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Although sympathetic suppression is considered one of the mechanisms for cardioprotection afforded by sodium–glucose cotransporter 2 (SGLT2) inhibitors, whether SGLT2 inhibition acutely modifies sympathetic arterial pressure (AP) regulation remains unclear. We examined the acute effect of an SGLT2 inhibitor, empagliflozin (10 mg/kg), on open-loop baroreflex static characteristics in streptozotocin (STZ)-induced type 1 diabetic and control (CNT) rats (n = 9 each). Empagliflozin significantly increased urine flow [CNT: 25.5 (21.7–31.2) vs. 55.9 (51.0–64.5), STZ: 83.4 (53.7–91.7) vs. 121.2 (57.0–136.0) μL·min−1·kg−1, median (1st–3rd quartiles), P < 0.001 for empagliflozin and STZ]. Empagliflozin decreased the minimum sympathetic nerve activity (SNA) [CNT: 15.7 (6.8–18.4) vs. 10.5 (2.9–19.0), STZ: 36.9 (25.7–54.9) vs. 32.8 (15.1–37.5) %, P = 0.021 for empagliflozin and P = 0.003 for STZ], but did not significantly affect the peripheral arc characteristics assessed by the SNA–AP relationship. Despite the significant increase in urine flow and changes in several baroreflex parameters, empagliflozin preserved the overall sympathetic AP regulation in STZ-induced diabetic rats. The lack of a significant change in the peripheral arc may minimize reflex sympathetic activation, thereby enhancing a cardioprotective benefit of empagliflozin. [ABSTRACT FROM AUTHOR]

Key points We tested the hypothesis that in human hypertension, an increased tonicity/sensitivity of the peripheral chemoreflex causes a sympathetically mediated restraint of nutritive blood flow to the exercising muscles. Fourteen patients with treated hypertension (age 69 ± 11 years, 136 ± 12/80 ± 11 mmHg; mean ± SD) were studied under conditions of intravenous 0.9% saline (control) and low‐dose dopamine (2 µg kg−1 min−1) to inhibit the peripheral chemoreflex, at baseline, during isocapnic hypoxic rebreathing and during rhythmic handgrip exercise (3 min, 50% maximum voluntary contraction). At baseline, dopamine did not change mean blood pressure (95 ± 10 vs. 98 ± 10 mmHg, P = 0.155) but increased brachial artery blood flow (59 ± 20 vs. 48 ± 16 ml min−1, P = 0.030) and vascular conductance (0.565 ± 0.246 vs. 0.483 ± 0.160 ml min−1 mmHg−1; P = 0.039). Dopamine attenuated the increase in mean blood pressure (∆3 ± 4 vs. ∆8 ± 6 mmHg, P = 0.007) to isocapnic hypoxic rebreathing and reduced peripheral chemoreflex sensitivity by 28 ± 37% (P = 0.044). Rhythmic handgrip exercise induced increases in brachial artery blood flow and vascular conductance (both P < 0.05 vs. rest after 45 s) that were greater with dopamine than saline (e.g. Δ76 ± 54 vs. Δ60 ± 43 ml min−1 and Δ0.730 ± 0.440 vs. Δ0.570 ± 0.424 ml min−1 mmHg−1, respectively, at 60 s; main effect of condition both P < 0.0001). Our results indicate that the peripheral chemoreflex is tonically active at rest and restrains the blood flow and vascular conductance increases to exercise in treated human hypertension. It was hypothesised that in human hypertension, an increased tonicity/sensitivity of the peripheral chemoreflex causes a sympathetically mediated restraint of nutritive blood flow to the exercising muscles. Treated patients with hypertension (n = 14) were studied under conditions of intravenous 0.9% saline (control) and low‐dose dopamine (2 µg kg−1 min−1) to inhibit the peripheral chemoreflex. Low‐dose dopamine reduced resting ventilation and peripheral chemoreflex sensitivity, and while mean blood pressure was unchanged, brachial artery blood flow and vascular conductance were increased. Low‐dose dopamine augmented the brachial artery blood flow and vascular conductance responses to rhythmic handgrip. These findings indicate that the peripheral chemoreflex is tonically active at rest and restrains the blood flow, and vascular conductance increases to exercise in treated human hypertension. [ABSTRACT FROM AUTHOR]

Background: Sympathetic nerve activity (SNA) plays a central role in the pathogenesis of several diseases such as sepsis and chronic kidney disease (CKD). Activation of microglia in the paraventricular nucleus of the hypothalamus (PVN) has been implicated in SNA. The mechanisms responsible for the adverse prognosis observed in sepsis associated with CKD remain to be determined. Therefore, we aimed to clarify the impact of increased SNA resulting from microglial activation on hemodynamics and organ damage in sepsis associated with CKD. Methods and results: In protocol 1, male Sprague–Dawley rats underwent either nephrectomy (Nx) or sham surgery followed by cecal ligation and puncture (CLP) or sham surgery. After CLP, Nx-CLP rats exhibited decreased blood pressure, increased heart rate, elevated serum creatinine and bilirubin levels, and decreased platelet count compared to Nx-Sham rats. Heart rate variability analysis revealed an increased low to high frequency (LF/HF) ratio in Nx-CLP rats, indicating increased SNA. Nx-CLP rats also had higher creatinine and bilirubin levels and lower platelet counts than sham-CLP rats after CLP. In protocol 2, Nx-CLP rats were divided into two subgroups: one received minocycline, an inhibitor of microglial activation, while the other received artificial cerebrospinal fluid (CSF) intracerebroventricularly via an osmotic minipump. The minocycline-treated group (Nx-mino-CLP) showed attenuated hypotensive and increased heart rate responses compared to the CSF-treated group (Nx-CSF-CLP), and the LF/HF ratio was also decreased. Echocardiography showed larger left ventricular dimensions and inferior vena cava in the Nx-mino-CLP group. In addition, creatinine and bilirubin levels were lower and platelet counts were higher in the Nx-mino-CLP group compared to the Nx-CSF-CLP group. Conclusions: In septic rats with concomitant CKD, SNA was significantly enhanced and organ dysfunction was increased. It has been suggested that the mechanism of exacerbated organ dysfunction in these models may involve abnormal systemic hemodynamics, possibly triggered by activation of the central sympathetic nervous system through activation of microglia in the PVN. [ABSTRACT FROM AUTHOR]

Chemerin is an adipokine that contributes to metabolism regulation. Nucleus tractus solitarius (NTS) is the first relay station in the brain for accepting various visceral afferent activities for regulating cardiovascular activity. However, the roles of chemerin in the NTS in regulating sympathetic activity and blood pressure are almost unknown. This study aimed to determine the role and potential mechanism of chemerin in the NTS in modulating sympathetic outflow and blood pressure. Bilateral NTS microinjections were performed in anaesthetized adult male Sprague–Dawley rats. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Chemerin and its receptor chemokine‐like receptor 1 (CMKLR1) were highly expressed in caudal NTS (cNTS). Microinjection of chemerin‐9 to the cNTS increased RSNA, MAP and HR, which were prevented by CMKLR1 antagonist α‐NETA, superoxide scavenger tempol or N‐acetyl cysteine, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium or apocynin. Chemerin‐9 increased superoxide production and NADPH oxidase activity in the cNTS. The increased superoxide production induced by chemerin‐9 was inhibited by α‐NETA. The effects of cNTS microinjection of chemerin‐9 on the RSNA, MAP and HR were attenuated by the pretreatment with paraventricular nucleus (PVN) microinjection of NMDA receptor antagonist MK‐801 rather than AMPA/kainate receptor antagonist CNQX. These results indicate that chemerin‐9 in the NTS increases sympathetic outflow, blood pressure and HR via CMKLR1‐mediated NADPH oxidase activation and subsequent superoxide production in anaesthetized normotensive rats. Glutamatergic inputs in the PVN are needed for the chemerin‐9‐induced responses. [ABSTRACT FROM AUTHOR]

