Peripheral Sympathetic Denervation Research Articles

Hyperadrenergic Orthostatic Hypotension With Pure Peripheral Sympathetic Denervation Associated With Sjogren’s Syndrome

Hyperadrenergic orthostatic hypertension (hyper OH), defined as OH with elevated levels of upright plasma norepinephrine (NE), is assumed to be a clinical expression of peripheral sympathetic denervation (PSD). Primary Sjogren’s syndrome (pSS) is an autoimmune disease that not only affects the exocrine glands but also develops autonomic neuropathy with PSD. We present a hyper OH with PSD possibly associated with pSS and successfully treated with intravenous immunoglobulin (IVIg). The case was a 60-year-old man who developed recurrent syncope on rapid standing from a sitting position. Head-up tilt test and NE infusion test showed hyper OH with PSD. This case report raises the possible associations between hyper OH and autonomic neuropathy as pSS developed.

Sympathetic and sensory nerve fiber function in multiple system atrophy and idiopathic Parkinson\u2019s disease

ObjectiveTo explore small fiber somatosensory and sympathetic function in PD and MSA.MethodsWe recruited 20 PD patients (7 women, median age 65.5 years; IQR 54.75–70.0), 10 MSA patients (4 women; median age 68 years; IQR 66.25–74.0), and 10 healthy subjects (HC; 4 women, median age 68; IQR 59.0–71.0 years). Autonomic testing included forehead cooling, intradermal microdialysis of norepinephrine (NE; 10–5; 10–6; 10–7; and 10–8), and orthostatic hypotension (OH); somatosensory testing included quantitative sensory testing (QST) according to the protocol of the German Research Network on Neuropathic Pain (DFNS).ResultsOH occurred more frequently in PD (p = 0.018) and MSA (p = 0.002) compared to HC. Vasoconstriction responses were stronger in PD compared to MSA during forehead cooling (p = 0.044) and microdialysis of physiologically concentrated NE solutions (10–7; 10–8; p = 0.017). PD and MSA had impaired cold (PD: p < 0.01; MSA: p < 0.05) and warm detection thresholds (PD and MSA, both p < 0.05). The mechanical detection threshold was higher in PD (p < 0.01). Conversely, mechanical pain thresholds were decreased in PD and MSA (both p < 0.001), indicating mechanical hyperalgesia.ConclusionIn contrast to MSA, we found evidence of peripheral adrenoreceptor hypersensitivity in PD, probably caused by peripheral sympathetic denervation. Sensory testing revealed peripheral neuropathy and central pain sensitization in PD and MSA. Jointly, our data demonstrate autonomic and somatosensory dysfunction in PD and MSA.

Biofluid Markers for Prodromal Parkinson's Disease: Evidence From a Catecholaminergic Perspective.

Parkinson's disease (PD) is the most frequent of all Lewy body diseases, a family of progressive neurodegenerative disorders characterized by intra-neuronal cytoplasmic inclusions of α-synuclein. Its most defining features are bradykinesia, tremor, rigidity and postural instability. By the time PD manifests with motor signs, 70% of dopaminergic midbrain neurons are lost, and the disease is already in the middle or late stage. However, there are various non-motor symptoms occurring up to 20 years before the actual parkinsonism that are closely associated with profound deficiency of myocardial noradrenaline content and peripheral sympathetic denervation, as evidenced by neuroimaging experiments in recent years. Additionally, there is an inherent autotoxicity of catecholamines in the neuronal cells in which they are produced, forming toxic catecholaldehyde intermediates that make α-synuclein prone to aggregation, initiating a cascade of events that ultimately leads to neuronal death. The etiopathogenesis of PD and related synucleinopathies thus may well be a prototypical example of a catecholamine-regulated neurodegeneration, given that the synucleinopathy in PD spreads in synergy with central and peripheral catecholaminergic dysfunction from the earliest phases onward. That is why catecholamines and their metabolites, precursors, or derivatives in cerebrospinal fluid or plasma could be of particular interest as biomarkers for prodromal and de novo PD. Because there is great demand for such markers, this mini-review summarizes all catecholamine-related studies to date, in addition to providing profound neurochemical evidence on a systemic and cellular level to further emphasize this hypothesis and with emphasis on extracellular vesicles as a novel diagnostic and therapeutic incentive.

