Postganglionic Sudomotor Dysfunction and Brain Glucose Hypometabolism in Patients with Multiple System Atrophy.

BACKGROUND: Sudomotor dysfunction is common in patients with multiple system atrophy (MSA). Postganglionic sudomotor dysfunction in MSA, which can be assessed using quantitative sudomotor axon reflex testing (QSART), results from the degeneration of preganglionic sympathetic neurons and direct loss of postganglionic fibers. OBJECTIVE: We investigate whether abnormal QSART responses in patients with MSA are associated with disease severity. METHODS: In this retrospective study, patients with probable MSA who underwent both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and autonomic function tests were included. Autonomic function test results were integrated divided into three sub-scores, including sudomotor, cardiovagal, and adrenergic sub-scores. The sudomotor sub-score represented postganglionic sudomotor function. Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, Part II, and sum of Part I and II scores (Part I + II) to reflect disease severity and 18F-FDG-PET/CT results were collected. RESULTS: Of 74 patients with MSA, 62.2%demonstrated abnormal QSART results. The UMSARS Part I + II score was significantly higher in the abnormal QSART group than in the normal QSART group (p = 0.037). In the regression analysis, both UMSARS Part I (ß= 1.185, p = 0.013) and Part II (ß= 1.266, p = 0.021) scores were significantly associated with the sudomotor sub-score. On 18F-FDG-PET/CT, the abnormal QSART group exhibited more severely decreased metabolic activity in the cerebellum and basal ganglia in patients with MSA-P and MSA-C, respectively. The sudomotor sub-score was significantly associated with regional metabolism in these areas. CONCLUSION: Patients with MSA and postganglionic sudomotor dysfunction may have worse disease severity and greater neuropathological burden than those without.

Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure.

AIMS: Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. METHODS AND RESULTS: Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. CONCLUSIONS: Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation.

Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM (db/db). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice, and the kinetics of pacing-induced Ca2+ transients (recorded from isolated cardiomyocytes) were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control.NEW & NOTEWORTHY Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in db/db mice after ß-sympathetic blockade.

Pre- and postganglionic vasomotor dysfunction causes distal limb coldness in multiple system atrophy.

BACKGROUND: The detailed pathophysiology of limb coldness in multiple system atrophy (MSA) is unknown. METHODS: We evaluated cutaneous vasomotor neural function in 18 MSA patients with or without limb coldness, and in 20 healthy volunteers as controls. We measured resting skin sympathetic nerve activity (SSNA) and spontaneous changes of the sympathetic skin response (SSR) and skin blood flow (skin vasomotor reflex: SVR), as well as SVR and reflex changes of SSNA after electrical stimulation. The parameters investigated were the SSNA frequency at rest, amplitude of SSNA reflex bursts, absolute decrease and percent reduction of SVR, recovery time, and skin blood flow velocity. RESULTS: Both the resting frequency of SSNA and the amplitude of SSNA reflex bursts were significantly lower in the MSA group than the control group (p<0.001 and p<0.05, respectively). There were no significant differences between the two groups with regard to the absolute decrease or percent reduction of SVR volume. The recovery time showed no significant difference between all MSA patients and control groups, but it was significantly prolonged in six MSA patients with limb coldness compared with that in the control group and that in MSA patients without limb coldness (p<0.01). The skin blood flow velocity was significantly slower in the MSA group than in the control group (p<0.001). CONCLUSION: In MSA patients, limb coldness might occur due to impairments of the peripheral circulation based on prolongation of vasoconstriction and a decrease of skin blood flow velocity secondary to combined pre- and postganglionic skin vasomotor dysfunction.

A role for interleukin 17A in IBD-related neuroplasticity.

BACKGROUND: Changes to the structure and function of the innervation of the gut contribute to symptom generation in inflammatory bowel diseases (IBD). However, delineation of the mechanisms of these effects has proven difficult. Previous work on sympathetic neurons identified interleukin (IL)-17A as a novel neurotrophic cytokine. Since IL-17A is involved in IBD pathogenesis, we tested the hypothesis that IL-17A contributes to neuroanatomical remodeling during IBD. METHODS: Immunohistochemistry for tyrosine hydroxylase was used to identify sympathetic axons in mice with dextran sulphate sodium (DSS)-induced colitis and controls. Axon outgrowth from sympathetic neurons in response to incubation in cytokines or endoscopic patient biopsy supernatants was quantified. KEY RESULTS: DSS-induced colitis led to an increase in tyrosine hydroxylase immunoreactivity in the inflamed colon but not the spleen. Colonic supernatants from mice with colitis and biopsy supernatants from Crohn's disease patients increased axon outgrowth from mouse sympathetic neurons compared to supernatants from uninflamed controls. An antibody that neutralized IL-17A blocked the ability of DSS-induced colitis and Crohn's disease supernatants to induce axon extension. CONCLUSIONS AND INFERENCES: These findings identify IL-17A as a potential mediator of neuroanatomical remodeling of the gut innervation during IBD.

