Reduction In Sympathetic Tone Research Articles

Bone Mechanical Loading Reduces Heart Rate and Increases Heart Rate Variability via the Autonomic Nervous System in Anesthetized Mice

Mechanical loading of bone creates interstitial fluid flow and shear stress within the bone lacunocanalicular system, leading to alterations of bone size and mass. Bone plays an important role as an endocrine organ, releasing endocrine signaling molecules that impact systemic physiology. Further, the central and peripheral nervous systems regulate bone mass in response to strain through alterations in autonomic tone. This suggests the potential for interplay between bone and other organs via endocrine signaling and autonomic innervation. In this study, our group investigated this potential interplay by focusing on bone and heart. We hypothesized that mechanical bone loading of mice in vivo would result in altered cardiac function. To test this hypothesis, we performed acute in vivo mechanical loading on right leg tibias of anesthetized TOPGAL and CD-1 mice. Tibias underwent compressive cyclic loading (a sine wave) that modulates between -0.3N and -9.0N for 300 cycles at 2 Hz. Cardiac function was monitored with lead II electrocardiogram (ECG) data, heart rate (HR), and heart rate variability (HRV). Immediate, transient reduction in resting HR (0.93 ± 0.013 fold change from baseline, n=6-7, p<0.01 compared to control) was achieved during tibial loading in 6-month-old male and female mice, with concurrent increase in HRV (1.24 ± 0.11 fold change from baseline, n=6-7, p<0.01). Both HR and HRV returned to baseline levels upon completion of the loading process. ECG measurements, QRS and corrected QT (QTc), were not found to be altered (p>0.05) during loading and 30 minutes following loading. In further studies, 1N-2N did not produce a decrease in HR, while 3N (0.92 ± 0.077 fold change from baseline, n=12, p<0.05) and 9N (0.93 ± 0.061 fold change from baseline, n=13, p<0.05) decreased HR. There was decreased magnitude and responsiveness with aging to 11 months old at 3N and 9N (p>0.05), suggesting the response may weaken with age. The immediate, transient nature of the changes to resting HR and HRV suggest a neural mechanism for this response. To test this mechanism, we inhibited local neuronal afferent activity by injecting lidocaine (2.5mg/kg) near the tibia prior to loading. In doing so, the decrease in HR during loading was significantly diminished (vehicle 0.90 ± 0.060 vs. lidocaine 0.97 ± 0.042 fold change from baseline, n=7-8, p<0.05). To test the efferent arm of the response, mice were injected with the parasympathetic, muscarinic acetylcholine receptor antagonist atropine (2mg/kg), or the sympathetic, β1/β2 receptor antagonist propranolol (10mg/kg). Propranolol significantly inhibited the HR decrease during loading (vehicle 0.88 ± 0.095 vs. propranolol 0.98 ± 0.026 fold change from baseline, n=7-8, p<0.05), while atropine did not (n=8-11, p>0.05). These findings suggest that reductions in sympathetic tone on the heart during bone loading led to the decrease in HR. In conclusion, this study uncovered a reflexive neural connection between bone and heart that is affected by age and mediated by afferent neurons in the tibia and alterations in efferent sympathetic tone to the heart. These findings provide new knowledge that builds on the current science of bone remodeling and its regulation. This study was funded by HRSA Medical Student Education Grant T99HP39202 and NIH P01AG039355. This is the full abstract presented at the American Physiology Summit 2024 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.

PS-B10-5: EFFECTS OF CHRONIC ACETYLCHOLINESTERASE INHIBITION WITH PYRIDOSTIGMINE ON CARDIOVASCULAR SYSTEM AND AUTONOMIC BALANCE IN SPONTANEOUSLY HYPERTENSIVE RATS

Objective: The imbalance in autonomic nervous system, characterized by increased sympathetic and attenuated parasympathetic activity, plays an important role in the pathogenesis of hypertension. The spontaneously hypertensive rats (SHR) which are one of the most studied animal models of essential hypertension, are characterized by autonomic nervous system imbalance. Our study was aimed to determine the effect of chronic inhibition of acetylcholinesterase with pyridostigmine on cardiovascular parameters and sympatho-vagal balance in SHR and Wistar-Kyoto (WKY) rats. Design and method: Adult male SHR and WKY rats were treated with pyridostigmine (25 mg/kg/day) in drinking solution for 2 weeks. The rats were implanted with telemetric transducers to measure blood pressure (BP) and heart rate (HR). Autonomic balance was evaluated by power spectral analysis of systolic blood pressure variability (SBPV) and heart rate variability (HRV). Sympatho-vagal balance was also evaluated pharmacologically by administration of methylatropine (antagonist of muscarinic acetylcholine receptors) and propranolol (antagonist of beta-adrenergic receptors) in a separate set of rats. Results: SHR have elevated BP, increased vascular sympathetic activity (low frequency component of SBPV), and reduced HRV compared to WKY. Pyridostigmine significantly reduced HR in rats of both strains (during both dark and light phase) and BP during the dark (active) phase compared to untreated controls. Acetylcholinesterase activity in plasma was significantly reduced by pyridostigmine treatment in both strains (SHR 53 ± 3%, WKY 46 ± 3%). Sympatho-vagal balance examination revealed reduced cardiac vagal tone in SHR as evidenced by blunted HR response to the muscarinic receptor blocker methylatropine and increased cardiac sympathetic tone as evidenced by elevated HR response to the beta-blocker propranolol. Pyridostigmine treatment increased cardiac vagal tone and decreased cardiac sympathetic tone in SHR to the levels of untreated WKY. Moreover, pyridostigmine increased HRV and reduced low frequency component of SBPV in SHR indicating the restoration of autonomic balance. The reduction of sympathetic tone in pyridostigmine-treated rats was also evident from the reduction of plasma levels of noradrenaline. The potentiation of cardiac parasympathetic activity by pyridostigmine treatment was confirmed by the attenuation of restraint stress-induced tachycardia in both strains. Conclusions: Chronic stimulation of peripheral cholinergic system with pyridostigmine leads to the improvement of autonomic nervous system balance in SHR by increasing cardiac vagal tone and reducing sympathetic tone. Thus, chronic treatment with acetylcholinesterase inhibitors seems to be a promising therapeutic strategy for the restoration of autonomic balance in cardiovascular diseases.