Background: Fibrosis after nephrotoxic injury is common. Activation of the paraventricular nucleus (PVN) renin-angiotensin system (RAS) and sympathetic nervous system (SNS) are common mechanism of renal fibrosis. However, there have limited knowledge about which brain regions are most affected by Angiotensin II (Ang II) after nephrotoxic injury, what role does Angiotensin II type 1a receptors (AT1R) signaling play and how this affects the outcomes of the kidneys. Methods: In nephrotoxic folic acid–induced chronic kidney disease (FA-CKD) mouse models, we have integrated retrograde tracer techniques with studies on AT1afl/fl mice to pinpoint an excessively active central pathway that connects the paraventricular nucleus (PVN) to the rostral ventrolateral medulla (RVLM). This pathway plays a pivotal role in determining the kidney's fibrotic response following injury induced by folic acid. Results: FA-CKD (vs sham) had increased in the kidney SNS activity and Ang II expression in the central PVN. The activation of Ang II in the PVN triggers the activation of the PVN-RVLM pathway, amplifies SNS output, thus facilitating fibrosis development in FA-CKD mouse. Blocking sympathetic traffic or deleting AT1a in the PVN alleviated renal fibrosis in FA-CKD mice. Conclusions: The FA-CKD mice have increased the expression of Ang II in PVN, thereby activating AT1a-positive PVN neurons project to the RVLM, where SNS activity is engaged to initiate fibrotic processes. The Ang II in PVN may contribute to the development of kidney fibrosis after nephrotoxic folic acid-induced kidney injury. [ABSTRACT FROM AUTHOR]

Abstract Background Sympathetic nerve activity (SNA) plays a central role in the pathogenesis of several diseases such as sepsis and chronic kidney disease (CKD). Activation of microglia in the paraventricular nucleus of the hypothalamus (PVN) has been implicated in SNA. The mechanisms responsible for the adverse prognosis observed in sepsis associated with CKD remain to be determined. Therefore, we aimed to clarify the impact of increased SNA resulting from microglial activation on hemodynamics and organ damage in sepsis associated with CKD. Methods and results In protocol 1, male Sprague–Dawley rats underwent either nephrectomy (Nx) or sham surgery followed by cecal ligation and puncture (CLP) or sham surgery. After CLP, Nx-CLP rats exhibited decreased blood pressure, increased heart rate, elevated serum creatinine and bilirubin levels, and decreased platelet count compared to Nx-Sham rats. Heart rate variability analysis revealed an increased low to high frequency (LF/HF) ratio in Nx-CLP rats, indicating increased SNA. Nx-CLP rats also had higher creatinine and bilirubin levels and lower platelet counts than sham-CLP rats after CLP. In protocol 2, Nx-CLP rats were divided into two subgroups: one received minocycline, an inhibitor of microglial activation, while the other received artificial cerebrospinal fluid (CSF) intracerebroventricularly via an osmotic minipump. The minocycline-treated group (Nx-mino-CLP) showed attenuated hypotensive and increased heart rate responses compared to the CSF-treated group (Nx-CSF-CLP), and the LF/HF ratio was also decreased. Echocardiography showed larger left ventricular dimensions and inferior vena cava in the Nx-mino-CLP group. In addition, creatinine and bilirubin levels were lower and platelet counts were higher in the Nx-mino-CLP group compared to the Nx-CSF-CLP group. Conclusions In septic rats with concomitant CKD, SNA was significantly enhanced and organ dysfunction was increased. It has been suggested that the mechanism of exacerbated organ dysfunction in these models may involve abnormal systemic hemodynamics, possibly triggered by activation of the central sympathetic nervous system through activation of microglia in the PVN.

Type 2 diabetes (T2D) is often accompanied by hypertension, exaggerated blood pressure (BP) responses to sympatho‐excitatory stressors, and raised cardiovascular disease risk. Appropriate respiratory–sympathetic coupling and sympathetic transduction to BP are important for short‐ and longer‐term BP control. We tested the hypotheses that respiratory modulation of muscle sympathetic nerve activity (MSNA) and its transduction to BP would be impaired in T2D and associated with higher BP and respiratory‐coupled BP variability. Resting MSNA, respiration and beat‐to‐beat BP were recorded in 20 T2D (49.1 ± 7.4 years; mean ± SD) and 13 healthy control (46.3 ± 9.4 years) participants. MSNA and the transduction of sympathetic bursts (signal‐averaging) to mean arterial pressure (MAP) were compared at low and high lung volume phases. The peak MAP response following a sympathetic burst was lower during the high lung volume than low lung volume phase in controls (P = 0.005), whereas it was unchanged with phase in T2D participants (P = 0.522). Respiratory modulation of MSNA was impaired in T2D participants, who had an attenuated reduction in burst incidence from low to the high lung volume phase, versus controls (27.8 ± 38.4% vs. 49.4 ± 24.6%, respectively; P = 0.043). The T2D participants were grouped into unimpaired respiratory modulators (burst incidence modulation median or above) or impaired respiratory modulators (below median). Impaired modulators had higher systolic BP (133 ± 14 vs. 121 ± 11 mmHg, P = 0.046), greater Traube–Hering wave amplitudes (6.3 ± 2.4 vs. 4.6 ± 1.1 mmHg; P = 0.028) and higher BP variability (MAP average real variability, 2.0 ± 0.7 vs. 1.4 ± 0.3, P = 0.033). Respiratory modulation of MSNA and sympathetic transduction to BP are altered in T2D patients and may contribute to their increased hypertension and cardiovascular risk. Key points: Respiratory–sympathetic coupling and sympathetic transduction to blood pressure (BP) contribute to short‐ and longer‐term BP control. Our understanding of these processes in health and type 2 diabetes (T2D), a condition with high prevalence of hypertension and cardiovascular risk, is incomplete.We found that respiration and sympathetic transduction to BP are coupled in healthy individuals. The mean arterial pressure response to a sympathetic burst was reduced during the high lung volume compared to the low lung volume phase. This coupling was absent in T2D.Respiratory modulation of muscle sympathetic nerve activity (MSNA) is impaired in T2D, with a blunted reduction of MSNA observed during the high lung volume phase.T2D patients with impaired respiratory MSNA modulation had augmented systolic BP, respiratory‐related BP excursions (Traube–Hering waves) and BP variability.Abnormal respiratory modulation of MSNA and sympathetic transduction to BP in T2D may contribute to altered blood pressure control and cardiovascular risk in this population. [ABSTRACT FROM AUTHOR]

The leading cause of death in people living with HIV (PLWH) is cardiovascular disease, and the high prevalence of tobacco cigarette (TC) smoking is a major contributor. Switching to electronic cigarettes (ECs) has been promoted as a harm reduction strategy. We sought to determine if acute EC compared to TC smoking had less harmful effects on arrhythmogenic risk factors including acute changes in hemodynamics, heart rate variability (HRV), and ventricular repolarization (VR). In PLWH who smoke, changes in hemodynamics, HRV, and VR were compared pre/post acutely using an EC, TC, or puffing on an empty straw on different days in random order, in a crossover study. Thirty‐seven PLWH (36 males, mean age 40.5 ± 9.1 years) participated. Plasma nicotine was greater after TC versus EC use (10.12 ± 0.96 vs. 6.18 ± 0.99 ng/mL, respectively, p = 0.004). HR increased significantly, and similarly, after acute EC and TC smoking compared to control. Changes in HRV that confer increased cardiac risk (LF/HF ratio) were significantly smaller after acute EC versus TC use, consistent with a harm reduction effect. In a post‐hoc analysis of PLWH with and without positive concurrent recreational drug use as indicated by point of care urine toxicology testing, this differential effect was only seen in PLWH not currently using recreational drugs. Changes in VR were not different among the three exposures. In PLWH who smoke, EC compared to TC smoking resulted in smaller adverse changes in HRV. This differential effect was accompanied by a smaller increase in plasma nicotine, and was negated by concurrent recreational drug use. Additional studies are warranted in this vulnerable population disproportionately affected by tobacco‐related health disparities. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to clarify the impact of age on the sympathoinhibitory response to cardiopulmonary baroreceptor loading in females. Nine older females (mean ± SD, 70 ± 6 yr) and 11 younger females (20 ± 1 yr) completed the study. A passive leg raising (PLR) test was performed wherein the participants were positioned supine (baseline, 0°), and their lower limbs were passively lifted at 10°, 20°, 30°, and 40° (3 min at each angle). Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. The central venous pressure was estimated based on peripheral venous pressure (eCVP), which was monitored using a cannula in the right large antecubital vein. Baseline MSNA was higher in older females than in younger females. MSNA burst frequency (BF) decreased during the PLR test in both older and younger females, but the magnitude of the decrease in MSNA BF was smaller in older females than in younger females (older, −3.5 ± 1.5 vs. younger, −6.3 ± 1.5 bursts/min at 40° from baseline, P = 0.014). The eCVP increased during the PLR in both groups, and there was no difference in the changes in eCVP between the two groups (older, +1.07 ± 0.37 vs. younger, +1.12 ± 0.33 mmHg at 40° from baseline, P = 0.941). These results suggest that inhibition of sympathetic vasomotor outflow during cardiopulmonary baroreceptor loading could be blunted with advancing age in females. NEW & NOTEWORTHY: There were no available data concerning the effect of age on the sympathoinhibitory response to cardiopulmonary baroreceptor loading in females. The magnitude of the decrease in muscle sympathetic nerve activity during passive leg raising (10°–40°) was smaller in older females than in young females. In females, inhibition of sympathetic vasomotor outflow during cardiopulmonary baroreceptor loading could be blunted with advancing age. [ABSTRACT FROM AUTHOR]