Effect of Doxazosin on Autonomic Nervous Control and Urodynamics of Rat Urinary Bladder during Modeled Infravesical Obstruction.

The therapeutic effect of doxazosin (40 µg/kg/day over one month) on urinary bladder was examined in female rats with modeled chronic infravesical obstruction (IVO) produced by graduated mechanical constriction of the proximal urethral segment. In one month, IVO induced a pronounced vesical hypertrophy both in treated and untreated rats that manifested in increased bladder weight and capacity, the latter increment being pronouncedly greater in treated rats. In untreated IVO rats, infusion cystometry revealed elevated basal intravesical pressure of void bladder P0, markedly increased maximal (premicturitional) pressure Pmax, and increased amplitude of spontaneous oscillations of intravesical pressure ΔPdet in filled bladder. Doxazosin produced no significant effect on Pmax rise during IVO, but prevented elevation of P0 and increment of ΔPdet in filled bladder. During gradual filling of urinary bladder in control (intact) rats, the parasympathetic vesical influences increased progressively, while in untreated IVO rats, the adrenergic influences prevailed even at maximal filling of the bladder. In IVO rats, doxazosin prevented the bias of the sympathetic-parasympathetic balance in the filled bladder in favor of sympathetic influences, but did not prevent this bias in a void bladder. It is hypothesized that α-adrenoblockers improve micturition during IVO caused by benign prostatic hyperplasia not only by decreasing the urethral resistance to urine flow due to down-regulation of prostate smooth muscle tone, but also by a direct action of these blockers on detrusor adrenergic receptors and central structures involved in urinary bladder control.

Sympathoexcitation in ANG II-salt hypertension involves reduced SK channel function in the hypothalamic paraventricular nucleus.

Hypertension (HTN) resulting from subcutaneous infusion of ANG II and dietary high salt (HS) intake involves sympathoexcitation. Recently, we reported reduced small-conductance Ca(2+)-activated K(+) (SK) current and increased excitability of presympathetic neurons in the paraventricular nucleus (PVN) in ANG II-salt HTN. Here, we hypothesized that ANG II-salt HTN would be accompanied by altered PVN SK channel activity, which may contribute to sympathoexcitation in vivo. In anesthetized rats with normal salt (NS) intake, bilateral PVN microinjection of apamin (12.5 pmol/50 nl each), the SK channel blocker, remarkably elevated splanchnic sympathetic nerve activity (SSNA), renal sympathetic nerve activity (RSNA), and mean arterial pressure (MAP). In contrast, rats with ANG II-salt HTN demonstrated significantly attenuated SSNA, RSNA, and MAP (P < 0.05) responses to PVN-injected apamin compared with NS control rats. Next, we sought to examine the individual contributions of HS and subcutaneous infusion of ANG II on PVN SK channel function. SSNA, RSNA, and MAP responses to PVN-injected apamin in rats with HS alone were significantly attenuated compared with NS-fed rats. In contrast, sympathetic nerve activity responses to PVN-injected apamin in ANG II-treated rats were slightly attenuated with SSNA, demonstrating no statistical difference compared with NS-fed rats, whereas MAP responses to PVN-injected apamin were similar to NS-fed rats. Finally, Western blot analysis showed no statistical difference in SK1-SK3 expression in the PVN between NS and ANG II-salt HTN. We conclude that reduced SK channel function in the PVN is involved in the sympathoexcitation associated with ANG II-salt HTN. Dietary HS may play a dominant role in reducing SK channel function, thus contributing to sympathoexcitation in ANG II-salt HTN.