A Role for Hypocretin/Orexin in Metabolic and Sleep Abnormalities in a Mouse Model of Non-metastatic Breast Cancer

We investigated relationships among immune, metabolic, and sleep abnormalities in mice with non-metastatic mammary cancer. Tumor-bearing mice displayed interleukin-6 (IL-6)-mediated peripheral inflammation, coincident with altered hepatic glucose processing and sleep. Tumor-bearing mice were hyperphagic, had reduced serum leptin concentrations, and enhanced sensitivity to exogenous ghrelin. We tested whether these phenotypes were driven by inflammation using neutralizing monoclonal antibodies against IL-6; despite the reduction in IL-6 signaling, metabolic and sleep abnormalities persisted. We next investigated neural populations coupling metabolism and sleep, and observed altered activity within lateral-hypothalamic hypocretin/orexin (HO) neurons. We used a dual HO-receptor antagonist to test whether increased HO signaling was causing metabolic abnormalities. This approach rescued metabolic abnormalities and enhanced sleep quality in tumor-bearing mice. Peripheral sympathetic denervation prevented tumor-induced increases in serum glucose. Our results link metabolic and sleep abnormalities via the HO system, and provide evidence that central neuromodulators contribute to tumor-induced changes in metabolism.

Clinical characteristics of supine hypertension in de novo Parkinson disease.

Supine hypertension is frequently associated with autonomic failure. However, its clinical characteristics in patients with Parkinson disease (PD) remain unclear. The present study aimed to clarify the characteristics of supine hypertension in patients with de novo PD. The subjects were 72 patients with de novo PD. We studied blood pressure and plasma norepinephrine levels after the patients rested for 20 min in the supine position. Changes in blood pressure were also examined on head-up tilt-table testing. The disease duration was 1.7 ± 1.6 years (average ± SD). Thirty-three (45.8 %) patients had supine hypertension (defined as a blood pressure of ≥140/90 mmHg). Supine blood pressure positively correlated with the degree of orthostatic hypotension. Age and the proportion of patients with akinetic-rigid motor subtype or preexisting hypertension were higher among patients with supine hypertension than among those without supine hypertension. The Mini-Mental State Examination score was lower in patients with supine hypertension than in those without supine hypertension. Sex, disease duration, disease severity, and peripheral sympathetic nervous activity as evaluated by the cardiac uptake of (123)I-metaiodobenzylguanidine and the plasma norepinephrine level did not differ between patients with and those without supine hypertension. Older age, akinetic-rigid motor subtype, and preexisting hypertension are independent risk factors for supine hypertension. Supine hypertension alone may be associated with milder peripheral sympathetic nervous denervation than orthostatic hypotension alone. As for global cognitive decline, supine hypertension is a far riskier comorbidity of early-stage PD than is orthostatic hypotension.

Effect of Peripheral Artery Sympathetic Denervation on Muscle Microperfusion and Macroperfusion in an Animal Peripheral Artery Disease Model Using Contrast-Enhanced Ultrasound and Doppler Flow Measurement

PurposeTo determine the effects of catheter-based peripheral sympathetic denervation (CPSD) on peripheral artery sympathetic tone and peripheral microperfusion (PMP). Materials and MethodsThe effects of bilateral CPSD in common iliac arteries on PMP of the biceps femoris were determined in pigs using contrast-enhanced ultrasound, and mean transit time (mTT) and wash-in rate (WiR) were calculated during steady-state infusion of INN-sulfur-hexafluoride. Measurements were performed bilaterally at rest and during infusion of adenosine 70 μg/kg/min after unilateral moderate left external iliac artery stenosis. ResultsBefore CPSD, PMP decreased significantly (P < .05) under adenosine stress compared with resting conditions, with right mTT of 7.5 seconds ± 3.6 versus 16.9 seconds ± 11.9 and WiR of 63.1 arbitrary units (AU) ± 49.0 versus 25.0 AU ± 17.5 and left mTT of 29.2 seconds ± 18.0 versus 56.3 seconds ± 38.7 and WiR of 13.6 AU ± 8.4 versus 6.0 AU ± 4.1. After CPSD, PMP did not differ significantly (P > .05) between conditions of adenosine stress and rest, with right mTT of 19.9 seconds ± 24.7 versus 23.2 seconds ± 21.0 and WiR of 16.2 AU ± 25.0 versus 20.5 AU ± 19.7 and left mTT of 23.3 seconds ± 23.1 versus 25.8 seconds ± 21.7 and WiR of 12.5 AU ± 6.2 versus 20.0 AU ± 12.1. ConclusionsCPSD reduced peripheral artery sympathetic tone and may be an alternative to surgical or computed tomography–guided sympathectomy for the treatment of end-stage peripheral artery disease and Raynaud phenomenon.