The stress-induced cardiovascular response is based on the defensive reaction in mammals. It has been shown that the sympathetic vasomotor pathway of acute psychological stress is indirectly mediated via neurons in the rostroventral medulla (RVM) from the hypothalamic stress center. In this study, direct projections to the RVM and distribution of neuroexcitatory marker c-Fos-expressed neurons were investigated during social defeat stress (SDS) in conscious rats. The experimental rat that was injected with a neural tracer, FluoroGold (FG) into the unilateral RVM, was exposed to the SDS. Double-positive neurons of both c-Fos and FG were locally distributed in the lateral/ventrolateral periaqueductal gray matter (l/vl PAG) in the midbrain. These results suggest that the neurons in the l/vl PAG contribute to the defensive reaction evoked by acute psychological stress, such as the SDS. During the SDS period, arterial pressure (AP) and heart rate (HR) showed sustained increases in the rat. Therefore, we performed chemical stimulation by excitatory amino acid microinjection within the l/vl PAG and measured cardiovascular response and sympathetic nerve activity in some anesthetized rats. The chemical stimulation of neurons in the l/vl PAG caused significant increases in arterial pressure and renal sympathetic nerve activity. Taken together, our results suggest that neurons in the l/vl PAG are a possible candidate for the cardiovascular descending pathway that modulates sympathetic vascular resistance evoked by acute psychological stress, like the SDS. NEW & NOTEWORTHY: The sympathetic vasomotor pathway of an acute psychological stress-induced cardiovascular response is mediated via neurons in the RVM indirectly from the hypothalamus. In this study, we showed the relaying area of the efferent sympathetic vasomotor pathway from the hypothalamus to the RVM. The results suggested that the pressor response during psychological stress is mediated via neurons in the lateral/ventrolateral PAG to the RVM. [ABSTRACT FROM AUTHOR]

BACKGROUND The effectiveness of renal denervation (RDN) in reducing blood pressure and systemic sympathetic activity in hypertensive patients has been established. However, the underlying central mechanism remains unknown. This study aimed to investigate the role of RDN in regulating cardiovascular function via the central renin–angiotensin system (RAS) pathway. METHODS Ten-week-old spontaneously hypertensive rats (SHR) were subjected to selective afferent renal denervation (ADN) using capsaicin solution. We hypothesized that ADN would effectively reduce blood pressure and rebalance the RAS component of the paraventricular nucleus (PVN) in SHR. RESULTS The experimental results show that the ADN group exhibited significantly lower blood pressure, reduced systemic sympathetic activity, decreased chronic neuronal activation marker C-FOS expression in the PVN, and improved arterial baroreflex function, compared with the Sham group. Furthermore, ACE and AT1 protein expression was reduced while ACE2 and MAS protein expression was increased in the PVN of SHR after ADN. CONCLUSIONS These findings suggest that RDN may exert these beneficial effects through modulating the central RAS pathway. [ABSTRACT FROM AUTHOR]

Purpose: Central and peripheral chemoreceptors are hypersensitized in patients with heart failure with reduced ejection fraction. Whether this autonomic alteration occurs in patients with heart failure with preserved ejection fraction (HFpEF) remains little known. We test the hypothesis that the central and peripheral chemoreflex control of muscle sympathetic nerve activity (MSNA) is altered in HFpEF. Methods: Patients aged 55–80 years with symptoms of heart failure, body mass index ≤ 35 kg/m2, left ventricular ejection fraction > 50%, left atrial volume index > 34 mL/m2, left ventricular early diastolic filling velocity and early diastolic tissue velocity of mitral annulus ratio (E/e′ index) ≥ 13, and BNP levels > 35 pg/mL were included in the study (HFpEF, n = 9). Patients without heart failure with preserved ejection fraction (non-HFpEF, n = 9), aged-paired, were also included in the study. Peripheral chemoreceptors stimulation (10% O2 and 90% N2, with CO2 titrated) and central chemoreceptors stimulation (7% CO2 and 93% O2) were conducted for 3 min. MSNA was evaluated by microneurography technique, and forearm blood flow (FBF) by venous occlusion plethysmography. Results: During hypoxia, MSNA responses were greater (p < 0.001) and FBF responses were lower in patients with HFpEF (p = 0.006). Likewise, MSNA responses during hypercapnia were higher (p < 0.001) and forearm vascular conductance (FVC) levels were lower (p = 0.030) in patients with HFpEF. Conclusions: Peripheral and central chemoreflex controls of MSNA are hypersensitized in patients with HFpEF, which seems to contribute to the increase in MSNA in these patients. In addition, peripheral and central chemoreceptors stimulation in patients with HFpEF causes muscle vasoconstriction. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether male stress is related to seminal stress biomarkers and pregnancy achievement in women exposed to their partner's seminal plasma (SP) in the intracytoplasmic sperm injection (ICSI) cycle. In this pilot prospective study, 20 couples undergoing ICSI, as well as 5 fertile sperm donors and 10 saliva donors, were investigated. Women were exposed to their partner's SP via unprotected sexual intercourse during the ICSI cycle and intravaginal application on the day of ovum pick-up (Day-OPU). Semen samples were collected from male partners by masturbation on the Day-OPU. Saliva and serum samples were collected prior to masturbation. Body fluids were frozen at − 80 °C until assayed. Biomarkers of activity of the sympathetic adrenomedullary axis (salivary alpha-amylase and adrenaline), sympathetic neural axis (noradrenaline and dopamine), hypothalamic–pituitary–adrenal (HPA) system (cortisol), and immune system (C-reactive protein and interleukin (IL)-18) were estimated to examine their association with SP composition and clinical pregnancy achievement. The clinical pregnancy rate was 45.0%. In the unsuccessful ICSI group, blunted levels of salivary and serum cortisol were found compared to the successful ICSI group and the fertile sperm donors. With regard to seminal markers, decreased cortisol level and elevated noradrenaline, noradrenaline/cortisol ratio, and lL-18 levels were strongly associated with ICSI failure (areas under the ROC curves were, 0.813, 0.848, 0.899, and 0.828, respectively). These findings confirm that stress response systems activity affects SP composition, which in turn is associated with ICSI outcomes in women exposed to their partner's SP during an ICSI cycle. [ABSTRACT FROM AUTHOR]

Hypertension is a prevalent cardiovascular disease. Exercise is widely recognized as an effective treatment for hypertension, and it may also influence the composition of the intestinal microflora. However, it remains unclear whether exercise can specifically regulate the intestinal microflora in the context of hypertension treatment. In this study, tail blood pressure in spontaneously hypertensive rats (SHR) was measured using a blood pressure meter after exercise intervention and fecal bacteria transplantation following exercise. Blood lipid levels were assessed using an automatic biochemical analyzer, and 16S rRNA sequencing was employed to analyze the intestinal microflora. Histological examinations of ileal tissue were conducted using HE and Masson staining. Intestinal permeability, inflammatory status, and sympathetic activity were evaluated by measuring the levels of diamine oxidase, D-lactic acid, C-reactive protein, interleukin-6, tumor necrosis factor-α, lipopolysaccharide, norepinephrine, angiotensin II, cyclic adenosine monophosphate, and cyclic guanosine monophosphate. Exercise was found to reduce blood pressure and blood lipid levels in SHR. It also improved the composition of the intestinal microflora, as evidenced by a reduced Firmicutes/Bacteroidetes ratio, an increase in bacteria that produce acetic and butyric acid, and higher Chao 1 and Shannon diversity indices. Furthermore, exercise reduced the thickness of the fibrotic and muscular layers in the ileum, increased the goblet cell/villus ratio and villus length, and decreased intestinal permeability, inflammatory markers, and sympathetic nerve activity. The intestinal microbial flora regulated by exercise demonstrated similar effects on hypertension. In conclusion, exercise appears to regulate the intestinal microflora, and this exercise-induced change in flora may contribute to improvements in hypertension in rats.