Relationship between sympathetic activity and pain intensity in fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a syndrome characterised by chronic musculoskeletal pain, hyperalgesia on specific areas of tenderness (tender points) and by an autonomic nervous system dysfunction consistent with sympathetic overactivity. It is not known whether there is any relationship between the amount of cardiovascular sympathetic activity and the magnitude of pain. Our objective was to assess this potential relationship in patients with FM. METHODS: Electrocardiogram, finger blood pressure, respiration and post-ganglionic sympathetic discharge activity (muscle sympathetic nerve activity, MSNA) were continuously recorded at rest in 25 patients with primary FMS. The autonomic profile was assessed by MSNA and spectral indices of cardiac sympathetic (LFRR) and vagal (HFRR) modulation and of sympathetic vasomotor control (LF-SAP) computed by spectrum analysis of RR and systolic arterial pressure (SAP) variability. Cardiac baroreflex function was evaluated by the index α (αLF). Baroreceptor modulation of the sympathetic vasomotor control (sBRS) was assessed by the MSNA/diastolic pressure relationship. RESULTS: Pain intensity was linearly correlated with LFRR/HFRR (r² = 0.21; p=0.03), LFSAP (r² = 0.26; p=0.02) and MSNA (burst rate) (r² = 0.45; p=0.003). Pain intensity was inversely correlated with the αLF index (r² = 0.24; p=0.02) and the sBRS (r² = 0.28; p=0.03). Thus, the higher the sympathetic drive to the heart and vessels, the higher the magnitude of chronic pain. Also, the gains of both the cardiac and MSNA baroreceptor control were inversely related to the pain intensity. CONCLUSIONS: These findings raise the theoretical possibility that in FM patients the use of anti-adrenergic agents might lessen chronic pain intensity by reducing the underlying excessive sympathetic activity.

Mouse models of sepsis elicit spontaneous action potential discharge and enhance intracellular Ca2+ signaling in postganglionic sympathetic neurons.

Sepsis is a severe systemic inflammatory disorder that rapidly activates the sympathetic nervous system to enhance catecholamine secretion from postganglionic sympathetic neurons and adrenal chromaffin cells. Although an increase in preganglionic drive to postganglionic sympathetic tissues has been known to contribute to this response for quite some time, only recently was it determined that sepsis also has direct effects on adrenal chromaffin cell Ca2+ signaling and epinephrine release. In the present study, we characterized the direct effects of sepsis on postganglionic sympathetic neuron function. Using the endotoxemia model of sepsis in mice, we found that almost a quarter of postganglionic neurons acquired the ability to fire spontaneous action potentials, which was absent in cells from control mice. Spontaneously firing neurons possessed significantly lower rheobases and fired a greater number of action potentials at twice the rheobase compared to neurons from control mice. Sepsis did not significantly affect voltage-gated Ca2+ currents. However, global Ca2+ signaling was enhanced in postganglionic neurons isolated from 1 to 24 h endotoxemic mice. A similar increase in the amplitude of high-K+-stimulated Ca2+ transients was observed during the cecal ligation and puncture model of sepsis. The enhanced excitability and Ca2+ signaling produced during sepsis likely amplify the effect of increased preganglionic drive on norepinephrine release from postganglionic neurons. This is important, as sympathetic neurons are integral to the anti-inflammatory autonomic reflex that is activated during sepsis.

Sympathetic activity and markers of cardiovascular risk in nondiabetic severely obese patients: the effect of the initial 10% weight loss.

BACKGROUND: Obesity is associated with elevated cardiovascular mortality, which may be attributed, in part, to sympathetic nervous system (SNS) activation and an associated poor metabolic profile. We examined the effects of laparoscopic adjustable gastric band (LAGB) on SNS activity and cardiovascular profile when the initial weight loss of 10%, corresponding to the recommendation of clinical guidelines, was reached. METHODS: Direct muscle sympathetic nerve activity (MSNA, microneurography), baroreflex function, and cardiovascular profile were examined before and after a predetermined weight loss of 10% in 23 severely obese nondiabetic individuals. RESULTS: The 10% weight loss was achieved at an average of 7.3 ± 1.4 months (range = 1.3-23.3 months). This was associated with significant improvement in office systolic and diastolic blood pressure (BP) (-12 mm Hg and -5 mm Hg, respectively), a decrease in MSNA (33 ± 3 to 22 ± 3 bursts per minute), improvement in cardiac (16 ± 3 to 31 ± 4 ms/mm Hg) and sympathetic (-2.23 ± 0.39 to -4.30 ± 0.96 bursts/100 heartbeats/mm Hg) baroreflex function, total cholesterol (5.33 ± 0.13 to 4.97 ± 0.16 mmol/L), fasting insulin (29.3 ± 2.4 to 19.6 ± 1.1 mmol/L), and creatinine clearance (172 ± 11 to 142 ± 8 ml/min). None of the cardiovascular risk improvement related to the rate of weight loss. The change in systolic and diastolic BP correlated with change in waist circumference (r = 0.46, P = 0.04; r = 0.50, P = 0.02, respectively). CONCLUSIONS: The initial 10% weight loss induced by LAGB was associated with substantial hemodynamic, metabolic, SNS, and renal function improvements. Changes in waist circumference appear to be an important factor contributing to BP adaptation after LAGB surgery.