Sympathetic pharmacological denervation in ageing rats: effects on ovulatory response and follicular population

The present study analyses the participation of ovarian innervation during reproductive senescence. We use the model of acute peripheral pharmacological sympathetic denervation with guanethidine in young (3 months old), middle-aged (12 months old) or old (18 months old) rats with spontaneous or induced ovulation. Ovarian levels of norepinephrine (NE) were measured by HPLC and the oestrous cycle, the number of ovulating animals and the percentage of atretic follicles were also assessed. Aged animals showed a progressive reduction in ovulatory capacity and an increase in ovarian NE content. Acute denervation increased the percentage of healthy follicles in 12- and 18-month-old rats compared with control adult animals. Combined treatment of denervation plus stimulation with gonadotrophins doubled the number of ova shed in young adult rats and restablished a partial ovulation in 12-month-old rats. The results suggest that ovarian noradrenergic innervation plays a modulator role in ovarian physiology during the ageing ovary process. The action of ovarian noradrenergic innervation seems to be associated with folliculogenesis and the ovarian response to gonadotrophins.

Autonomic Recovery from Peak Arm Exercise in Fit and Unfit Individuals with Paraplegia

Altered autonomic cardiovascular control in persons with paraplegia may reflect peripheral sympathetic denervation caused by the injury or deconditioning due to skeletal muscle paralysis. Parameters of autonomic cardiovascular control may be improved in fit persons with paraplegia similar to effects reported in the noninjured population. To determine differences in resting and recovery HR and cardiac autonomic control in fit and unfit individuals with paraplegia. Eighteen healthy males with paraplegia below T6 were studied; nine participated in aerobic exercise conditioning (fit: >or=30 min.d, >or=3 d.wk, >or=6 months), and nine were sedentary (unfit). Analysis of heart rate variability (HRV) was used to determine spectral power (ln transformed) in the high- (lnHF) and low-frequency (lnLF) bandwidths, and the LF/HF ratio was calculated. Data were collected at baseline (BL) and at 2, 10, 30, 60, and 90 min of recovery from peak arm cycle ergometry. The relative intensity achieved on the peak exercise test was comparable between the groups (i.e., 88% peak predicted HR). However, peak watts (P<0.001) and oxygen consumption (P<0.01) were higher in the fit compared with the unfit group (56 and 51%, respectively). Recovery lnHF was increased (P<0.05), and recovery lnLF (P<0.01) and LF/HF (P<0.05) were reduced in the fit compared with the unfit group. Mean recovery autonomic activity was not different from BL in the fit group. In the unfit group, mean recovery lnHF was reduced, and mean recovery lnLF and LF/HF remained elevated above BL. These data suggest that fit individuals with paraplegia have improved cardiac autonomic control during the postexercise recovery period compared with their unfit counterparts.