Background Fibrosis after nephrotoxic injury is common. Activation of the paraventricular nucleus (PVN) renin-angiotensin system (RAS) and sympathetic nervous system (SNS) are common mechanism of renal fibrosis. However, there have limited knowledge about which brain regions are most affected by Angiotensin II (Ang II) after nephrotoxic injury, what role does Angiotensin II type 1a receptors (AT1R) signaling play and how this affects the outcomes of the kidneys. Methods In nephrotoxic folic acid–induced chronic kidney disease (FA-CKD) mouse models, we have integrated retrograde tracer techniques with studies on AT1afl/fl mice to pinpoint an excessively active central pathway that connects the paraventricular nucleus (PVN) to the rostral ventrolateral medulla (RVLM). This pathway plays a pivotal role in determining the kidney’s fibrotic response following injury induced by folic acid. Results FA-CKD (vs sham) had increased in the kidney SNS activity and Ang II expression in the central PVN. The activation of Ang II in the PVN triggers the activation of the PVN-RVLM pathway, amplifies SNS output, thus facilitating fibrosis development in FA-CKD mouse. Blocking sympathetic traffic or deleting AT1a in the PVN alleviated renal fibrosis in FA-CKD mice. Conclusions The FA-CKD mice have increased the expression of Ang II in PVN, thereby activating AT1a-positive PVN neurons project to the RVLM, where SNS activity is engaged to initiate fibrotic processes. The Ang II in PVN may contribute to the development of kidney fibrosis after nephrotoxic folic acid-induced kidney injury.

Abstract The purpose of this study was to clarify sex differences in the inhibition of sympathetic vasomotor outflow which is caused by the loading of cardiopulmonary baroreceptors. Ten young males and ten age-matched females participated. The participants underwent a passive leg raising (PLR) test wherein they were positioned supine (baseline, 0º), and their lower limbs were lifted passively at 10º, 20º, 30º, and 40º. Each angle lasted for 3 min. Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. Baseline MSNA was lower in females compared to males. MSNA burst frequency was decreased during the PLR in both males (− 6.2 ± 0.4 bursts/min at 40º) and females (− 6.5 ± 0.4 bursts/min at 40º), but no significant difference was detected between the two groups (P = 0.61). These results suggest that sex has minimal influence on the inhibition of sympathetic vasomotor outflow during the loading of cardiopulmonary baroreceptors in young individuals.

Background Gestational diabetes can lead to increased blood pressure in offspring, accompanied by impaired renal sodium excretion function and vasoconstriction and diastole dysfunction. However, there are few studies on whether it is accompanied by increased sympathetic nerve activity.Methods Pregnant C57BL/6 mice were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at day 0 of gestation. The mice of control mother offspring (CMO) and diabetic mother offspring (DMO) at 16 weeks of age were infused with vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or tempol (1 mmol/L, 0.4 μL/h) into the bilateral paraventricular nucleus (PVN) of mice for 4 weeks, respectively.Results Compared with CMO group, SBP and peripheral sympathetic nerve activity (increased heart rate, LF/HF and plasma norepinephrine and decreased SDNN and RMSSD) were increased in DMO group, which was accompanied by increased angiotensin II type-1 receptor (AT1R) expression and function in PVN. The increase in AT1R expression levels was attributed to a decrease in the methylation level of the AT1R promoter region, resulting in an increase in AT1R mRNA levels in PVN of DMO. Moreover, compared with CMO group, the levels of oxidative stress were increased and DNMT1 expression was decreased in PVN of DMO. Bilateral PVN infusion of tempol attenuated oxidative stress increased the level of DNMT1 expression and the binding of DNMT1 to the AT1R promoter region, which reduced mRNA and protein expression level of AT1R, heart rate and SBP in DMO, but not in CMO.Conclusions The present study provides evidence for overactive sympathetic nervous systems in the pathogenesis of gestational diabetes-induced hypertension in offspring. Central antioxidant intervention in the PVN may be an important treatment strategy for fetal-programmed hypertension.

The sympathetic nervous system modulates arterial blood pressure. Individuals with obstructive sleep apnea (OSA) experience numerous nightly hypoxic episodes and exhibit elevated sympathetic activity to the cardiovascular system leading to hypertension. This suggests that OSA disrupts normal respiratorysympathetic coupling. This study investigates the role of the postinspiratory complex (PiCo) and preBötzinger complex (preBötC) in respiratory-sympathetic coupling under control conditions and following exposure to chronic intermittent hypoxia (CIH) for 21 days (5% O2-80 bouts/day). The surface of the ventral brainstem was exposed in urethane (1.5 g/kg) anesthetized, spontaneously breathing adult mice. Cholinergic (ChAT), glutamatergic (Vglut2), and neurons that co-express ChAT and Vglut2 at PiCo, as well as Dbx1 and Vglut2 neurons at preBötC, were optogenetically stimulated while recording activity from the diaphragm (DIA), vagus nerve (cVN), and cervical sympathetic nerve (cSN). Following CIH exposure, baseline cSN activity increased, breathing frequency increased, and expiratory time decreased. In control mice, stimulating PiCo specific cholinergic-glutamatergic neurons caused a sympathetic burst during all phases of the respiratory cycle, whereas optogenetic activation of cholinergicglutamatergic PiCo neurons in CIH mice increased sympathetic activity only during postinspiration and late expiration. Stimulation of glutamatergic PiCo neurons increased cSN activity during the postinspiratory phase in control and CIH mice. Optogenetic stimulation of ChAT containing neurons in the PiCo area did not affect sympathetic activity under control or CIH conditions. Stimulating Dbx1 or Vglut2 neurons in preBötC evoked an inspiration and a concomitant cSN burst under control and CIH conditions. Taken together, these results suggest that PiCo and preBötC contribute to respiratory-sympathetic coupling, which is altered by CIH, and may contribute to the hypertension observed in patients with OSA. [ABSTRACT FROM AUTHOR]

Identifying alterations caused by aging could be an important tool for improving the diagnosis of cardiovascular diseases. Changes in vascular tone regulation involve various mechanisms, like NO synthase activity, activity of the sympathetic nervous system, production of prostaglandin, endothelium-dependent relaxing, and contracting factors, etc. Surprisingly, Ca2+-dependent Cl− channels (CaCCs) are involved in all alterations of the vascular tone regulation mentioned above. Furthermore, we discuss these mechanisms in the context of ontogenetic development and aging. The molecular and electrophysiological mechanisms of CaCCs activation on the cell membrane of the vascular smooth muscle cells (VSMC) and endothelium are explained, as well as the age-dependent changes that imply the activation or inhibition of CaCCs. In conclusion, due to the diverse intracellular concentration of chloride in VSMC and endothelial cells, the activation of CaCCs depends, in part, on intracellular Ca2+ concentration, and, in part, on voltage, leading to fine adjustments of vascular tone. The activation of CaCCs declines during ontogenetic development and aging. This decline in the activation of CaCCs involves a decrease in protein level, the impairment of Ca2+ influx, and probably other alterations in vascular tone regulation. [ABSTRACT FROM AUTHOR]

Early in the twentieth century, Walter B. Cannon (1871–1945) introduced his overarching hypothesis of "homeostasis" (Cannon 1932)—the ability to sustain physiological values within a narrow range necessary for life during periods of stress. Physical exercise represents a stress in which motor, respiratory and cardiovascular systems must be integrated across a range of metabolic stress to match oxygen delivery to oxygen need at the cellular level, together with appropriate thermoregulatory control, blood pressure adjustments and energy provision. Of these, blood pressure regulation is a complex but controlled variable, being the function of cardiac output and vascular resistance (or conductance). Key in understanding blood pressure control during exercise is the coordinating role of the autonomic nervous system. A long history outlines the development of these concepts and how they are integrated within the exercise context. This review focuses on the renaissance observations and thinking generated in the first three decades of the twentieth century that opened the doorway to new concepts of inquiry in cardiovascular regulation during exercise. The concepts addressed here include the following: (1) exercise and blood pressure, (2) central command, (3) neurovascular transduction with emphasis on the sympathetic nerve activity and the vascular end organ response, and (4) tonic neurovascular integration. [ABSTRACT FROM AUTHOR]

The purpose of this study was to clarify sex differences in the inhibition of sympathetic vasomotor outflow which is caused by the loading of cardiopulmonary baroreceptors. Ten young males and ten age-matched females participated. The participants underwent a passive leg raising (PLR) test wherein they were positioned supine (baseline, 0º), and their lower limbs were lifted passively at 10º, 20º, 30º, and 40º. Each angle lasted for 3 min. Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. Baseline MSNA was lower in females compared to males. MSNA burst frequency was decreased during the PLR in both males (− 6.2 ± 0.4 bursts/min at 40º) and females (− 6.5 ± 0.4 bursts/min at 40º), but no significant difference was detected between the two groups (P = 0.61). These results suggest that sex has minimal influence on the inhibition of sympathetic vasomotor outflow during the loading of cardiopulmonary baroreceptors in young individuals. [ABSTRACT FROM AUTHOR]