Association between left ventricular regional sympathetic denervation and mechanical dyssynchrony in phase analysis: a cardiac CZT study.

PURPOSE: To evaluate the relationships among myocardial sympathetic innervation, perfusion and mechanical synchronicity assessed with cardiac cadmium-zinc-telluride (CZT) scintigraphy. METHODS: A group of 29 patients underwent an evaluation of myocardial perfusion with (99m)Tc-tetrofosmin CZT scintigraphy and adrenergic innervation with (123)I-metaiodobenzylguanidine (MIBG) CZT scintigraphy. The summed rest score (SRS), motion score (SMS) and thickening score (STS), as well as the summed (123)I-MIBG defect score (SS-MIBG), were determined. Regional tracer uptake for both (99m)Tc-tetrofosmin and (123)I-MIBG was also calculated. Finally, the presence of significant myocardial mechanical dyssynchrony was evaluated in phase analysis on gated CZT images and the region of latest mechanical activation identified. RESULTS: Significant mechanical dyssynchrony was present in 17 patients (59 %) and associated with higher SRS (P = 0.030), SMS (P < 0.001), STS (P = 0.003) and early SS-MIBG (P = 0.037) as well as greater impairments in left ventricular ejection fraction (P < 0.001) and end-diastolic volume (P < 0.001). In multivariate analysis a higher end-diastolic volume remained the only predictor of mechanical dyssynchrony (P = 0.047). Interestingly, while in the whole population regional myocardial perfusion and adrenergic activity were strongly correlated (R = 0.68), in patients with mechanical dyssynchrony the region of latest mechanical activation was predicted only by greater impairment in regional (123)I-MIBG uptake (P = 0.012) that overwhelmed the effect of depressed regional perfusion. CONCLUSION: Left ventricular mechanical dyssynchrony is associated with greater depression in contractile function and greater impairments in regional myocardial perfusion and sympathetic activity. In patients with dyssynchrony, the region of latest mechanical activation is characterized by a significantly altered adrenergic tone.

[Treatment of a patient with refractory cardiac arrhythmias using stellate ganglion block. Access by the classical and ultrasound-guided approach]. / Tratamiento de las arritmias cardíacas refractarias mediante bloqueo del ganglio estrellado en un paciente. Acceso por técnica clásica y ecodirigida.

Stellate ganglion block is a technique that is often used by anesthesiologists for the treatment of complex regional pain syndromes of the upper extremity. This technique interrupts cardiac sympathetic innervation and has been proposed as treatment for refractory arrhythmias. We present the case of a patient with arrhythmias that were refractory to pharmacological treatment, and were finally treated by continuous stellate ganglion block. Left stellate ganglion is a lynchpin of cardiac arrhythmias due to being a structure where the majority of postganglion sympathetic fibers responsible for preferentially innervating the atriventricular node, bundle of His and ventricular mass are originated, fundamentals in the origin and maintenance of ventricular arrhythmias.

Infarct-derived chondroitin sulfate proteoglycans prevent sympathetic reinnervation after cardiac ischemia-reperfusion injury.

