Peripheral Sympathetic Nerve Research Articles

Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α2-Adrenergic Receptors in PC12 Cells.

Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α2-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α2-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gβγ-activated phospholipase C (PLC)-β/Ca2+ signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α2A-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α2A-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α2A-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.

Locally produced nerve growth factor is a novel regulator of (juxta)glomerular and collecting duct functions in the kidney

The dense network of sympathetic efferent and sensory afferent nerves innervating the kidney is well recognized, however the elements and the functional importance of neurotrophin signaling in renal tissues are much less known. Peripherally innervated tissues are known to produce and release nerve growth factor (NGF) which belongs to the neurotrophin family of neuronal signaling proteins and is essential for the growth and survival of peripheral sensory and sympathetic nerves. This study aimed to characterize the expression and role of NGF in the kidney. We hypothesized that NGF is produced by multiple renal tubular and vascular cell types and helps to maintain hemodynamic and tubular transport functions. Local NGF expression was studied using histological sections of kidneys harvested from NGF-GFP reporter mice. To address the functional importance of NGF signaling, a new mouse model was generated by crossing Ren1d-Cre and NGF-floxed mice and Cre/lox-mediated knockout of NGF from cells of the renin lineage co-labeled with the multicolor reporter Confetti (Ren1d-Confetti-NGF KO). WT and NGF KO mice were placed in metabolic cages for urine collections and analysis, and systolic blood pressure (SBP) was measured with tail-cuff pletysmography. Intercalated cells of the collecting duct (CD) showed by far the highest NGF expression among all renal cell types based on the reporter signal in NGF-GFP mice, in addition to select cells in the renal interstitium including juxtaglomerular (JG) renin cells. Since both CD cells and JG cells are part of the renin lineage, the applied genetic strategy using Ren1d-Confetti-NGF KO mice was ideal, and showed diminished NGF expression compared to WT. Urine excretion rate and albuminuria were 3-fold increased in Ren1d-Confetti-NGF KO vs. WT mice, while there was no difference in SBP between WT and KO groups. Immunohistochemistry showed aberrant CD structure with multiple small, undifferentiated cells with apparently lost polarity and reduced AQP2 labeling in CD principal cells in Ren1d-Confetti-NGF KO mice compared to WT. In addition, the characteristic strong apical membrane AQP2 (in principal cells) and H+-ATPase (in intercalated cells) labeling in WT mice was diminished in Ren1d-Confetti-NGF KO mice. JG renin cell number per nephron was significantly reduced in Ren1d-Confetti-NGF KO (2.5±1.0) vs. WT mice (6.2±1.5, n=4 mice each). In summary, our results suggest high level of NGF expression in the adult kidney that plays important physiological functional roles in maintaining collecting duct water and electrolyte reabsorption and acid secretion, and intrarenal renin production. Deficient intrarenal NGF production may cause kidney disease, suggesting the importance of altered renal neurotrophin signaling in pathology development. DK064234, DK123564, DK135290. 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.

Neural recordings can differentiate between spontaneously metastasizing melanomas and melanomas with low metastatic potential.

Multiple studies report that melanomas are innervated tumors with sensory and sympathetic fibers where these neural fibers play crucial functional roles in tumor growth and metastasis with branch specificity. Yet there is no study which reports the direct neural recording and its pattern during in-vivo progression of the cancer. We performed daily neural recordings from male and female mice bearing orthotopic metastasizing- melanomas and melanomas with low metastatic poential, derived from B16-F10 and B16-F1 cells, respectively. Further, to explore the origins of neural activity, 6-Hydroxidopamine mediated chemical sympathectomy was performed followed by daily microneurographic recordings. We also performed the daily bioluminescent imaging to track in vivo growth of primary tumors and distant metastasis to the cranial area. Our results show that metastasizing tumors display high levels of neural activity while tumors with low metastatic potential lack it indicating that the presence of neural activity is linked to the metastasizing potential of the tumors. Moreover, the neural activity is not continuous over the tumor progression and has a sex-specific temporal patterns where males have two peaks of high neural activity while females show a single peak. The neural peak activity originated in peripheral sympathetic nerves as sympathectomy completely eliminated the peak activity in both sexes. Peak activities were highly correlated with the distant metastasis in both sexes. These results show that sympathetic neural activity is crucially involved in tumor metastasis and has sex-specific role in malignancy initiation.