Abstract The leading cause of death in people living with HIV (PLWH) is cardiovascular disease, and the high prevalence of tobacco cigarette (TC) smoking is a major contributor. Switching to electronic cigarettes (ECs) has been promoted as a harm reduction strategy. We sought to determine if acute EC compared to TC smoking had less harmful effects on arrhythmogenic risk factors including acute changes in hemodynamics, heart rate variability (HRV), and ventricular repolarization (VR). In PLWH who smoke, changes in hemodynamics, HRV, and VR were compared pre/post acutely using an EC, TC, or puffing on an empty straw on different days in random order, in a crossover study. Thirty‐seven PLWH (36 males, mean age 40.5 ± 9.1 years) participated. Plasma nicotine was greater after TC versus EC use (10.12 ± 0.96 vs. 6.18 ± 0.99 ng/mL, respectively, p = 0.004). HR increased significantly, and similarly, after acute EC and TC smoking compared to control. Changes in HRV that confer increased cardiac risk (LF/HF ratio) were significantly smaller after acute EC versus TC use, consistent with a harm reduction effect. In a post‐hoc analysis of PLWH with and without positive concurrent recreational drug use as indicated by point of care urine toxicology testing, this differential effect was only seen in PLWH not currently using recreational drugs. Changes in VR were not different among the three exposures. In PLWH who smoke, EC compared to TC smoking resulted in smaller adverse changes in HRV. This differential effect was accompanied by a smaller increase in plasma nicotine, and was negated by concurrent recreational drug use. Additional studies are warranted in this vulnerable population disproportionately affected by tobacco‐related health disparities.

Key points While the hypothalamic orexinergic nervous system is established as having a pivotal role in the long‐term regulation of various organismic functions, including wakefulness, metabolism and hypertensive states, whether this system contributes to the rapid autonomic cardiovascular regulation during physical activity remains elusive. This study aimed to elucidate the role of the orexinergic nervous system in transmitting volitional motor signals, i.e. central command, to drive somatomotor and sympathetic cardiovascular responses. We first found that this system is activated by voluntary locomotor exercise as evidenced by an increased expression of Fos, a marker of neural activation, in the orexinergic neurons of Sprague–Dawley rats engaged in spontaneous wheel running. Next, using transgenic Orexin‐Cre rats for optogenetic manipulation of orexinergic neurons, we found that optogenetic excitation of orexinergic neurons caused sympathoexcitation on a subsecond timescale under anaesthesia. In freely moving conscious rats, this excitatory stimulation rapidly elicited exploration‐like behaviours, predominantly locomotor activity, along with pressor and tachycardiac responses. Meanwhile, optogenetic inhibition of orexinergic neurons during spontaneous wheel running immediately suppressed locomotor activities and blood pressure elevation without affecting basal cardiovascular homeostasis. Taken together, these findings demonstrate the essential role of the orexinergic nervous system in the central circuitry that transmits central command signals for locomotor exercise. This study not only offers insights into the brain circuit mechanisms precisely regulating autonomic cardiovascular systems during voluntary exercise but also likely contributes to our understanding of brain mechanisms underlying abnormal cardiovascular adjustments to exercise in pathological conditions, such as hypertension. The hypothalamic orexinergic nervous system plays various roles in the long‐term regulation of autonomic and endocrine functions, as well as motivated behaviours. We present a novel, rapid role of the orexinergic nervous system, revealing its significance as a crucial substrate in the brain circuit mechanisms that coordinate somatomotor and autonomic cardiovascular controls for locomotor exercise. Our data demonstrate that orexinergic neurons relay volitional motor signals, playing a necessary and sufficient role in the autonomic cardiovascular regulation required for locomotor exercise in rats. The findings contribute to our understanding of how the brain precisely regulates autonomic cardiovascular systems during voluntary exercise, providing insights into the central neural mechanisms that enhance physical performance moment‐by‐moment during exercise. [ABSTRACT FROM AUTHOR]

Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end‐organ function. Recently, the transduction of resting bursts of muscle SNA (MSNA) has been investigated and shown to have a role in the maintenance of blood pressure through changes in vascular tone in humans. In the present study, we investigate whether directly recorded resting cardiac SNA (CSNA) regulates heart rate (HR), coronary blood flow (CoBF), coronary vascular conductance (CVC), cardiac output (CO) and mean arterial pressure. Instrumentation was undertaken to record CSNA and relevant vascular variables in conscious sheep. Recordings were performed at baseline, as well as after the infusion of a β‐adrenoceptor blocker (propranolol) to determine the role of β‐adrenergic signalling in sympathetic transduction in the heart. The results show that after every burst of CSNA, there was a significant effect of time on HR (n = 10, ∆: +2.1 ± 1.4 beats min–1, P = 0.002) and CO (n = 8, ∆: +100 ± 150 mL min–1, P = 0.002) was elevated, followed by an increase in CoBF (n = 9, ∆: +0.76 mL min–1, P = 0.001) and CVC (n = 8, ∆: +0.0038 mL min–1 mmHg–1, P = 0.0028). The changes in HR were graded depending on the size and pattern of CSNA bursts. The HR response was significantly attenuated after the infusion of propranolol. Our study is the first to explore resting sympathetic transduction in the heart, suggesting that CSNA can dynamically change HR mediated by an action on β‐adrenoceptors. Key points: Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end‐organ function.Previous studies have examined sympathetic transduction primarily in the skeletal muscle and shown that bursts of muscle SNA alter blood flow to skeletal muscle and mean arterial pressure, although this has not been examined in the heart.We investigated sympathetic transduction in the heart and show that, in the conscious condition, the size of bursts of SNA to the heart can result in incremental increases in heart rate and coronary blood flow mediated by β‐adrenoceptors.The pattern of bursts of SNA to the heart also resulted in incremental increases in heart rate mediated by β‐adrenoceptors.This is the first study to explore the transduction of bursts of SNA to the heart. [ABSTRACT FROM AUTHOR]

Although Gaussian white noise (GWN) inputs offer a theoretical framework for identifying higher-order nonlinearity, an actual application to the data of the neural arc of the carotid sinus baroreflex did not succeed in fully predicting the well-known sigmoidal nonlinearity. In the present study, we assumed that the neural arc can be approximated by a cascade of a linear dynamic (LD) component and a nonlinear static (NS) component. We analyzed the data obtained using GWN inputs with a mean of 120 mmHg and standard deviations (SDs) of 10, 20, and 30 mmHg for 15 min each in anesthetized rats (n = 7). We first estimated the linear transfer function from carotid sinus pressure to sympathetic nerve activity (SNA) and then plotted the measured SNA against the linearly predicted SNA. The predicted and measured data pairs exhibited an inverse sigmoidal distribution when grouped into 10 bins based on the size of the linearly predicted SNA. The sigmoidal nonlinearity estimated via the LD-NS model showed a midpoint pressure (104.1 ± 4.4 mmHg for SD of 30 mmHg) lower than that estimated by a conventional stepwise input (135.8 ± 3.9 mmHg, P < 0.001). This suggests that the NS component is more likely to reflect the nonlinearity observed during pulsatile inputs that are physiological to baroreceptors. Furthermore, the LD-NS model yielded higher R2 values compared with the linear model and the previously suggested second-order Uryson model in the testing dataset. [ABSTRACT FROM AUTHOR]

Purpose: Sympathetic nerve activity towards muscle (MSNA) and skin (SSNA) regulates various physiological parameters. MSNA primarily functions in blood pressure and flow, while SSNA operates in thermoregulation. Physical and cognitive stressors have been shown to have effects on both types of sympathetic activity, but there are inconsistencies as to what these effects are. This article aims to address the discrepancies in the literature and compare MSNA and SSNA responses. Methods: Microelectrode recordings were taken from the common peroneal nerve in 29 participants: MSNA (n = 21), SSNA (n = 16) and both MSNA and SSNA (n = 8). Participants were subjected to four different 2-min stressors: two physical (isometric handgrip task, cold pressor test) and two cognitive (mental arithmetic task, Stroop colour–word conflict test), the latter of which saw participants separated into responders and non-responders to the stressors. It was hypothesised that the physical stressors would have a greater effect on MSNA than SSNA, while the cognitive stressors would operate conversely. Results: Peristimulus time histogram (PSTH) analysis showed the mental arithmetic task to significantly increase both MSNA and SSNA; the isometric handgrip task and cold pressor test to increase MSNA, but not SSNA; and Stroop test to have no significant effects on changing MSNA or SSNA from baseline. Additionally, stress responses did not differ between MSNA and SSNA in participants who had both sets of data recorded. Conclusions: This study has provided evidence to support the literature which claims cognitive stressors increase sympathetic activity, and provides much needed SSNA data in response to stressors. [ABSTRACT FROM AUTHOR]