Intrathecal clonidine suppresses zymosan-induced peripheral leukocyte migration in a mouse air pouch model via activation of spinal muscarinic type 2 receptors and sympathoadrenal medullary activity

These studies were performed to examine the potential anti-inflammatory effect of intrathecal (IT) clonidine (an α 2-adrenoceptor agonist) on zymosan-induced leukocyte migration in a mouse air pouch model. IT clonidine dose-dependently suppressed zymosan-induced leukocyte migration and this effect was blocked by IT idazoxan (an α 2-adrenoceptor antagonist) pretreatment. Since a number of studies have previously shown that spinal α 2-adrenoceptors are functionally associated with spinal cholinergic activity, we next examined whether spinal acetylcholine (ACh) receptors were also involved in mediating this anti-inflammatory effect of IT clonidine. IT pretreatment with atropine (a muscarinic receptor antagonist), but not hexamethonium (a nicotinic receptor antagonist) completely blocked the anti-migratory effect of IT clonidine. Subsequent experiments showed that IT pretreatment with methoctramine (a muscarinic M 2 antagonist), but not pirenzepine (an M 1 antagonist) or 4-DAMP (an M 3 antagonist), suppressed clonidine's anti-inflammatory effect. Finally, we studied the potential roles of the sympathetic nervous system and the hypothalamo-pituitary–adrenal axis in clonidine's anti-inflammatory effect. Adrenalectomy or systemic injection of propranolol (a β-adrenoceptor antagonist) blocked clonidine's effect. However, pretreatment with RU486 (a corticosteroid antagonist) or peripheral sympathetic denervation using 6-hydroxydopamine had no effect. Furthermore, IT clonidine increased Fos expression in zymosan treated mice exclusively in T7–T11 sympathetic preganglionic neurons (which mainly project to the adrenal medulla), but not those of the T1–T6 or T12–L2 spinal segments. Moreover, IT methoctramine significantly reduced this increase in Fos expression. Collectively, these findings suggest that IT clonidine suppresses peripheral leukocyte migration via a sympathoadrenal medullary pathway, and that this suppressive effect is mediated by spinal M 2 receptors.

The anti-inflammatory effect of peripheral bee venom stimulation is mediated by central muscarinic type 2 receptors and activation of sympathetic preganglionic neurons

The anti-inflammatory effect (AI) induced by peripheral injection of diluted bee venom (dBV) involves activation of spinal cord circuits and is mediated by catecholamine release from adrenal medulla, but the precise neuronal mechanisms involved are not fully understood. In a recent study, we demonstrated that an increase in spinal acetylcholine is involved in mediating the anti-inflammatory effect of dBV and that this mediation also involves adrenomedullary activation. The present study utilized the mouse air pouch inflammation model to evaluate the involvement of spinal acetylcholine receptors and sympathetic preganglionic neurons (SPNs) in dBV's anti-inflammatory effect (dBVAI). Intrathecal (IT) pretreatment with atropine (muscarinic cholinergic antagonist) but not hexamethonium (nicotinic cholinergic antagonist) significantly suppressed dBVAI on zymosan-evoked leukocyte migration. Subsequent experiments showed that IT pretreatment with methoctramine (a muscarinic receptor type 2; M 2 antagonist), but not pirenzepine (an M 1 antagonist) or 4-DAMP (an M 3 antagonist), suppressed the dBVAI. In addition, dBV stimulation specifically increased Fos expression in SPNs of the T7–T11, but not the T1–T6 or T12–L2 spinal cord segments, in animals with zymosan-induced inflammation. Moreover, IT methoctramine pretreatment suppressed this dBV-induced Fos expression specifically in SPNs of T7–T11 level. Peripheral sympathetic denervation using 6-hydroxydopamine (6-OHDA) treatment (which spares sympathetic adrenal medullary innervation) did not alter dBVAI. Collectively these results indicate that dBV stimulation leads to spinal cord acetylcholine release that in turn acts on spinal M 2 receptors, which via a hypothesized disinhibition mechanism activates SPNs that project to the adrenal medulla. This activation ultimately leads to the release of adrenal catecholamines that contribute to dBVAI.

Effects of functional peripheral sympathetic denervation induced by guanethidine on follicular development and ovulation of the adult female guinea pig

The present study investigates the effects of functional sympathetic peripheral denervation induced by guanethidine sulphate (GTD) to adult female guinea pigs in the follicular (FPh) or luteal phases (LPh) on their oestrous cyclicity and ovulation. No differences were observed in oestrous cyclicity or the average number of corpora lutea present in the ovaries between the control and denervated animals. Guanethidine sulphate administration resulted in a significant decrease in ovarian norepinephrine content, higher for the left ovary than for the right one. Serum oestrogen and progesterone concentrations, the mean of follicles, and its diameter were different, depending on the oestral cycle in which the treatment was performed. These results suggest that in adult normal female guinea pigs, ovarian innervation participates in the regulation of follicular development in an inhibitory way.