Acetic Acid: An Underestimated Metabolite in Ethanol-Induced Changes in Regulating Cardiovascular Function.

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.

Naloxone selectively inhibits vasoconstriction caused by phenylephrine but not endogenous noradrenaline in the rat mesenteric vasculature.

Although naloxone is an antagonist of the opioid µ receptor, its effect on the peripheral sympathetic nerve function in the blood vessels has not yet been definitively elucidated. Therefore, we examined the effects of naloxone on vasoconstriction of the vascular smooth muscle of rats. Isolated rat mesenteric vascular-intestinal loop preparations were treated with either endogenous or exogenous α1 adrenoceptor agonists followed by prazosin, a selective antagonist of the α1 adrenoceptor, or naloxone, and noradrenaline overflow was measured. Vasoconstriction caused by peri-arterial nerve stimulation (PNS) and phenylephrine, an exogenous agonist of the α1 adrenoceptor, was abolished by prazosin. However, prazosin did not affect PNS-induced endogenous noradrenaline overflow. Naloxone did not affect either PNS-induced endogenous noradrenaline overflow or vasoconstriction. However, naloxone did inhibit phenylephrine-induced vasoconstriction. In addition, naloxone did not affect the angiotensin II-induced vasoconstriction. These results demonstrate that naloxone selectively inhibits vasoconstriction caused by phenylephrine, but not vasoconstriction caused by endogenous noradrenaline released from sympathetic nerve cells in the rat mesenteric vasculature.

Anthocyanin attenuates high salt-induced hypertension via inhibiting the hyperactivity of the sympathetic nervous system

ABSTRACT 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.

A HYPERADRENERGIC STATE IN HYPERTENSION IS ASSOCIATED WITH MOOD DISTURBANCE AND IMPAIRED STRESS-MODULATED VASOMOTOR RESPONSES

Objective: Increasing evidence suggests a high prevalence of affective disorders in hypertension, however, the physiological associations remain unclear. Noradrenergic activation in the central and peripheral nervous systems is a putative mechanism that may explain the link between both conditions. Here, we investigate whether these stress-sensitive co-morbidities may be dependent on basal noradrenergic activity and whether vascular responses to centrally acting stimuli vary according to noradrenergic activity. Design and method: We examined the relation of affective disorders and stress-mediated vascular responses to plasma concentrations of normetanephrine (NMN), a measure of noradrenergic activity, in subjects with primary hypertension. Subjects on antidepressant medication, alpha- and beta-blockers were excluded. The Patient Health Questionnaire (PHQ-9), the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR-16), and Generalised Anxiety Disorder-7 (GAD-7) questionnaires were used for the evaluation of symptoms of depression and anxiety. Forearm blood flow (strain gauge plethysmography) was used to assess vascular responses to mental stress (Stroop colour-word test) and slow breathing (by biofeedback), interventions that respectively increase or decrease noradrenergic activity in the pre-frontal cortex and locus coeruleus. Results: 100 subjects (53% male) with (mean ± SD) age 43.4 ± 10.9 years were recruited. 88% of subjects were treated with anti-hypertensive medications and 4% had type 2 diabetes. 31% and 34% of the study population scored moderate to severe depression for PHQ-9 and QIDSSR-16 respectively indicating significant mood disturbance. Scores representing low mood and high anxiety were 2-3-fold higher for hypertensive subjects in the highest compared to lowest NMN tertiles (PHQ-9: 9.2 ± 5.8 vs 3.8 ± 2.7, P < 0.001; QIDSSR-16: 12.3 ± 4.9 vs 4.5 ± 3.5, P = 0.003; GAD-7: 9.0 ± 5.5 vs 4.6 ± 3.8, P = 0.003). Forearm vasodilator responses to mental stress and vasoconstrictor responses to slow breathing were attenuated in those with high compared to low NMN (28.3 ± 21% vs. 47.1 ± 30% increases for mental stress and 3.7 ± 21% vs. 18.6 ± 15% decreases for slow breathing for highest vs. lowest tertiles of NMN, both P < 0.01). Conclusions: A hyperadrenergic state in hypertension is associated with mood disturbance and impaired stress-modulated vasomotor responses. This association may be mediated by chronic stress impinging on pathways regulating central arousal and peripheral sympathetic nerve activity.