Body Weight and Metabolic Rate Changes in Narcolepsy: Current Knowledge and Future Directions.

Narcolepsy is a known auto-immune disease that presents mainly in the teenage years with irresistible sleep attacks. Patients with narcolepsy, especially NT1, have been found to have a high prevalence of obesity and other metabolic derangements. This narrative review aimed to address the relationship between narcolepsy and changes in weight and metabolic rate, and discuss potential mechanisms for weight gain and metabolic changes and future research agendas on this topic. This article will provide a balanced, up-to-date critical review of the current literature, and delineate areas for future research, in order to understand the pathophysiological metabolic changes in narcolepsy. Articles using predefined keywords were searched for in PubMed and Google Scholar databases, with predefined inclusion and exclusion criteria. Compared to controls, patients with narcolepsy are more likely to be obese and have higher BMIs and waist circumferences. According to recent research, weight gain in narcolepsy patients may be higher during the disease's outset. The precise mechanisms causing this weight gain remains unknown. The available information, albeit limited, does not support differences in basal or resting metabolic rates between patients with narcolepsy and controls, other than during the time of disease onset. The evidence supporting the role of orexin in weight gain in humans with narcolepsy is still controversial, in the literature. Furthermore, the available data did not show any appreciable alterations in the levels of CSF melanin-concentrating hormone, plasma and CSF leptin, or serum growth hormone, in relation to weight gain. Other mechanisms have been proposed, including a reduction in sympathetic tone, hormonal changes, changes in eating behavior and physical activity, and genetic predisposition. The association between increased body mass index and narcolepsy is well-recognized; however, the relationship between narcolepsy and other metabolic measures, such as body fat/muscle distribution and metabolic rate independent of BMI, is not well documented, and the available evidence is inconsistent. Future longitudinal studies with larger sample sizes are needed to assess BMR in patients with narcolepsy under a standard protocol at the outset of narcolepsy, with regular follow-up.

Effect of adaptive servo-ventilation for central sleep apnoea in systolic heart failure on muscle sympathetic nerve activity: a SERVE-HF randomised ancillary study.

Adaptive servo-ventilation (ASV) effectively suppresses central sleep apnoea (CSA) but has been associated with increased all-cause and cardiovascular mortality in chronic heart failure patients with reduced ventricular ejection fraction (HFrEF). All-cause and, especially, cardiovascular mortality in chronic heart failure is highly correlated with sympathetic tone. This analysis of SERVE-HF data investigated the effect of ASV on sympathetic tone in patients with HFrEF and CSA. HFrEF patients in the SERVE-HF trial (left ventricular ejection fraction (LVEF) ≤45%, apnoea-hypopnoea index (AHI) ≥15 events·h-1 with predominant CSA) were randomly assigned to receive guideline-based heart failure treatment alone (controls) or plus ASV. For this analysis, the primary outcome was change in muscle sympathetic nerve activity (MSNA) at 3-month follow-up. The effects of baseline MSNA and change in MSNA over time on mortality in the main study were also assessed. 40 patients with HFrEF were included in this analysis (age 71.3±11.7 years, LVEF 34.2±7.7%, 57.5% in New York Heart Association (NYHA) Functional Class II, 42.5% in NYHA Functional Class III, AHI 35.2±11 events·h-1). Sympathetic tone evolution during follow-up did not differ between groups (controls: 47.6±8.3 bursts·min-1 at baseline to 44.6±11.2 bursts·min-1; ASV group: 43.0±9.0 bursts·min-1 at baseline to 42.74±9.45 bursts·min-1). The reduction in sympathetic tone was associated with significantly increased cardiovascular mortality in the ASV group, whereas in the control group reduced sympathetic tone appeared to be protective. Suppression of CSA with ASV did not seem to have a significant effect on chronic heart failure-related sympathetic activation. Simultaneous suppression of CSA and reduction in MSNA was associated with increased cardiovascular mortality.