Sympathetic nerves can regenerate after injury to reinnervate target tissues. Sympathetic regeneration is well documented after chronic cardiac ischemia, so we were surprised that the cardiac infarct remained denervated following ischemia-reperfusion (I-R). We used mice to ask if the lack of sympathetic regeneration into the scar was due to blockade by inhibitory extracellular matrix within the infarct. We found that chondroitin sulfate proteoglycans (CSPGs) were present in the infarct after I-R, but not after chronic ischemia, and that CSPGs caused inhibition of sympathetic axon outgrowth in vitro. Ventricle explants after I-R and chronic ischemia stimulated sympathetic axon outgrowth that was blocked by nerve growth factor antibodies. However, growth in I-R cocultures was asymmetrical, with axons growing toward the heart tissue consistently shorter than axons growing in other directions. Growth toward I-R explants was rescued by adding chondroitinase ABC to the cocultures, suggesting that I-R infarct-derived CSPGs prevented axon extension. Sympathetic ganglia lacking protein tyrosine phosphatase sigma (PTPRS) were not inhibited by CSPGs or I-R explants in vitro, suggesting PTPRS is the major CSPG receptor in sympathetic neurons. To test directly if infarct-derived CSPGs prevented cardiac reinnervation, we performed I-R in ptprs-/- and ptprs+/- mice. Cardiac infarcts in ptprs-/- mice were hyperinnervated, while infarcts in ptprs+/- littermates were denervated, confirming that CSPGs prevent sympathetic reinnervation of the cardiac scar after I-R. This is the first example of CSPGs preventing sympathetic reinnervation of an autonomic target following injury, and may have important consequences for cardiac function and arrhythmia susceptibility after myocardial infarction.

Sympathetic nerve activity in stress-induced cardiomyopathy.

PURPOSE: To evaluate directly recorded efferent sympathetic nerve traffic in patients with stress-induced cardiomyopathy (SIC). BACKGROUND: SIC is a syndrome affecting mostly postmenopausal women following severe emotional stress. Though the precise pathophysiology is not well understood, a catecholamine overstimulation of the myocardium is thought to underlie the pathogenesis. METHODS: Direct recordings of multiunit efferent postganglionic muscle sympathetic nerve activity (MSNA) were obtained from 12 female patients, 5 in the acute (24-48 h) and 7 in the recovery phase (1-6 months), with apical ballooning pattern and 12 healthy matched controls. MSNA was expressed as burst frequency (BF), burst incidence (BI) and relative median burst amplitude (RMBA %). One of the twelve patients in this study was on beta blockade treatment due to a different illness, at time of onset of SIC. All patients were investigated with ongoing medication. RESULTS: MSNA was lower in patients with SIC as compared to matched controls, but did not differ between the acute and recovery phase of SIC. RMBA %, blood pressure and heart rate did not differ between the groups. CONCLUSION: MSNA is shown to be lower in patients with SIC compared to healthy controls, suggesting that sympathetic neuronal outflow is rapidly reduced following the initial phase of SIC. A distension of the ventricular myocardium, due to excessive catecholamine release over the heart in the acute phase, may increase the firing rate of unmyelinated cardiac c-fibre afferents resulting in widespread sympathetic inhibition. Such a mechanism may underlie the lower MSNA reported in our patients.

Disorders of blood pressure regulation-role of catecholamine biosynthesis, release, and metabolism.

Catecholamines (epinephrine and norepinephrine) are synthesised and produced by the adrenal medulla and postganglionic nerve fibres of the sympathetic nervous system. It is known that essential hypertension has a significant neurogenic component, with the rise in blood pressure mediated at least in part by overactivity of the sympathetic nervous system. Moreover, novel therapeutic strategies aimed at reducing sympathetic activity show promise in the treatment of hypertension. This article reviews recent advances within this rapidly changing field, particularly focusing on the role of genetic polymorphisms within key catecholamine biosynthetic enzymes, cofactors, and storage molecules. In addition, mechanisms linking the sympathetic nervous system and other adverse cardiovascular states (obesity, insulin resistance, dyslipidaemia) are discussed, along with speculation as to how recent scientific advances may lead to the emergence of novel antihypertensive treatments.

Sympathetic nerve traffic and asymmetric dimethylarginine in chronic kidney disease.