Diabetes mellitus-induced lower urinary tract symptoms and hepatic steatosis in an older male.

SummaryDiabetes mellitus type 2 (DM-2) is one of the important causes of low-grade chronic inflammation (meta inflammation) seen in almost all tissues in the body. Other possible mechanisms involved in the development of lower urinary tract symptoms (LUTS) with DM-2 are the hypertonicity of the peripheral sympathetic nerves and hyperinsulinemia effects on the autonomous nervous system activity. These further suggests that abnormalities in glucose homeostasis influence the hyperproliferation of the prostate cells resulting in benign prostatic hyperplasia (BPH). Similarly, hepatic steatosis, a form of non-alcoholic fatty liver disease (NAFLD) prevalence among patients with DM-2, is as high as 75%. NAFLD has no symptoms in most diabetic patients. In this study, we present a case of a 64-year-old Black male who had worsening urinary urgency and hesitancy for 4 months, with increasing abdominal girth. Patient was found to have symptoms, diagnostic studies, and physical exam findings indicative of BPH and fatty liver disease. He was treated with hepato-protective medications, tighter control of his blood glucose levels, and blood pressure meds for 13 months. Upon follow-up, most of his symptoms were resolved. Timeline of BPH resolution and decrease in liver size following treatment suggest that DM-2 has a strong correlation with the development of BPH and fatty liver disease in most patients living with diabetes.Learning pointsMen with type 2 diabetes mellitus (DM-2) tend to have significantly lower serum PSA level, lower testosterone levels, and larger prostate volume compared to non-diabetic male patients.Patients with DM-2 have higher prevalence of hepatic steatosis, liver cirrhosis, and end-stage liver failure.The role of metformin in reducing hepatic steatosis as stated by several studies is yet to be validated as our patient has been on metformin for 22 years for the management of DM-2 with fatty liver disease.

Sympathetic neural reactivity to the Trier social stress test.

Sympathetic responsiveness to laboratory mental stress is highly variable, making interpretations of its role in stress reactivity challenging. The present study assessed muscle sympathetic nerve activity (MSNA, microneurography) responsiveness to the Trier social stress test (TSST), which employs an anticipatory stress phase, followed by a public speaking and mental arithmetic task. We hypothesized that sympathetic reactivity to the anticipatory phase would offer a more uniform response between individuals due to elimination of confounds (i.e. respiratory changes, muscle movement, etc.) observed during more common stress tasks. Participants included 26healthy adults (11men, 15 women, age: 25±6years, body mass index: 24±3kg/m2 ). Continuous heart rate (electrocardiogram) and beat-to-beat blood pressure (finger plethysmography) were recorded from all participants, while MSNA recordings were obtained in 20 participants. MSNA burst frequency was significantly reduced during anticipatory stress. During the speech, although burst frequency was unchanged, total MSNA was significantly increased. Changes in diastolic arterial pressure were predictive of changes in MSNA during anticipatory (β=-0.680, P=0.001), but not the speech (P=0.318) or mental maths (P=0.051) phases. Lastly, sympathetic reactivity to anticipatory stress was predictive of subsequent reactivity to both speech (β=0.740, P=0.0002) and maths (β=0.663, P=0.001). In conclusion, anticipatory social stress may offer a more versatile means of assessing sympathetic reactivity to mental stress in the absence of confounds and appears to predict reactivity to subsequent mental stress paradigms. KEY POINTS: Cardiovascular reactivity to laboratory mental stress is predictive of future health outcomes. However, reactivity of the sympathetic nervous system to mental stress is highly variable. The current study assessed peripheral muscle sympathetic nerve activity in response to the Trier social stress test, a psychosocial stressor that includes anticipatory stress, public speaking and mental arithmetic. Our findings demonstrate that sympathetic neural activity is consistently reduced during anticipatory stress. Conversely, the classically observed inter-individual variability of sympathetic responsiveness was observed during speech and maths tasks. Additionally, sympathetic reactivity to the anticipatory period accurately predicted how an individual would respond to both speech and maths tasks, outlining the utility of anticipatory stress in future research surrounding stress reactivity. Utilization of the Trier social stress test in autonomic physiology may offer an alternative assessment of sympathetic responsiveness to stress with more consistent inter-individual responsiveness and may be a useful tool for further investigation of stress reactivity.