Chemical sympathectomy alters cytotoxic T lymphocyte responses to herpes simplex virus infection.

Numerous studies have sought to delineate the impact of neuroendocrine function on overall immune responsiveness. Using various murine models, we and others have previously shown that both adrenal-dependent and adrenal-independent mechanisms regulate components of the primary and memory cellular immune responses to herpes simplex virus type 1 (HSV-1) infection. We have extended these studies by determining the impact of 6-hydroxydopamine (6-OHDA)-induced peripheral sympathetic denervation on these responses. C57BL/6 mice treated with 6-OHDA (200 mg/kg) were inhibited in their ability to generate primary, HSV-specific cytotoxic T lymphocytes (CTL) in response to HSV infection. Sympathectomy also suppressed the activation and function of HSV-specific memory CTL (CTLm). In addition, administration of 6-OHDA resulted in a transient but substantial increase in levels of circulating corticosterone and hypothalamic Fos expression. Together, these findings suggest that peripheral sympathetic denervation may modulate immune function via activation of the hypothalamic-pituitary-adrenal (HPA) axis.

Cardiac sympathetic denervation in Ross syndrome demonstrated by MIBG-SPECT

We investigated cardiac sympathetic innervation by metaiodobenzylguanidine (MIBG) imaging in a patient with tonic pupils, loss of tendon reflexes, and segmental anhidrosis (Ross syndrome). Despite normal cardiovascular reflex tests, we observed a reduced global myocardial MIBG uptake as well as a regional uptake defect over the posterolateral cardiac territory indicating left ventricular peripheral sympathetic denervation. MIBG imaging seems to be a useful noninvasive diagnostic method for detection of early—possibly subclinical—cardiac autonomic impairment in Ross syndrome and provides further evidence of injury to postganglionic autonomic neurons as the underlying pathological mechanism of the disease.

Effects of peripheral sympathetic denervation induced by guanethidine administration on the mechanisms regulating puberty in the female guinea pig.

The effects of peripheral sympathetic denervation induced by guanethidine administration to newborn and 10-day-old female guinea pigs on puberty, ovulation and the follicular population were analysed. Peripheral sympathetic denervation beginning at birth resulted in the loss of ovarian norepinephrine content (0.95. +/- 0.1 ng/mg wet tissue in untreated control animals vs non detectable in treated animals). Guanethidine administration to newborn or 10-day-old guinea pigs advanced puberty (age of vaginal opening: 27 +/- 1.2 days (newborn), 26 +/- 1.7 (10-day-old) vs 37 +/- 0.7 (control), P < 0.001) and ovulation. The number of corpora lutea in control and denervated animals was similar (3.5 +/- 0.2 vs 3.3 +/- 0.3). The relative weight (mg/100 g body weight) of the ovaries and adrenals in the denervated animals autopsied during the late follicular phase (24-48 h after vaginal opening) increased (ovaries: 27.8 +/- 1.3, 28.9 +/- 3.0 vs 20.9 +/- 0.8, P < 0.05; adrenals 36.4 +/- 1.4, 37.0 +/- 0.8 vs 31.6 +/- 1.5, P < 0.05), while the uterine weight diminished (179 +/- 13, 149 +/- 28 vs 292 +/- 20). When the animals were killed during the late luteal phase (9-11 days after vaginal closure), the relative weight of the ovaries of newborn guanethidine-treated animals was higher than that of the control animals (21.4 +/- 1.7 vs 16.8 +/- 1.4, P < 0.05). The mean number of follicles counted in the ovaries of denervated animals was significantly higher than in control animals (1736 +/- 230 vs 969 +/- 147, P < 0.05). The mean diameter of the follicles in the untouched control ovary in animals killed in the late follicular phase was significantly larger than from animals killed in the late luteal phase (263 +/- 3.9 microns vs 248 +/- 3.0 microns, P < 0.01). The mean diameter of the follicles measured in the ovaries of denervated animals was significantly higher than in controls (animals treated from birth 274 +/- 2.0 microns vs 255 +/- 2.4, P < 0.05; animals treated from day 10, 286 +/- 2.3 microns vs 257 +/- 2.3, P < 0.05). When the mean diameter of the follicles in the left and right ovary of the untouched control was analysed, the follicular diameter in the left ovary was significantly larger than in the right ovary (309 +/- 6.0 microns vs 214 +/- 3.9, P < 0.01); the response of the left and right ovaries to sympathetic denervation was the opposite. The results obtained in the present study suggest that ovarian innervation plays a role in the regulation of follicular growth, maturation and atresia which is not related to changes in steroid secretion by the ovary, but to other regulatory mechanisms.