Acetic acid is a bioactive short-chain fatty acid produced in large quantities from ethanol metabolism. In this review, we describe how acetic acid/acetate generates oxidative stress, alters the function of pre-sympathetic neurons, and can potentially influence cardiovascular function in both humans and rodents after ethanol consumption. Our recent findings from in vivo and in vitro studies support the notion that administration of acetic acid/acetate generates oxidative stress and increases sympathetic outflow, leading to alterations in arterial blood pressure. Real-time investigation of how ethanol and acetic acid/acetate modulate neural control of cardiovascular function can be conducted by microinjecting compounds into autonomic control centers of the brain and measuring changes in peripheral sympathetic nerve activity and blood pressure in response to these compounds. [ABSTRACT FROM AUTHOR]

Background: 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. Objectives: To explore the roles of orexin receptors in the paraventricular nucleus on sexual behaviors and uncover its potential mechanisms in males. Materials and methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Carotid bodies are the principal sensory organs for detecting changes in arterial blood oxygen concentration, and the carotid body chemoreflex is a major regulator of the sympathetic tone, blood pressure and breathing. Intermittent hypoxia is a hallmark manifestation of obstructive sleep apnoea (OSA), which is a widespread respiratory disorder. In the first part of this review, we discuss the role of carotid bodies in heightened sympathetic tone and hypertension in rodents treated with intermittent hypoxia, and the underlying cellular, molecular and epigenetic mechanisms. We also present evidence for hitherto‐uncharacterized role of carotid body afferents in triggering cellular and molecular changes induced by intermittent hypoxia. In the second part of the review, we present evidence for a contribution of a hypersensitive carotid body to OSA and potential therapeutic intervention to mitigate OSA in a murine model. [ABSTRACT FROM AUTHOR]

Background: Anthocyanin plays a protective role in cardiovascular disease through antioxidant effect. Whether anthocyanin can reduce salt-induced hypertension and the related mechanisms remain unclear. Methods: Chronic infusion of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or anthocyanin (10 mg/kg, 0.4 μL/h) into bilateral paraventricular nucleus (PVN) of Sprague-Dawley rats was performed. Then, the rats were fed a high salt diet (8% NaCl, HS) or normal salt diet (0.9%, NaCl, NS) for 4 weeks. Results: High salt diet induced an increase in blood pressure and peripheral sympathetic nerve activity (increased LF/HF and decreased SDNN and RMSSD), which was accompanied by increased reactive oxygen species (ROS) production and angiotensin II type-1 receptor (AT1R) expression and function in the PVN. Moreover, the NOD-like receptor protein 3 (NLRP3) and related inflammatory proteins (caspase-1) expression, the pro-inflammatory cytokine levels including IL-1β and TNF-α were higher in PVN of rats with a high salt diet. Bilateral PVN infusion of anthocyanin attenuated NLRP3-dependent inflammation (NLRP3, caspase-1, IL-1β and TNF-α) and ROS production, reduced AT1R expression and function in PVN and lowered peripheral sympathetic nerve activity and blood pressure in rats with salt-induced hypertension. Conclusions: Excessive salt intake activates NLRP3-dependent inflammation and oxidative stress and increased AT1R expression and function in the PVN. Bilateral PVN infusion of anthocyanin lowers peripheral sympathetic nerve activity and blood pressure in rats with salt-induced hypertension by improvement of expression and function of AT1R in the PVN through inhibiting NLRP3 related inflammatory and oxidative stress. [ABSTRACT FROM AUTHOR]

The sympathetic nervous system modulates arterial blood pressure. Individuals with obstructive sleep apnea (OSA) experience numerous nightly hypoxic episodes and exhibit elevated sympathetic activity to the cardiovascular system leading to hypertension. This suggests that OSA disrupts normal respiratory-sympathetic coupling. This study investigates the role of the postinspiratory complex (PiCo) and preBötzinger complex (preBötC) in respiratory-sympathetic coupling under control conditions and following exposure to chronic intermittent hypoxia (CIH) for 21 days (5% O2–80 bouts/day). The surface of the ventral brainstem was exposed in urethane (1.5 g/kg) anesthetized, spontaneously breathing adult mice. Cholinergic (ChAT), glutamatergic (Vglut2), and neurons that co-express ChAT and Vglut2 at PiCo, as well as Dbx1 and Vglut2 neurons at preBötC, were optogenetically stimulated while recording activity from the diaphragm (DIA), vagus nerve (cVN), and cervical sympathetic nerve (cSN). Following CIH exposure, baseline cSN activity increased, breathing frequency increased, and expiratory time decreased. In control mice, stimulating PiCo specific cholinergic-glutamatergic neurons caused a sympathetic burst during all phases of the respiratory cycle, whereas optogenetic activation of cholinergic-glutamatergic PiCo neurons in CIH mice increased sympathetic activity only during postinspiration and late expiration. Stimulation of glutamatergic PiCo neurons increased cSN activity during the postinspiratory phase in control and CIH mice. Optogenetic stimulation of ChAT containing neurons in the PiCo area did not affect sympathetic activity under control or CIH conditions. Stimulating Dbx1 or Vglut2 neurons in preBötC evoked an inspiration and a concomitant cSN burst under control and CIH conditions. Taken together, these results suggest that PiCo and preBötC contribute to respiratory-sympathetic coupling, which is altered by CIH, and may contribute to the hypertension observed in patients with OSA.

Introduction: Hypertension is the leading cause of death in the cardiovascular system. Indeed, untreated hypertension can affect one's general health, but medicine can help hypertensive people reduce their chance of developing high blood pressure. However, secondary hypertension remains an unresolved illness. Areas covered: This review will go through the typical and unusual device-based therapies for resistant hypertension that have arisen in recent years. Further to that, the innovations developed in device-based RH treatment will be covered, as well as the research and studies assessing these novel technologies. Expert opinion: The innovative device-based techniques that target resistant hypertension provide a potential therapy that has been backed by a number of studies and clinical trials, whereas pharmacological non-adherence and increased sympathetic activity are recognized to be the primary causes of resistant hypertension. Nevertheless, some limitations will be critical for the future of these RH systems, with the device's design and larger RCTs playing a significant role in determining whether a position in routine treatment could be warranted.

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.

Abstract Sodium–glucose cotransporter 2 (SGLT2) inhibitors have exerted cardioprotective effects in clinical trials, but underlying mechanisms are not fully understood. As mitigating sympathetic overactivity is of major clinical concern in the mechanisms of heart failure treatments, we examined the effects of modulation of glucose handling on baroreflex-mediated sympathetic nerve activity and arterial pressure regulations in rats with chronic myocardial infarction (n = 9). Repeated 11-min step input sequences were used for an open-loop analysis of the carotid sinus baroreflex. An SGLT2 inhibitor, empagliflozin, was intravenously administered (10 mg/kg) after the second sequence. Neither the baroreflex neural nor peripheral arc significantly changed during the last observation period (seventh and eighth sequences) compared with the baseline period although urinary glucose excretion increased from near 0 (0.0089 ± 0.0011 mg min−1 kg−1) to 1.91 ± 0.25 mg min−1 kg−1. Hence, empagliflozin does not acutely modulate the baroreflex regulations of sympathetic nerve activity and arterial pressure in this rat model of chronic myocardial infarction.