Low-intensity Extracorporeal Shockwave Therapy as an Adjunct to Xiaflex® in the Treatment of Peyronie's Disease

ABSTRACT Introduction Low-intensity extracorporeal shockwave therapy (Li-ESWT) may have physiologic effects including neo-angiogenesis, upregulation of vasoactive endothelial growth factors, nerve recovery, reduction of fibrotic changes, cavernosal tissue remodeling, and reduction in sympathetic tone. Collagenase clostridium histolyticum (CCH) is the only US FDA-approved drug for the non-surgical treatment of Peyronie's disease (PD). Treatment is intended to be completed in conjunction with penile traction therapy, but studies have demonstrated poor patient compliance. New adjunct therapies that have synergistic effects when used in combination with CCH are desirable but have not been explored. Objective To study if Li-ESWT has additive, synergistic, or no effect when used in combination with CCH to treat PD-associated fibrosis and PD-associated erectile dysfunction. Methods 40 adult male Sprague-Dawley rats were divided evenly into five groups: sham (S), control (T), CCH only (XT), low setting Li-ESWT and CCH (XTL), and CCH and high setting Li-ESWT (XTH). Normal saline was injected sub-tunical in the sham group. Transforming growth factor beta-1 (TGF-B1) was injected into the tunica albuginea of the remaining groups to induce Peyronies-like fibrosis. After 4 weeks of TGF-B1 induction, CCH was injected in all three groups over two injections separated by 48 hours, and then treatment with Li-ESWT (UroGold™ 100) was initiated. Treatment was delivered biweekly for 3 weeks (6 total sessions). Device settings were 600 shocks at 3 Hz, at level 6 (0.093 mJ/mm2) for the XTL group and at level 12 (0.125 mJ/mm2) for the XTH group. After 10 weeks, erectile function was measured by ratio of intracavernosal pressure (ICP) to mean arterial pressure (MAP). Histological analysis by H&E, Trichome stain, and Western blot analysis of Collagen I (COL1A1), III (COL3A1), and alpha-smooth muscle actin (a-SMA) were also performed. Results There was no significant difference found in erectile function as measured by ICP/MAP between PD model and treatment groups (P > 0.05). Histological comparison showed no significant reduction of fibrosis when Li-ESWT was added to CCH, despite intensity, on microscopic examination. On Western blot analysis, there was a reduction of ∼500% in COL1A1 expression when the XT group was compared to the T group. While there was no significant change of COL1A1 between the XT group and the XTL group, there was found to be a decrease of ∼500% expression when the XT group was compared to the XTH group. Expression of COL3A1 in the treatment groups XTL and XTH was comparable to that of the XT group. There was no observable trend in a-SMA expression. Conclusions Different adjunct treatments to CCH need to be explored to augment the effect of the only approved non-surgical treatment for PD. Decreased COL1A1 expression seen in the XTH group, but not XTL, relative to the T group may suggest an energy-dependent effect to decrease fibrosis. Li-ESWT was hypothesized to be a promising candidate, but we have failed to show substantial benefit in our proposed setting. Disclosure Yes, this is sponsored by industry/sponsor: Sexual Medicine Society of North America Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Endo Pharmaceuticals

Evaluating Different Low-intensity Extracorporeal Shockwave Therapy Intensities in the Treatment of Peyronie's Disease in a Rat Model

ABSTRACT Introduction Low-intensity extracorporeal shockwave therapy (Li-ESWT) is postulated to have physiologic effects including neo-angiogenesis, upregulation of vasoactive endothelial growth factors, nerve recovery, reduction of fibrotic changes, cavernosal tissue remodeling, and reduction in sympathetic tone. To date, randomized clinical trials have failed to demonstrate a change in penile curvature, with mixed results on erectile function, in Peyronie's disease (PD) patients. Objective To evaluate the treatment effect of Li-ESWT for amelioration of PD-associated fibrosis and PD-associated erectile dysfunction using a rat model of PD. Methods 32 adult male Sprague-Dawley rats were divided evenly into four groups: sham (S), control (T), low setting Li-ESWT (TL), and high setting Li-ESWT (TH). Normal saline was injected into the tunica albuginea (TA) of the sham group. Transforming growth factor beta-1 (TGF-B1) was injected into the TA of the remaining groups to induce Peyronies-like fibrosis. After 5 weeks of TGF-B1 induction, treatment with Li-ESWT shockwave (UroGold 100™) was initiated. Treatment was delivered biweekly for 3 weeks (6 total sessions). Device settings were 600 shocks at 3 Hz, at level 6 (0.093 mJ/mm2) for the Low group and at level 12 (0.125 mJ/mm2) for the High group. Two weeks after the end of treatment, erectile function was measured by ratio of intracavernosal pressure (ICP) to mean arterial pressure (MAP). Histological analysis by H&E and Trichrome staining was performed. Western blot analysis of Collagens I (COL1A1), III (COL3A1), elastin, alpha-smooth muscle actin (a-SMA), and TGF-B1 was performed. Results There was no significant difference demonstrated in erectile function between T control group and TL and TH groups (P > 0.05). However, there seems to be a trend in decreased amount of fibrosis upon examination of the prepared histologic sections. Animals in the TL and TH groups had decreased COL1A1, COL3A1, elastin, and TGF-B1 expression in the TA compared to the T group. a-SMA expression in the treatment groups was found to be increased compared to both S and T groups. Conclusions Our preliminary data shows that Li-ESWT treatments, at different intensities, may decrease fibrosis induced by TGF-B1 TA injections. Additionally, Li-ESWT was not found to have conclusive positive effects on erectile function. Disclosure Yes, this is sponsored by industry/sponsor: Sexual Medicine Society of North America Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Endo Pharmaceuticals