Reflex sympathetic dystrophy in a patient with peripheral sympathetic denervation

Reflex sympathetic dystrophy (RSD) includes persistent pain in an extremity, associated with features of vasomotor dysfunction and, later, dystrophic changes. Many theories have been proposed to explain these clinical features and include sympathetic dysfunction. We report a unique case of RSD following an upper limb fracture in a patient with established severe peripheral sympathetic denervation as part of idiopathic chronic autonomic failure. This case provides evidence that the clinical features of RSD were not mediated via increased sympathetic nerve activity in the affected limb. Locally released neuropeptides or autocoids therefore may be involved in the pathogenesis of RSD. The term sympathetic in RSD may be inappropriate and require revision.

An animal model of the relationship between systemic hypertension and repetitive episodic hypoxia as seen in sleep apnoea.

Multiple factors may be responsible for acute and chronic blood pressure changes during obstructive sleep apnoea. A popular hypothesis is that recurrent episodic hypoxia stimulates chemoreceptors which, in turn, cause sympathetically mediated vasoconstriction and perhaps long-term vascular remodelling. Disruption of sleep architecture secondary to frequent arousals may also cause chronic stress which may contribute to diurnal hypertension. A less likely factor elevating blood pressure is the effect of abrupt intra-thoracic pressure changes on venous return and cardiac output. The rat responds to chronic, recurrent episodic hypocapnic hypoxia (12-s bursts of nitrogen followed by air into Plexiglas chambers, every 30 s, 7 h d-1, 2-4% nadir ambient oxygen) with sustained increase in diurnal blood pressure 11-14 mmHg). Subsequent studies reveal that carotid sinus nerve section (chemodenervation) and chemically induced peripheral sympathetic denervation with the neurotoxin 6-OH dopamine both eliminate this blood pressure-elevating effect of chronic episodic hypoxaemia. Using this model, Sprague-Dawley rats have been challenged with both eucapnic hypoxia and asphyxia and failed to show an additional blood pressure elevation above that caused by hypoxia (hypocapnic) alone. It appears that hypocapnic hypoxia creates a maximal stimulus to the sympathetic nervous system to which the addition of hypercarbia does not increase the blood pressure response. An alternative explanation is that the rat has protective mechanisms that limit the diurnal blood pressure response from further increase.

Responses of plasma catecholamines to tilt in patients with diabetes mellitus.

The immediate heart rate acceleration, blood pressure reaction, plasma adrenaline (PA), and plasma noradrenaline (PNA) responses to a 90 degrees and 2 sec tilt were evaluated in 13 male patients with type I diabetes. A disturbed immediate acceleration, as measured by a previously described acceleration index (AI), was found in 5 patients. All patients with normal AI but only one of those with abnormal AI showed an increase in PA during the first minute after tilt (p less than 0.02). A late diastolic blood pressure fall occurred in 6 patients and the fall was minor (5 mmHg) in 5 of these. Patients with a late diastolic blood pressure fall showed a significantly lower increase in PNA 1-8 min after tilt than those without (55 +/- 13% versus 163 +/- 24% (mean +/- SE), p less than 0.005). An abnormal immediate acceleration to tilt is associated with an impaired sympatho-adrenal reaction, and even a minor diastolic blood pressure fall indicates peripheral sympathetic denervation.