Autonomic adjustments of the cardiovascular system are critical for initiating and sustaining exercise by facilitating the redistribution of blood flow and oxygen delivery to meet the metabolic demands of the active skeletal muscle. Afferent feedback from active skeletal muscles evokes reflex increases in sympathetic nerve activity and blood pressure (BP) (i.e., exercise pressor reflex) and contributes importantly to these primary neurovascular adjustments to exercise. When altered, this reflex contributes significantly to the exaggerated sympathetic and BP response to exercise observed in many cardiovascular-related diseases, highlighting the importance of examining the reflex and its underlying mechanism(s). A leading risk factor for the pathogenesis of cardiovascular disease in both males and females is aging. Although regular exercise is an effective strategy for mitigating the health burden of aging, older adults face a greater risk of experiencing an exaggerated cardiovascular response to exercise. However, the role of aging in mediating the exercise pressor reflex remains highly controversial, as conflicting findings have been reported. This review aims to provide a brief overview of the current understanding of the influence of aging on cardiovascular responses to exercise, focusing on the role of the exercise pressor reflex and proposing future directions for research. We reason that this review will serve as a resource for health professionals and researchers to stimulate a renewed interest in this critical area. [ABSTRACT FROM AUTHOR]

Cardiotoxicity is the most worrying cardiovascular alteration in patients treated with chemotherapy. To improve the understanding regarding the cardiotoxicity, we studied whether 1) patients with cardiac dysfunction related to anthracycline-based chemotherapy have augmented sympathetic nerve activity and decreased exercise capacity and 2) these responses are similar to those observed in patients with heart failure caused by other etiologies. Sixteen patients with heart failure with reduced ejection fraction related to anthracycline-based chemotherapy with or without chest radiation (HFrEFCA), 10 patients with heart failure with reduced ejection not related to cancer therapy (HFrEF), and 16 age-and body mass index (BMI)-matched healthy control subjects were studied. Left ventricular ejection fraction (LVEF, echocardiography), peak oxygen consumption (peak VO2, cardiopulmonary exercise test), muscle sympathetic nerve activity (MSNA, microneurography), and forearm blood flow (FBF, venous occlusion plethysmography) were measured. We found that peak oxygen consumption peak VO2 and LVEF were significantly reduced in patients with HFrEFCA compared with that of control subjects (P < 0.0001) but similar to those found in patients with HFrEFCA. The sympathetic nerve activity burst frequency and incidence were significantly higher in patients with HFrEFCA than that in control subjects (P < 0.0001). No differences were found between patients with HFrEF and HFrEFCA. Peak VO2 was inversely associated with MSNA burst frequency (r = -0.53, P = 0.002) and burst incidence (r = -0.38, P = 0.01) and directly associated with LVEF (r = 0.71, P < 0.0001). Taken together, we conclude that patients who develop heart failure due to anthracycline- based chemotherapy have sympathetic neural overdrive and reduced exercise capacity. In addition, these physiological changes are similar to those observed in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Patients with heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) exhibit severe exercise intolerance that may be due, in part, to inappropriate cardiovascular and hemodynamic adjustments to exercise. Several neural mechanisms and locally released vasoactive substances work in concert through complex interactions to ensure proper adjustments to meet the metabolic demands of the contracting skeletal muscle. Specifically, accumulating evidence suggests that disease-related alterations in neural mechanisms (e.g., central command, exercise pressor reflex, arterial baroreflex, and cardiopulmonary baroreflex) contribute to heightened sympathetic activation and impaired ability to attenuate sympathetic vasoconstrictor responsiveness that may contribute to reduced skeletal muscle blood flow and severe exercise intolerance in patients with HFrEF. In contrast, little is known regarding these important aspects of physiology in patients with HFpEF, though emerging data reveal heightened sympathetic activation and attenuated skeletal muscle blood flow during exercise in this patient population that may be attributable to dysregulated neural control of the circulation. The overall goal of this review is to provide a brief overview of the current understanding of disease-related alterations in the integrative neural cardiovascular responses to exercise in both HFrEF and HFpEF phenotypes, with a focus on sympathetic nervous system regulation during exercise. [ABSTRACT FROM AUTHOR]

Early life over-nutrition, as experienced in maternal obesity, is a risk factor for developing cardiorespiratory and metabolic diseases. Here we investigated the effects of high-fat diet (HFD) consumption on the breathing pattern and sympathetic discharge to blood vessels in juvenile offspring from dams fed with HFD (O-HFD). Adult female Holtzman rats were given a standard diet (SD) or HFD from 6 wk before gestation to weaning. At weaning (P21), the male offspring from SD dams (O-SD) and O-HFD received SD until the experimental day (P28-P45). Nerve recordings performed in decerebrated in situ preparations demonstrated that O-HFD animals presented abdominal expiratory hyperactivity under resting conditions and higher vasoconstrictor sympathetic activity levels. The latter was associated with blunted respiratory-related oscillations in sympathetic activity, especially in control animals. When exposed to elevated hypercapnia or hypoxia levels, the O-HFD animals mounted similar ventilatory and respiratory motor responses as the control animals. Hypercapnia and hypoxia exposure also increased sympathetic activity in both groups but did not reinstate the respiratory-sympathetic coupling in the O-HFD rats. In freely behaving conditions, O-HFD animals exhibited higher resting pulmonary ventilation and larger variability of arterial pressure levels than the O-SD animals due to augmented sympathetic modulation of blood vessel diameter. Maternal obesity modified the functioning of cardiorespiratory systems in offspring at a young age, inducing active expiration and sympathetic overactivity under resting conditions. These observations represent new evidence about pregnancy-related complications that lead to the development of respiratory distress and hypertension in children of obese mothers. NEW & NOTEWORTHY: Maternal obesity is a risk factor for developing cardiorespiratory and metabolic diseases. This study highlights the changes on the breathing pattern and sympathetic discharge to blood vessels in juvenile offspring from dams fed with HFD. Maternal obesity modified the functioning of cardiorespiratory systems in offspring, inducing active expiration and sympathetic overactivity. These observations represent new evidence about pregnancy-related complications that lead to the development of respiratory distress and hypertension in children of obese mothers. [ABSTRACT FROM AUTHOR]

The hypothalamic paraventricular nucleus (PVN) is essential to peripheral chemoreflex neurocircuitry, but the specific efferent pathways utilized are not well defined. The PVN sends dense projections to the nucleus tractus solitarii (nTS), which exhibits neuronal activation following a hypoxic challenge. We hypothesized that nTS‐projecting PVN (PVN‐nTS) neurons contribute to hypoxia‐induced nTS neuronal activation and cardiorespiratory responses. To selectively target PVN‐nTS neurons, rats underwent bilateral nTS nanoinjection of retrogradely transported adeno‐associated virus (AAV) driving Cre recombinase expression. We then nanoinjected into PVN AAVs driving Cre‐dependent expression of Gq or Gi designer receptors exclusively activated by designer drugs (DREADDs) to test the degree that selective activation or inhibition, respectively, of the PVN‐nTS pathway affects the hypoxic ventilatory response (HVR) of conscious rats. We used immunohistochemistry for Fos and extracellular recordings to examine how DREADD activation influences PVN‐nTS neuronal activation by hypoxia. Pathway activation enhanced the HVR at moderate hypoxic intensities and increased PVN and nTS Fos immunoreactivity in normoxia and hypoxia. In contrast, PVN‐nTS inhibition reduced both the HVR and PVN and nTS neuronal activation following hypoxia. To further confirm selective pathway effects on central cardiorespiratory output, rats underwent hypoxia before and after bilateral nTS nanoinjections of C21 to activate or inhibit PVN‐nTS terminals. PVN terminal activation within the nTS enhanced tachycardic, sympathetic and phrenic (PhrNA) nerve activity responses to hypoxia whereas inhibition attenuated hypoxia‐induced increases in nTS neuronal action potential discharge and PhrNA. The results demonstrate the PVN‐nTS pathway enhances nTS neuronal activation and is necessary for full cardiorespiratory responses to hypoxia. Key points: The hypothalamic paraventricular nucleus (PVN) contributes to peripheral chemoreflex cardiorespiratory responses, but specific PVN efferent pathways are not known.The nucleus tractus solitarii (nTS) is the first integration site of the peripheral chemoreflex, and the nTS receives dense projections from the PVN.Selective GqDREADD activation of the PVN‐nTS pathway was shown to enhance ventilatory responses to hypoxia and activation (Fos immunoreactivity (IR)) of nTS neurons in conscious rats, augmenting the sympathetic and phrenic nerve activity (SSNA and PhrNA) responses to hypoxia in anaesthetized rats.Selective GiDREADD inhibition of PVN‐nTS neurons attenuates ventilatory responses, nTS neuronal Fos‐IR, action potential discharge and PhrNA responses to hypoxia.These results demonstrate that a projection from the PVN to the nTS is critical for full chemoreflex responses to hypoxia. [ABSTRACT FROM AUTHOR]

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have exerted cardioprotective effects in clinical trials, but underlying mechanisms are not fully understood. As mitigating sympathetic overactivity is of major clinical concern in the mechanisms of heart failure treatments, we examined the effects of modulation of glucose handling on baroreflex-mediated sympathetic nerve activity and arterial pressure regulations in rats with chronic myocardial infarction (n = 9). Repeated 11-min step input sequences were used for an open-loop analysis of the carotid sinus baroreflex. An SGLT2 inhibitor, empagliflozin, was intravenously administered (10 mg/kg) after the second sequence. Neither the baroreflex neural nor peripheral arc significantly changed during the last observation period (seventh and eighth sequences) compared with the baseline period although urinary glucose excretion increased from near 0 (0.0089 ± 0.0011 mg min−1 kg−1) to 1.91 ± 0.25 mg min−1 kg−1. Hence, empagliflozin does not acutely modulate the baroreflex regulations of sympathetic nerve activity and arterial pressure in this rat model of chronic myocardial infarction. [ABSTRACT FROM AUTHOR]