Renal Denervation and Celiac Ganglionectomy Decrease Mean Arterial Pressure Similarly in Genetically Hypertensive Schlager (BPH/2J) Mice.

Renal denervation (RDNX) lowers mean arterial pressure (MAP) in patients with resistant hypertension. Less well studied is the effect of celiac ganglionectomy (CGX), a procedure which involves the removal of the nerves innervating the splanchnic vascular bed. We hypothesized that RDNX and CGX would both lower MAP in genetically hypertensive Schlager (BPH/2J) mice through a reduction in sympathetic tone. Telemeters were implanted into the femoral artery in mice to monitor MAP before and after RDNX (n=5), CGX (n=6), or SHAM (n=6). MAP, systolic blood pressure, diastolic blood pressure, and heart rate were recorded for 14 days postoperatively. The MAP response to hexamethonium (10 mg/kg, IP) was measured on control day 3 and postoperative day 10 as a measure of global neurogenic pressor activity. The efficacy of denervation was assessed by measurement of tissue norepinephrine. Control MAP was similar among the 3 groups before surgical treatments (≈130 mm Hg). On postoperative day 14, MAP was significantly lower in RDNX (-11±2 mm Hg) and CGX (-11±1 mm Hg) groups compared with their predenervation values. This was not the case in SHAM mice (-5±3 mm Hg). The depressor response to hexamethonium in the RDNX group was significantly smaller on postoperative day 10 (-10±5 mm Hg) compared with baseline control (-25±10 mm Hg). This was not the case in mice in the SHAM (day 10; -28±5 mm Hg) or CGX (day 10; -34±7 mm Hg) group. In conclusion, both renal and splanchnic nerves contribute to hypertension in BPH/2J mice, but likely through different mechanisms.

Sympathetic Effect of Auricular Transcutaneous Vagus Nerve Stimulation on Healthy Subjects: A Crossover Controlled Clinical Trial Comparing Vagally Mediated and Active Control Stimulation Using Microneurography.

Introduction: Auricular low-level transcutaneous vagus nerve stimulation (aLL-tVNS) has emerged as a promising technology for cardiac arrhythmia management but is still experimental. In this physiological study, we hypothesized that aLL-tVNS modulated the autonomic nervous balance through a reduction of sympathetic tone and an increase in heart rate variability (HRV). We investigated the muscle sympathetic nerve activity (MSNA) recorded by microneurography during vagally mediated aLL-tVNS and active control on healthy volunteers. Methods: In this crossover, double-blind controlled study, healthy men (N = 28; 27 ± 4 years old) were assigned to aLL-tVNS applied to cymba and lobe (active control) of the right ear. Each participant was randomly allocated to the three sequences (5 Hz, 20 Hz, and active control-5 Hz) during one session. MSNA signal was recorded at rest, during voluntarily apnea and aLL-tVNS. Sympathetic activity was expressed as: 1) number of bursts per minute (burst frequency, BF) and 2) MSNA activity calculated as BF x mean burst amplitude and expressed as changes from baseline (%). RR intervals, HRV parameters and sympathetic activity were analyzed during 5 min-baseline, 10 min-stimulation, and 10 min-recovery periods. Mixed regression models were performed to evaluate cymba-(5—20 Hz) effects on the parameters with stimulation. Results: During apnea and compared to baseline, BF and MSNA activity increased (p = 0.002, p = 0.001, respectively). No stimulation effect on RR intervals and HRV parameters were showed excepted a slightly increase of the LF/HF ratio with stimulation in the cymba-5Hz sequence (coef. ± SE: 0.76 ± 0.32%; p = 0.02). During stimulation, reductions from baseline in BF (Coef. ± SE: −4.8 ± 1.1, p < 0.001) was observed but was not statistically different from that one in the active control. Reduction of MSNA activity was not significantly different between sequences. Conclusion: Acute right cymba aLL-tVNS did not induce any overall effects neither on heart rate, HRV nor MSNA variables on healthy subjects when compared to active control. Interestingly, these findings questioned the role of active controls in medical device clinical trials that implied subjective endpoints.