Improved Renal Denervation Mitigated Hypertension Induced by Angiotensin II Infusion.

The benefits of renal sympathetic denervation (RDN) on blood pressure have been proved in a large number of clinical trials in recent years. However, the regulatory mechanism of RDN on hypertension remains elusive. Thus, it's essential to establish a simpler RDN model in mice. In this study, osmotic mini pumps filled with Angiotensin II were implanted in 14-week-old C57BL/6 mice. One week after the implantation of the mini-osmotic pump, a modified RDN procedure was performed on bilateral renal arteries of the mice using phenol. Age-sex-matched mice were given saline and served as sham group. Blood pressure was measured at baseline and every week subsequently for 21 days. Then, renal artery, abdominal aorta and heart were collected for histological examination using H&E and Masson staining. In this study, we present a simple, practical, repeatable, and standardized RDN model, which can control hypertension and alleviate cardiac hypertrophy. The technique can denervate peripheral renal sympathetic nerves without renal artery damage. Compared to previous models, the modified RDN facilitates the study of the pathobiology and pathophysiology of hypertension.

Sympathetic modulation of tumor necrosis factor alpha-induced nociception in the presence of oral squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) causes more severe pain and psychological stress than other types of cancer. Despite clinical evidence linking pain, stress, and cancer progression, the underlying relationship between pain and sympathetic neurotransmission in oral cancer is unknown. We found that human HNSCC tumors and mouse tumor tissue are innervated by peripheral sympathetic and sensory nerves. Moreover, β-adrenergic 1 and 2 receptors (β-ARs) are overexpressed in human oral cancer cell lines, and norepinephrine treatment increased β-AR2 protein expression as well as cancer cell proliferation in vitro. We have recently demonstrated that inhibition of tumor necrosis factor alpha (TNFα) signaling reduces oral cancer-induced nociceptive behavior. Norepinephrine-treated cancer cell lines secrete more TNFα which, when applied to tongue-innervating trigeminal neurons, evoked a larger Ca 2+ transient; TNF-TNFR inhibitor blocked the increase in the evoked Ca 2+ transient. Using an orthotopic xenograft oral cancer model, we found that mice demonstrated significantly less orofacial cancer-induced nociceptive behavior during systemic β-adrenergic inhibitory treatment with propranolol. Furthermore, chemical sympathectomy using guanethidine led to a significant reduction in tumor size and nociceptive behavior. We infer from these results that sympathetic signaling modulates oral cancer pain through TNFα secretion and tumorigenesis. Further investigation of the role of neurocancer communication in cancer progression and pain is warranted.

Role of autonomic system imbalance in neurogenic pulmonary oedema.

Neurogenic pulmonary oedema (NPE) is a life-threatening complication that develops rapidly and dramatically after an injury to the central nervous system (CNS). The autonomic system imbalance produced by severe brain damage may play an important role in the development of NPE. Activation of the sympathetic nervous system and inhibition of the vagus nerve system are essential prerequisites for autonomic system imbalance. The more severe the damage, the more pronounced the phenomenon. Sympathetic hyperactivity is associated with increased release of catecholamines from peripheral sympathetic nerve endings, which can cause dramatic changes in haemodynamics and cause pulmonary oedema. On the other hand, the abnormal inflammatory response caused by vagus nerve inhibition may also play an important role in the pathogenesis of NPE. The perspective of autonomic system imbalance seems to perfectly integrate the existing pathogenesis of NPE and can explain the entire development progression of NPE.

Schwannoma of the Facial Nerve with Facial Resuscitation with Facial Hypoglossal Neurotization

Schwannomas of facial nerve is a benign tumor that arises from Schwann cells, from the neural sheath of the peripheral, sensitive or sympathetic and sympathetic nerve nerves and in cranial nerve, except for the optical and olfactory nerves Cranials that lack Schwann cell pod.

Autonomic control of cerebral blood flow: fundamental comparisons between peripheral and cerebrovascular circulations in humans.