Introduction: Autonomic dysreflexia (AD) affects about 70% of individuals with spinal cord injury (SCI) and can have severe consequences, including death if not promptly detected and managed. The current gold standard for AD detection involves continuous blood pressure monitoring, which can be inconvenient. Therefore, a non-invasive detection device would be valuable for rapid and continuous AD detection. Methods: Implanted rodent models were used to analyze autonomic dysreflexia after spinal cord injury. Skin nerve activity (SKNA) features were extracted from ECG signals recorded non-invasively, using ECG electrodes. At the same time, blood pressure and ECG data sampled was collected using an implanted telemetry device. Heart rate variability (HRV) features were extracted from these ECG signals. SKNA and HRV parameters were analyzed in both the time and frequency domain. Results: We found that SKNA features showed an increase approximately 18 seconds before the typical rise in systolic blood pressure, indicating the onset of AD in a rat model with upper thoracic SCI. Additionally, low-frequency components of SKNA in the frequency domain were dominant during AD, suggesting their potential inclusion in an AD detection system for improved accuracy. Discussion: Utilizing SKNA measurements could enable early alerts to individuals with SCI, allowing timely intervention and mitigation of the adverse effects of AD, thereby enhancing their overall well-being and safety. [ABSTRACT FROM AUTHOR]

Abstract The maintenance of glucose homeostasis is obligatory for health and survival. It relies on peripheral glucose sensing and signalling between the brain and peripheral organs via hormonal and neural responses that restore euglycaemia. Failure of these mechanisms causes hyperglycaemia or diabetes. Current anti‐diabetic medications control blood glucose but many patients remain with hyperglycemic condition. Diabetes is often associated with hypertension; the latter is more difficult to control in hyperglycaemic conditions. We ask whether a better understanding of the regulatory mechanisms of glucose control could improve treatment of both diabetes and hypertension when they co‐exist. With the involvement of the carotid body (CB) in glucose sensing, metabolic regulation and control of sympathetic nerve activity, we consider the CB as a potential treatment target for both diabetes and hypertension. We provide an update on the role of the CB in glucose sensing and glucose homeostasis. Physiologically, hypoglycaemia stimulates the release of hormones such as glucagon and adrenaline, which mobilize or synthesize glucose; however, these counter‐regulatory responses were markedly attenuated after denervation of the CBs in animals. Also, CB denervation prevents and reverses insulin resistance and glucose intolerance. We discuss the CB as a metabolic regulator (not just a sensor of blood gases) and consider recent evidence of novel ‘metabolic’ receptors within the CB and putative signalling peptides that may control glucose homeostasis via modulation of the sympathetic nervous system. The evidence presented may inform future clinical strategies in the treatment of patients with both diabetes and hypertension, which may include the CB.

Abstract Although suppression of sympathetic activity is suggested as one of the underlying mechanisms for the cardioprotective effects afforded by sodium–glucose cotransporter 2 (SGLT2) inhibitors, whether the modulation of glucose handling acutely affects sympathetic regulation of arterial pressure remains to be elucidated. In Goto–Kakizaki diabetic rats, we estimated the open-loop static characteristics of the carotid sinus baroreflex together with urine glucose excretion using repeated 11-min step input sequences. After the completion of the 2nd sequence, an SGLT2 inhibitor empagliflozin (10 mg kg−1) or vehicle solution was administered intravenously (n = 7 rats each). Empagliflozin did not significantly affect the baroreflex neural or peripheral arc, despite significantly increasing urine glucose excretion (from 0.365 ± 0.216 to 8.514 ± 0.864 mg·min−1·kg−1, P

Autonomic adjustments of the cardiovascular system are critical for initiating and sustaining exercise by facilitating the redistribution of blood flow and oxygen delivery to meet the metabolic demands of the active skeletal muscle. Afferent feedback from active skeletal muscles evokes reflex increases in sympathetic nerve activity and blood pressure (BP) (i.e., exercise pressor reflex) and contributes importantly to these primary neurovascular adjustments to exercise. When altered, this reflex contributes significantly to the exaggerated sympathetic and BP response to exercise observed in many cardiovascular-related diseases, highlighting the importance of examining the reflex and its underlying mechanism(s). A leading risk factor for the pathogenesis of cardiovascular disease in both males and females is aging. Although regular exercise is an effective strategy for mitigating the health burden of aging, older adults face a greater risk of experiencing an exaggerated cardiovascular response to exercise. However, the role of aging in mediating the exercise pressor reflex remains highly controversial, as conflicting findings have been reported. This review aims to provide a brief overview of the current understanding of the influence of aging on cardiovascular responses to exercise, focusing on the role of the exercise pressor reflex and proposing future directions for research. We reason that this review will serve as a resource for health professionals and researchers to stimulate a renewed interest in this critical area.

Purpose: Evidence suggests that traditional low-frequency spinal cord stimulation (LF-SCS) reduces arterial blood pressure (BP) in patients with chronic pain and hypertension independent of improved pain symptoms. However, it remains unclear whether high-frequency spinal cord stimulation (HF-SCS) also lowers BP in chronic pain patients with hypertension. Therefore, in a retrospective study design, we tested the hypothesis that clinic BP would be significantly reduced following implantation of HF-SCS in patients with chronic pain and hypertension. Methods: Clinic BP within 3 months before and after surgical implantation of either a LF-SCS or HF-SCS device between 2010 and 2020 were collected from electronic medical records at The University of Kansas Health System (TUKHS). Results: A total of 132 patients had available records of clinic BP (64 ± 13 years of age). Patients with hypertension (n = 32) demonstrated a significantly greater reduction in systolic BP (−8 ± 12 versus 2 ± 9 mmHg, P < 0.001) following implantation compared with normotensive patients (n = 100). Importantly, the change in BP was inversely related to baseline BP independent of age and sex following implantation of HF-SCS (n = 70, R = −0.50, P < 0.001) or LF-SCS (n = 62, R = −0.42, P = 0.001). Higher pain scores before implantation were not associated with reduction in systolic BP (R = 0.10, P = 0.43) or diastolic BP (R = −0.08, P = 0.53) (n = 69) after implantation. Conclusion: These findings confirm previous studies showing reduced BP following implantation of LF-SCS in patients with chronic pain and hypertension and provide novel data regarding reduced BP following implantation of newer generation HF-SCS devices. [ABSTRACT FROM AUTHOR]

Skeletal muscle reflexes play a crucial role in determining the magnitude of the cardiovascular response to exercise. However, evidence supporting an association between the magnitude of the pressor response and the velocity of muscle deformation has remained to be elucidated. Thus, we investigated the impact of different muscle deformation rates on the neural discharge of muscle afferents and pressor and sympathetic responses in Sprague-Dawley rats. In an ex vivo muscle-nerve preparation, action potentials elicited by sinusoidal mechanical stimuli (137 mN) at different frequencies (0.01, 0.05, 0.1, 0.2, and 0.25 Hz) were recorded in mechanosensitive group III and IV fibers. The afferent response magnitude to sine-wave stimulation significantly varied at different frequencies (ANOVA, P = 0.01). Specifically, as compared with 0.01 Hz (0.83 ± 0.96 spikes/s), the response magnitudes were significantly greater at 0.20 Hz (4.07 ± 5.04 spikes/s, P = 0.031) and 0.25 Hz (4.91 ± 5.30 spikes/s, P = 0.014). In an in vivo decerebrated rat preparation, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to passive stretch (1 kg) of hindlimb skeletal muscle at different velocities of loading (slow, medium, and fast) were measured. Pressor responses to passive stretch were significantly associated with the velocity of muscle deformation (ANOVA, P < 0.001). The MAP response to fast stretch (D 56 ± 12 mmHg) was greater than slow (D 33 ± 11 mmHg, P = 0.006) or medium (D 30 ± 11 mmHg, P < 0.001) stretch. Likewise, the RSNA response was related to deformation velocity (ANOVA, P = 0.024). These findings suggest that the muscle neural afferent discharge and the cardiovascular response to mechanical stimulation are associated with muscle deformation velocity. [ABSTRACT FROM AUTHOR]