Abstract 816: Surgical Bilateral Stellate Ganglionectomy Reduces Mitochondrial Reactive Oxygen Species (mROS) and Prevents Sudden Cardiac Death (SCD) in Non-ischemic Heart Failure (HF)

Introduction: Current therapies for SCD are limited. Bilateral sympathetic stellate ganglionectomy ( BSG ) is a promising new adjunctive therapy in patients with ischemic HF who have incessant ventricular tachyarrhythmias ( VT/VF ) despite optimal medical management. The underlying mechanisms are unknown. The effect of BSG in non-ischemic HF is unclear. Hypothesis: BSG prevents VT/VF and SCD in non-ischemic HF by restoring sympathovagal balance and reducing mROS. Methods: We used a unique pressure-overload guinea pig model that closely mimics human non-ischemic HF, including a high incidence of spontaneous VT/VF/SCD. We randomized the animals to non-failing controls, HF+Sham, or HF+BSG surgery. We used intention to treat analysis to evaluate VT/VF-free survival. We analyzed continuous ECG (VT/VF burden, heart rate variability, QT variability) and echo (cardiac function). In isolated left ventricular (LV) myocytes, we measured Ca 2+ transients and mitochondrial reactive oxygen species (mROS) using targeted ratiometric probes. Results: Half of the HF+Sham animals experienced SCD in 4 weeks. In contrast, BSG abolished SCD, reduced VT/VF, and increased parasympathetic tone (beyond corresponding reductions in sympathetic tone). Fractional shortening of the LV was markedly reduced in HF+Sham (0.28±0.02) vs. control (0.50±0.01), but preserved by BSG (0.45±0.02). Whereas HF+Sham increased mROS levels in LV myocytes (fractional oxidation, F ox : 0.53±0.015) compared to control (0.29±0.020), BSG reduced mROS (0.38±0.035). Mitochondrial antioxidant capacity, as indexed by H 2 O 2 challenge of LV myocytes, was compromised in HF+Sham (F ox : 0.81±0.040) compared to control (0.44±0.061), but preserved by BSG (0.48±0.023). Conclusions: Surgical BSG prevents SCD in non-ischemic HF by reducing mROS, decreasing sympathetic tone, and by increasing parasympathetic tone (possibly by facilitating cholinergic transdifferentiation). This promising new minimally-invasive surgical therapy may be particularly useful in patients with non-ischemic HF on optimal medical therapy who require recurrent ICD shocks to prevent SCD. Patients in the early stages of HF who are not eligible for ICDs but remain at higher SCD risk may also benefit from BSG surgery.

Abstract 115: Surgical Bilateral Stellate Ganglionectomy Reduces Mitochondrial Reactive Oxygen Species (mROS) and Prevents Sudden Cardiac Death (SCD) in Non-ischemic Heart Failure (HF)

Introduction: Current therapies for SCD are limited. Bilateral sympathetic stellate ganglionectomy ( BSG ) is a promising new adjunctive therapy in patients with ischemic HF who have incessant ventricular tachyarrhythmias ( VT/VF ) despite optimal medical management. The underlying mechanisms are unknown. The effect of BSG in non-ischemic HF is unclear. Hypothesis: BSG prevents VT/VF and SCD in non-ischemic HF by restoring sympathovagal balance and reducing mROS . METHODS: We used a unique pressure-overload guinea pig model that closely mimics human non-ischemic HF, including a high incidence of spontaneous VT/VF/SCD. We randomized the animals to non-failing controls, HF+Sham, or HF+BSG surgery. We used intention to treat analysis to evaluate VT/VF-free survival. We analyzed continuous ECG (VT/VF burden, heart rate variability, QT variability) and echo (cardiac function). In isolated left ventricular (LV) myocytes, we measured Ca 2+ transients and mitochondrial reactive oxygen species (mROS) using targeted ratiometric probes. Results: Half of the HF+Sham animals experienced SCD in 4 weeks. In contrast, BSG abolished SCD, reduced VT/VF, and increased parasympathetic tone (beyond corresponding reductions in sympathetic tone). Fractional shortening of the LV was markedly reduced in HF+Sham (0.28±0.02) vs. control (0.50±0.01), but preserved by BSG (0.45±0.02). Whereas HF+Sham increased mROS levels in LV myocytes (fractional oxidation, F ox : 0.53±0.015) compared to control (0.29±0.020), BSG reduced mROS (0.38±0.035). Mitochondrial antioxidant capacity, as indexed by H 2 O 2 challenge of LV myocytes, was compromised in HF+Sham (F ox : 0.81±0.040) compared to control (0.44±0.061), but preserved by BSG (0.48±0.023). Conclusions: Surgical BSG prevents SCD in non-ischemic HF by reducing mROS, decreasing sympathetic tone, and by increasing parasympathetic tone (possibly by facilitating cholinergic transdifferentiation). This promising new minimally-invasive surgical therapy may be particularly useful in patients with non-ischemic HF on optimal medical therapy who require recurrent ICD shocks to prevent SCD. Patients in the early stages of HF who are not eligible for ICDs but remain at higher SCD risk may also benefit from BSG surgery.

