14 through 28. Echocardiography and right ventricle-catheterization were performed terminally. Real-time quantitative reverse transcription PCR, immunolocalization, microglia+astrocyte quantification, and terminal deoxynucleotidyl transferase dUTP nick end labeling were assessed. Plasma catecholamines were measured by ELISA. Human spinal cord autopsy samples (Control n=3; pulmonary arterial hypertension n=3) were assessed to validate preclinical findings. Increased cardiopulmonary afferent signaling was demonstrated in preclinical and clinical PH. Our findings delineated common dysregulated genes and pathways highlighting neuroinflammation and apoptosis in the remodeled TSC and highlighted increased sympathoexcitation in both rat models. Moreover, we validated significantly increased microglial and astrocytic activation and CX3CL1 expression in TSC of human pulmonary arterial hypertension. Finally, amelioration of TSC neuroinflammation by minocycline in monocrotaline rats inhibited microglial activation, decreased proinflammatory cytokines, sympathetic nervous system activation and significantly attenuated PH and RVF. Targeting neuroinflammation and associated molecular pathways and genes in the TSC may yield novel therapeutic strategies for PH and RVF.