Understanding the contribution of the autonomic nervous system to cerebral blood flow (CBF) control is challenging, and interpretations are unclear. The identification of calcium channels and adrenoreceptors within cerebral vessels has led to common misconceptions that the function of these receptors and actions mirror those of the peripheral vasculature. This review outlines the fundamental differences and complex actions of cerebral autonomic activation compared with the peripheral circulation. Anatomical differences, including the closed nature of the cerebrovasculature, and differential adrenoreceptor subtypes, density, distribution and sensitivity, provide evidence that measures on peripheral sympathetic nerve activity cannot be extrapolated to the cerebrovasculature. Cerebral sympathetic nerve activity seems to act opposingly to the peripheral circulation, mediated at least in part by changes in intracranial pressure and cerebral blood volume. Additionally, heterogeneity in cerebral adrenoreceptor distribution highlights region-specific autonomic regulation of CBF. Compensatory chemo- and autoregulatory responses throughout the cerebral circulation, and interactions with parasympathetic nerve activity are unique features to the cerebral circulation. This crosstalk between sympathetic and parasympathetic reflexes acts to ensure adequate perfusion of CBF to rising and falling perfusion pressures, optimizing delivery of oxygen and nutrients to the brain, while attempting to maintain blood volume and intracranial pressure. Herein, we highlight the distinct similarities and differences between autonomic control of cerebral and peripheral blood flow, and the regional specificity of sympathetic and parasympathetic regulation within the cerebrovasculature. Future research directions are outlined with the goal to further our understanding of autonomic control of CBF in humans.

Effects of dapagliflozin on peripheral sympathetic nerve activity in standard chow- and high-fat-fed rats after a glucose load

To clarify the effects of long-term administration of SGLT2 inhibitor, a hypoglycemic agent, on basal sympathetic nerve activity (SNA) and on SNA under development of insulin resistance, we measured peripheral SNA in response to a glucose load in standard chow- (SCF) and high-fat-fed (HFF) rats treated with or without dapagliflozin for 7 weeks. We conducted an intravenous glucose administration (IVGA), and evaluated SNA microneurographically recorded in the unilateral sciatic nerve. Dapagliflozin did not affect the steady state action potential (AP) rate just before the IVGA (baseline) in both the SCF and HFF rats. After the IVGA, in the SCF rats, the AP rate in dapagliflozin-treated group transiently decreased within 20 min after the IVGA, and was significantly lower (P < 0.05) than non-treated group for 60 min. In the HFF rats, no significant difference was seen in the AP rate between dapagliflozin-treated and non-treated groups. The rate in the dapagliflozin-treated group after the IVGA was significantly lower (P < 0.05) than the baseline whereas such difference was not found in the non-treated group. In conclusion, dapagliflozin attenuate SNA in response to glucose load, and that the SNA response is different between standard chow-fed- and high-fat-fed rats.

Maybe angiotensin II is getting on our nerves, and the role of exercise.

Maybe angiotensin II is getting on our nerves, and the role of exercise.

Abstract P373: The Occurrence Of Neurovascular And Adipose Neuropathy In The Genetically Diverse Het3 Mouse With Aging

Energy homeostasis and adipose tissue metabolism are regulated in large part through peripheral sympathetic nerve innervation of metabolically important tissues and organs. This neural communication from the brain to adipose tissues results in release of the neurotransmitter norepinephrine that regulates energy expenditure through modulation of lipolysis, adipogenesis, ‘browning’ (development of brown adipocytes in white adipose depots), and non-shivering thermogenesis. Subcutaneous white adipose tissue (scWAT) is an energy storing tissue that is highly plastic, responding to metabolic need by changing mass and cellularity, as well as responding to challenges (including cold temperature, exercise, fasting) by modifying neural activity and metabolism. Within scWAT lies a dense bed of nerves and blood vessels that are integrated closely, and in large part, rely on one another to function properly. Even if not directly innervating the blood vessels themselves (as is the case with capillaries), neurites that appear to innervate single adipocytes use these blood vessels as scaffolding to traverse the tissue. We have recently demonstrated that under pathological conditions (obesity and aging), scWAT innervation decreases through a process termed ‘adipose neuropathy’. With advanced age the small fiber peripheral nerve endings in adipose die back, including reducing contact with adipose-resident blood vessels (as observed previously in the C57BL6/J mouse). This likely poses a physiological challenge for metabolism and for vascular or adipose tissue health and function. For this work, we compared C57BL6/J mice with the more genetically diverse HET3 mouse model, established for the NIA’s Intervention Testing Program to more accurately represent the variability of age-related mortality/morbidity. We investigated incidence of peripheral neuropathy with aging (skin, scWAT muscle) as well as changes to the neurovascular supply of scWAT across several ages in both males and females. We also investigated the anti-aging drug Rapamycin as a potential means to prevent or reduce adipose neuropathy. We found that HET3 mice display a reduced neuropathy phenotype compared to inbred C56BL6/J mice. Importantly, the nerve die-back around blood vessels was not observed in the HET3 model. However, male HET3 mice did reveal neuropathic phenotypes by 62wks of age, characterized by decreased mechanoreception in hind paw skin, reduced NMJ occupation, and decreased expression of the Schwann cell marker Sox10 in scWAT. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126wks) when they began to show stronger phenotypes than males (excluding Sox10 analysis.) Despite its success as a longevity treatment in mice, rapamycin had little to no effect on reducing or preventing the onset of adipose neuropathy.