Central Administration of Hydrogen Sulfide Alleviates Rodent Angiotensin II Hypertension

IntroductionActivation of autonomic neural pathways plays a significant role in pathogenesis of hypertension (HTN). Hydrogen sulfide (H2S) is an endogenous neuro‐ and immunomodulatory molecule that is reportedly reduced in both rodent and human HTN. However, central role of H2S in HTN is not well understood. We hypothesized that chronic intracerebroventricular (ICV) infusion of sodium hydrosulfide (NaHS), an H2S donor, will alleviate rodent angiotensin II (Ang II) HTN.MethodsAdult male Sprague Dawley rats were implanted with radiotelemetry transmitters (DSI) in the descending aorta. Following baseline BP measurements, rats were randomly divided into three groups: (i) ICV NaHS; (ii) HTN; and (iii) ICV NaHS‐treated HTN rats. HTN was induced by chronic infusion of Ang II (200 ng/kg/min s.c.) for four weeks using mini‐osmotic pumps. ICV NaHS (30 nmol/h) or ICV saline was administered simultaneously with s.c. Ang II or saline infusion. At endpoint, H2S levels were measured in plasma samples of all rats.ResultsAt week four, mean arterial pressure (MAP) was significantly reduced in the ICV NaHS‐treated HTN group when compared with HTN group (104±7 vs. 166±5 mmHg, respectively; P&lt; 0.01). This was associated with a lower MAP at night in the ICV NaHS‐treated HTN vs. HTN group (Delta MAP from day to night: 15.29±4 vs. 31.37±17 mmHg, respectively), suggesting reduced sympathetic drive following treatment with NaHS. Interestingly, this also reflected in significantly higher plasma H2S levels in the ICV NaHS‐treated HTN vs. HTN group (0.070±0.000 AU vs. 0.067±0.000 AU, respectively; P&lt;0.05).ConclusionThese results support our hypothesis that alterations in central H2S signaling are associated with HTN, as centrally administered NaHS alleviated rodent Ang II HTN via reduction of sympathetic tone at night.Support or Funding InformationTUBITAK 2214‐A and UF CVM.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Reduction in sympathetic tone in patients with obstructive sleep apnoea: is fixed CPAP more effective than APAP? A randomised, parallel trial protocol

IntroductionObstructive sleep apnoea (OSA) is a prevalent disease associated with cardiovascular events. Hypertension is one of the major intermediary mechanisms leading to long-term cardiovascular adverse events. Intermittent hypoxia and hypercapnia...

FOXO in Neural Cells and Diseases of the Nervous System.

The evolutionarily conserved FOXO family of transcription factors has emerged as a significant arbiter of neural cell fate and function in mammals. From the neural stem cell (NSC) state through mature neurons under both physiological and pathological conditions, they have been found to modulate neural cell survival, stress responses, lineage commitment, and neuronal signaling. Lineage-specific FOXO knockout mice have provided an invaluable tool for the dissection of FOXO biology in the nervous system. Within the NSC compartments of the brain, FOXOs are required for the maintenance of NSC quiescence and for the clearance of reactive oxygen species. Within mature neurons, FOXO transcriptional activity is essential for the prevention of age-dependent axonal degeneration. Acutely, FOXO3 has been found to cause axonal degeneration upon withdrawal of neurotrophic factors. In more active neural signaling, FOXO6 promotes increased dendritic spine density of hippocampal neurons and is required for the consolidation of memories. In addition to the central nervous system (CNS), FOXOs also influence the functionality of the peripheral nervous system (PNS). FOXO1 knockout within the PNS results in a reduction of sympathetic tone and decreased levels of brain-derived norepinephrine and lower energy expenditure. FOXO3 knockout mice have impaired hearing which may be due to defects in synapse localization within the ear. Given the scope of FOXO activities in both the CNS and PNS, it will be of interest to study FOXOs within the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. From within the nervous system, FOXOs may also regulate important parameters such as whole-body metabolism, motor function, and catecholamine production, making FOXOs key players in physiologic homeostasis.

SGLT2 Inhibitors and Mechanisms of Hypertension.

We sought to review currently available data on the safety and efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 2 diabetes mellitus patients with hypertension. Inhibition of SGLT2 in the renal proximal tubule results in increased urinary glucose excretion and modest improvements of hemoglobin A1C. Treatment with any of the three currently FDA-approved SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) results in sustained systolic and diastolic blood pressure reduction, in part via minimal natriuresis and possible reductions in sympathetic tone. Recent randomized clinical trials in high cardiovascular risk patients with type 2 diabetes suggest that the unique effects of SGLT2 inhibitors on blood pressure and body weight may translate into reduced cardiovascular events and slowed kidney disease progression. However, concerns about volume depletion and acute kidney injury have been raised. SGLT2 inhibitors are viable second-line glucose-lowering agents for people with type 2 diabetes with high cardiovascular risk.