BACKGROUND AND OBJECTIVES: Sympathetic overactivity and high levels of the endogenous inhibitor of NO synthase asymmetric dimethylarginine (ADMA) are prevalent risk factors in chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In 48 stage 2 to 4 CKD patients, we investigated the relationship between efferent postganglionic muscle sympathetic nerve traffic (microneurography) and circulating ADMA and analyzed the links between these risk factors and estimated GFR (eGFR), proteinuria, and different parameters of left ventricular (LV) geometry. RESULTS: CKD patients characterized by sympathetic nerve traffic values in the third tertile showed the highest ADMA levels, and this association was paralleled by a continuous, positive relationship between these two risk factors (r = 0.32, P = 0.03) independent of other confounders. Both sympathetic nerve traffic and ADMA were inversely related to eGFR and directly to proteinuria and LV geometry. Remarkably, the variance of eGFR, proteinuria, and LV geometry explained by sympathetic nerve traffic and ADMA largely overlapped because sympathetic nerve traffic but not ADMA was retained as a significant correlate of the eGFR (P < 0.001) and of the relative wall thickness or the left ventricular mass index/LV volume ratio (P = 0.05) in models including both risk factors. ADMA, but not sympathetic nerve traffic, emerged as an independent correlate of proteinuria (P = 0.003) in a model including the same covariates. CONCLUSIONS: Sympathetic activity and ADMA may share a pathway leading to renal disease progression, proteinuria, and LV concentric remodeling in CKD patients.

Altered norepinephrine content and ventricular function in p75NTR-/- mice after myocardial infarction.

Cardiac sympathetic neurons stimulate heart rate and the force of contraction through release of norepinephrine. Nerve growth factor modulates sympathetic transmission through activation of TrkA and p75NTR. Nerve growth factor plays an important role in post-infarct sympathetic remodeling. We used mice lacking p75NTR to examine the effect of altered nerve growth factor signaling on sympathetic neuropeptide expression, cardiac norepinephrine, and ventricular function after myocardial infarction. Infarct size was similar in wildtype and p75NTR-/- mice after ischemia-reperfusion surgery. Likewise, mRNAs encoding vasoactive intestinal peptide, galanin, and pituitary adenylate cyclase activating peptides were identical in wildtype and p75NTR-/- cardiac sympathetic neurons, as was expression of the TrkA neurotrophin receptor. Norepinephrine content was elevated in the base of the p75NTR-/- ventricle compared to wildtype, but levels were identical below the site of occlusion. Left ventricular pressure, dP/dt(MAX), and dP/dt(MIN) were measured under isoflurane anesthesia 3 and 7 days after surgery. Ventricular pressure decreased significantly 3 days after infarction, and deficits in dP/dt(MAX) were revealed by stimulating beta receptors with dobutamine and release of endogenous norepinephrine with tyramine. dP/dt(MIN) was not altered by genotype or surgical group. Few differences were observed between genotypes 3 days after surgery, in contrast to low pressure and dP/dt(MAX) previously reported in control p75NTR-/- animals. Seven days after surgery ventricular pressure and dP/dt(MAX) were significantly lower in p75NTR-/- hearts compared to WT hearts. Thus, the lack of p75NTR did not enhance cardiac function after myocardial infarction.

Vascular-dependent effects of elevated glucose on postganglionic sympathetic neurons.

Perivascular sympathetic nerves are important determinants of vascular function that are likely to contribute to vascular complications associated with hyperglycemia and diabetes. The present study tested the hypothesis that glucose modulates perivascular sympathetic nerves by studying the effects of 7 days of hyperglycemia on norepinephrine (NE) synthesis [tyrosine hydroxylase (TH)], release, and uptake. Direct and vascular-dependent effects were studied in vitro in neuronal and neurovascular cultures. Effects were also studied in vivo in rats made hyperglycemic (blood glucose >296 mg/dl) with streptozotocin (50 mg/kg). In neuronal cultures, TH and NE uptake measured in neurons grown in high glucose (HG; 25 mM) were less than that in neurons grown in low glucose (LG; 5 mM) (P < 0.05; n = 4 and 6, respectively). In neurovascular cultures, elevated glucose did not affect TH or NE uptake, but it increased NE release. Release from neurovascular cultures grown in HG (1.8 ± 0.2%; n = 5) was greater than that from cultures grown in LG (0.37 ± 0.28%; n = 5; P < 0.05; unpaired t-test). In vivo, elevated glucose did not affect TH or NE uptake, but it increased NE release. Release in hyperglycemic animals (9.4 + 1.1%; n = 6) was greater than that in control animals (5.39 + 1.1%; n = 6; P < 0.05; unpaired t-test). These data identify a novel vascular-dependent effect of elevated glucose on postganglionic sympathetic neurons that is likely to affect the function of perivascular sympathetic nerves and thereby affect vascular function.