Abstract 14740: Sympathetic Down-regulation With Zamicastat Reduces Arrhythmogenicity in Isolated Hearts From Rats With Pulmonary Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a disease often causing right ventricular failure and death. During disease progression, structural and electrical remodeling of the right ventricle creates proarrhythmic substrates and triggers for arrhythmias. Studies of PAH patients show a hyperstimulation of the sympathetic nervous system (SNS) indicating that PAH may be mediated by SNS hyperactivation. Zamicastat (ZAM) is a reversible dopamine β-hydroxylase inhibitor that modulates SNS by reducing the biosynthesis of norepinephrine in peripheral sympathetic nerves. ZAM improves survival in the monocrotaline (MCT) rat model of PAH. Hypothesis: To evaluate the effect of ZAM on electrophysiological parameters in isolated hearts from MCT-treated rats. Methods: Male Wistar Han rats were randomized in 3 groups, Sham (n=6), MCT (n=15) and MCT+ZAM (n=17). On day zero, MCT and MCT+ZAM groups received MCT (60 mg/kg, SC) and Sham group received saline. Starting on day 12, MCT+ZAM rats were daily administered ZAM (30 mg/kg, PO) while all other animals were given vehicle. On day 28, hearts were excised and mounted on a Langendorff system. A bipolar circuit of two electrodes was placed on the epicardium for ECG recording. Provoked arrhythmias were induced with a burst pacing protocol (50Hz, 1 second) and the recovery time was measured as the time needed to reach 3 consecutive stable R-R intervals. Results: MCT increased the proportion of hearts exhibiting bundle branch blocks, 3 rd degree atrioventricular (AV) blocks, atrial fibrillation (AF), ventricular fibrillation (VF) and premature ventricular contractions (PVCs) when compared to Sham group. ZAM treatment suppressed 3 rd degree AV blocks, AF and VF. In addition, PVCs were less frequent in hearts from MCT+ZAM animals as compared to MCT group. Isolated hearts naturally entered a pause following overpacing-induced VF. MCT hearts showed a non-significant 1.7-fold increase in recovery time compared to Sham group. Hearts from MCT+ZAM animals had a significant ≈50% reduction in post-fibrillation pause. Conclusions: These data suggest that treatment with Zamicastat yields a lower proarrhythmic cardiac tissue decreasing the incidence of cardiac arrhythmias.

Sudor Anglicus: an epidemic targeting the autonomic nervous system

Renaissance England witnessed a series of brief epidemics of a rapid and often fatal illness, the predominant feature of which was a disturbance of the autonomic nervous system. Profuse sweating was both an emblematic and ominous sign of this Sudor Anglicus. Its story is medically fascinating as well as historically noteworthy. Possible sites of pathological involvement include the hypothalamus, serotonergic neurons in the brainstem or spinal cord, autonomic ganglia, peripheral sympathetic nerves, neuroeffector junctions, or eccrine glands. Of candidate etiologic agents, a virus is most likely, given the seasonal variation, geographic clustering, and pattern of spread of the epidemics. Hantaviruses, enteroviruses, influenza, and others provide clinical comparisons, but a definitive match with known viruses has remained elusive.

Stretching our understanding of baroreflex control in humans: evidence of a positive feedback pulmonary baroreflex.

Stretching our understanding of baroreflex control in humans: evidence of a positive feedback pulmonary baroreflex.