Abstract 086: Knockdown of the Neuronal (Pro)renin Receptor in the Paraventricular Nucleus of the Hypothalamus Attenuates ERK1/2 Activation and the Development of Salt Sensitive Hypertension

The (Pro)renin (PRR) receptor is a key player of the brain renin-angiotensin system. We previously reported that neuron-specific knockout of the PRR attenuated the development of salt-sensitive hypertension (SSH). However, the brain region responsible for this effect is unknown. To test our hypothesis that PRR plays a regulatory role in the paraventricular nucleus of the hypothalamus (PVN) during SSH development, we knocked down PRR using adeno-associated virus (AAV2)-mediated Cre recombinase micro-injection into the PVN of PRR-LoxP mice. Blood pressure (BP, mmHg), heart rate (HR, bpm), and autonomic function were monitored with radio telemetry. Immunofluorescence was used to determine cell localization of AAV2 in the PVN and ERK1/2 activation (pERK1/2). We found that AAV2-eGFP positive cells co-localized with the neuronal marker NeuN, but not with astrocytes (GFAP) or microglia (IBa1). PRR-LoxP mice were injected with either AAV2-eGPF (GFP) or AAV2-Cre-eGFP (Cre) bilaterally into the PVN (1.8x10 8 Vg). Three days post viral injection, mice received either DOCA-salt (50mg DOCA pellet + 0.9%NaCl drinking solution) or sham (sham pellet + tap water) treatment for 21 days. PVN injection of Cre or GFP had no effect on baseline BP. After 21 days of DOCA-salt treatment, the BP (119 ± 3 vs. 139 ± 7) was significantly lower in mice that received Cre compared with GFP. The cardiac sympathetic tone (ΔHR to propranolol: -123 ± 46 vs. -181 ± 16) and vasomotor sympathetic tone (ΔBP to chlorisondamine: -47 ± 9 vs. -69 ± 5) were also lowered in Cre compared GFP treated mice following DOCA-salt treatment. The pERK1/2 levels in the PVN were increased in the DOCA-salt compared to sham (fold change: 3.29 ± 0.62, P&lt;0.0001) treated mice. Importantly, the pERK1/2 elevation in the PVN was blocked by Cre (0.98 ± 0.15) compared with GFP with DOCA-salt treatment. PVN-targeted PRR knockdown had not effect on pERK1/2 in the subfornical organ compared to GFP (0.74 ± 0.05 vs. 1.0 ± 0.14); while, it reduced pERK1/2 in the rostral ventrolateral medulla (RVLM) (0.77 ± 0.06 vs. 1.23 ± 0.11, P&lt;0.001). In summary, PVN-targeted PRR deletion attenuates SSH and ERK1/2 activation in the PVN and RVLM, and is associated with reduction in sympathetic tone in mice indicating an important role of PVN PRR in BP regulation.

Abstract P335: Greater Reduction in Sympathetic Tone following ET B Receptor Blockade in Rats Lacking the Clock Gene Bmal1 during High Salt Diet

The absence of diurnal oscillations in blood pressure is associated with increased cardiovascular morbidity and mortality. The clock gene Bmal1 plays important roles in diurnal cardiovascular control as mice lacking Bmal1 have lower blood pressure and lack a diurnal rhythm. Our lab has previously reported a global Bmal1 knockout rat model that lacks a night-day difference in sodium excretion. Due to the importance of endothelin signaling in sodium homeostasis and autonomic tone, we sought to characterize the hemodynamic and autonomic responses of our Bmal1 knockout (KO) rat to high salt diet and endothelin receptor blockade. Male rats homozygous for the Bmal1 mutation (KO, n = 4) and wild type (WT, n = 7) littermate controls were implanted with telemetry transmitters to record blood pressure. After a recovery period of at least one week, the rats were placed on 7 days each of normal salt (0.49% NaCl) diet, high salt (4.0% NaCl) diet, followed by high salt diet containing the specific ET B receptor antagonist A192621 (10 mg/kg/day, p.o.). Rats were placed in metabolic cages for the last three days of each diet. Surprisingly, KO rats had a similar night-day difference in mean arterial pressure (MAP) as WT during normal salt diet (6.3 ± 0.4 vs. 6.9 ± 0.9 mmHg; respectively), high salt diet (7.1 ± 0.1 vs. 5.4 ± 0.9 mmHg; respectively), and high salt + A192621 (5.4 ± 0.4 vs. 4.8 ± 1.1 mmHg; respectively). KO and WT rats had similar 24-hr MAP during normal salt diet (104.1 ± 3.3 vs. 107.3 ± 1.2 mmHg; respectively), high salt diet (113.8 ± 4.1 vs. 114.0 ± 1.4 mmHg; respectively), and high salt + A192621 (136.3 ± 8.6 vs. 133.4 ± 3.1 mmHg; respectively). Despite these similar blood pressure responses to high salt diet and ET B antagonism, KO rats had a significantly greater reduction in vasomotor sympathetic to parasympathetic tone compared to WT rats as demonstrated by low frequency to high frequency (LF/HF) analysis of diastolic blood pressure variability (-0.9 ± 0.3 vs. 0.1 ± 0.2 ΔLF/HF relative to normal salt; respectively; p = 0.01). These results indicate that lack of Bmal1 may result in greater ET B receptor mediated vasomotor sympathetic tone in rats fed a high salt diet and that factors other than Bmal1 may be influential in circadian control of blood pressure in rats.

Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p < 0.05). Ischemia-reperfusion-induced renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

Integration of renal sensory afferents at the level of the paraventricular nucleus dictating sympathetic outflow

The sympathetic nervous system has been identified as a major contributor to the pathophysiology of chronic heart failure (CHF) and other diseases such as hypertension and diabetes, both in experimental animal models and patients. The kidneys have a dense afferent sensory innervation positioning it to be the origin of multimodal input to the central nervous system. Afferent renal nerve (ARN) signals are centrally integrated, and their activation results in a general increase in sympathetic tone, which is directed toward the kidneys as well as other peripheral organs innervated by the sympathetic nerves. In the central nervous system, stimulation of ARN increases the neuronal discharge frequency and neuronal activity in the paraventricular nucleus (PVN) of the hypothalamus. The activity of the neurons in the PVN is attenuated during iontophoretic application of glutamate receptor blocker, AP5. An enhanced afferent renal input to the PVN may be critically involved in dictating sympathoexcitation in CHF. Furthermore, renal denervation abrogates the enhanced neuronal activity within the PVN in rats with CHF, thereby possibly contributing to the reduction in sympathetic tone. Renal denervation also restores the decreased endogenous levels of neuronal nitric oxide synthase (nNOS) in the PVN of rats with CHF. Overall, these data demonstrate that sensory information originating in the kidney excites pre-autonomic sympathetic neurons within the PVN and this "renal-PVN afferent pathway" may contribute to elevated sympathetic nerve activity in hyper-sympathetic disease conditions such as CHF and hypertension.

PP.16.25

Objective: To assess the level of physical activity and its relationships with plasma lipids and cardiovascular risk factors in an urban Congolese population. Design and method: Based on their response to a questionnaire, 1,292 subjects aged 20 years and over, 731 women (56.6%) were allocated to either insufficient, low or moderate-to-intense level of physical activity. We compared the categories of physical activity for plasma lipids and prevalence of cv risk factors, and modeled the probability of hypercholesterolemia in a logistic regression. Results: Physical activity was insufficient in 645 subjects (49.9%), lower in 438 (33.9%), moderate-to-intense in 209 (16.2%). Insufficient physical activity (59.5 vs 37.4%) predominated among women, moderate-to-intense among men (7.7% vs 27.3%; P < 0.0001). The rate of moderate-to-intense physical activity in subjects aged 20–29 years amounted to 20.8% for the whole study population, to 34.4% for men and 8.8 % for women; in those aged 60 years or more the rate had decreased to 5.6% (P < 0.0001), 13.5% (P = 0.0003) and 0% (P = 0.1374), respectively. Participants with moderate-to-intense physical activity had lower body mass index, waist circumference, heart rate, total and LDL cholesterol and, hence, lower prevalence of overweight/obesity, central obesity and hypercholesterolemia than the other two categories. Their prevalence of hypertension tended to be higher, especially for men. In the logistic model, the likelihood of high cholesterol increased with age (OR per year, 1.021 [95% CI: 1.010 - 1.033]; P = 0.0002) and central obesity (presence vs absence: 1.985 [1.373 - 2.871]; P = 0.0003), and decreased with moderate-to-intense physical activity (0.719 [0.554 to 0.933]; P = 0.0132). Conclusions: These results highlight the potential cardiovascular benefit of physical activity through prevention of obesity and reduction of sympathetic tone and atherogenic lipids.

The role of the autonomic nervous system in Tourette Syndrome.

Tourette Syndrome (TS) is a neurodevelopmental disorder, consisting of multiple involuntary movements (motor tics) and one or more vocal (phonic) tics. It affects up to one percent of children worldwide, of whom about one third continue to experience symptoms into adulthood. The central neural mechanisms of tic generation are not clearly understood, however recent neuroimaging investigations suggest impaired cortico-striato-thalamo-cortical activity during motor control. In the current manuscript, we will tackle the relatively under-investigated role of the peripheral autonomic nervous system, and its central influences, on tic activity. There is emerging evidence that both sympathetic and parasympathetic nervous activity influences tic expression. Pharmacological treatments which act on sympathetic tone are often helpful: for example, Clonidine (an alpha-2 adrenoreceptor agonist) is often used as first choice medication for treating TS in children due to its good tolerability profile and potential usefulness for co-morbid attention-deficit and hyperactivity disorder. Clonidine suppresses sympathetic activity, reducing the triggering of motor tics. A general elevation of sympathetic tone is reported in patients with TS compared to healthy people, however this observation may reflect transient responses coupled to tic activity. Thus, the presence of autonomic impairments in patients with TS remains unclear. Effect of autonomic afferent input to cortico-striato-thalamo-cortical circuit will be discussed schematically. We additionally review how TS is affected by modulation of central autonomic control through biofeedback and Vagus Nerve Stimulation (VNS). Biofeedback training can enable a patient to gain voluntary control over covert physiological responses by making these responses explicit. Electrodermal biofeedback training to elicit a reduction in sympathetic tone has a demonstrated association with reduced tic frequency. VNS, achieved through an implanted device that gives pulsatile electrical stimulation to the vagus nerve, directly modulates afferent interoceptive signals. The potential efficacy of biofeedback/VNS in TS and the implications for understanding the underlying neural mechanisms of tics will be discussed.