Does sympathetic dysfunction occur before denervation in pure autonomic failure?

2018 ◽  
Vol 132 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Ling Guo ◽  
Murray D. Esler ◽  
Carolina Sari ◽  
Sarah Phillips ◽  
Elisabeth A. Lambert ◽  
...  

Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels—suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation.

Author(s):  
Sergio Perna ◽  
Rocco Leone ◽  
Maria Jussie Farace ◽  
Vincenzo Brescia-Morra ◽  
Giuseppe Campanella ◽  
...  

ABSTRACT:In a patient with pure autonomic failure, exercise did not modify beta-adrenoceptor density, probably due to an insufficient increase in plasma catecholamines. Isoproterenol infusion increased the number of beta-adrenoceptor by only 17%. Since in control subjects an increased beta-adrenoceptor level was found, following both physical stress and isoproterenol infusion, we suggest that the lack of increased beta-adrenoceptor levels may contribute to the poor circulatory adjustments observed in autonomic dysfunction during activities involving the sympathetic nervous system.


1999 ◽  
Vol 277 (6) ◽  
pp. R1780-R1785 ◽  
Author(s):  
Tetsuro Shirasaka ◽  
Masamitsu Nakazato ◽  
Shigeru Matsukura ◽  
Mayumi Takasaki ◽  
Hiroshi Kannan

The novel hypothalamic peptides orexin-A and orexin-B are known to induce feeding behavior when administered intracerebroventricularly, but little is known about other physiological functions. The renal sympathetic nerves play important roles in the homeostasis of body fluids and the circulatory system. We examined the effects of intracerebroventricularly administered orexins on mean arterial pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and plasma catecholamine in conscious rats. Orexin-A (0.3, 3.0 nmol) provoked an increase in MAP (94.3 ± 0.7 to 101.9 ± 0.7 mmHg and 93.1 ± 1.1 to 108.3 ± 0.8 mmHg, respectively) and RSNA (28.0 ± 7.0 and 57.9 ± 12.3%, respectively). Similarly, orexin-B (0.3, 3.0 nmol) increased MAP (93.9 ± 0.9 to 97.9 ± 0.9 mmHg and 94.5 ± 1.1 to 105.3 ± 1.7 mmHg, respectively). Orexin-A and -B at 3.0 nmol also increased HR. In other conscious rats, a high dose of orexin-A and -B increased plasma norepinephrine. Plasma epinephrine only increased with a high dose of orexin-A. These results indicate that central orexins regulate sympathetic nerve activity and affect cardiovascular functions.


2008 ◽  
Vol 54 (11) ◽  
pp. 1864-1871 ◽  
Author(s):  
David S Goldstein ◽  
Courtney Holmes

Abstract Background: Determinants of plasma norepinephrine (NE) and epinephrine concentrations are well known; those of the third endogenous catecholamine, dopamine (DA), remain poorly understood. We tested in humans whether DA enters the plasma after corelease with NE during exocytosis from sympathetic noradrenergic nerves. Methods: We reviewed plasma catecholamine data from patients referred for autonomic testing and control subjects under the following experimental conditions: during supine rest and in response to orthostasis; intravenous yohimbine (YOH), isoproterenol (ISO), or glucagon (GLU), which augment exocytotic release of NE from sympathetic nerves; intravenous trimethaphan (TRI) or pentolinium (PEN), which decrease exocytotic NE release; or intravenous tyramine (TYR), which releases NE by nonexocytotic means. We included groups of patients with pure autonomic failure (PAF), bilateral thoracic sympathectomies (SNS-x), or multiple system atrophy (MSA), since PAF and SNS-x are associated with noradrenergic denervation and MSA is not. Results: Orthostasis, YOH, ISO, and TYR increased and TRI/PEN decreased plasma DA concentrations. Individual values for changes in plasma DA concentrations correlated positively with changes in NE in response to orthostasis (r = 0.72, P &lt; 0.0001), YOH (r = 0.75, P &lt; 0.0001), ISO (r = 0.71, P &lt; 0.0001), GLU (r = 0.47, P = 0.01), and TYR (r = 0.67, P &lt; 0.0001). PAF and SNS-x patients had low plasma DA concentrations. We estimated that DA constitutes 2%–4% of the catecholamine released by exocytosis from sympathetic nerves and that 50%–90% of plasma DA has a sympathoneural source. Conclusions: Plasma DA is derived substantially from sympathetic noradrenergic nerves.


Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Marcel Ruzicka ◽  
Swapnil Hiremath ◽  
Frans H Leenens ◽  
Judith Leech ◽  
Shawn Aaron

Introduction: Central sympathetic hyperactivity as assessed by muscle sympathetic nerve activity recordings is thought to play a crucial role in the development and maintenance of hypertension (HTN) in patients with obstructive sleep apnea (OSA). Decreases in daytime and nocturnal blood pressure (BP) in response to treatment with continuous positive airway pressure (CPAP) are paralleled by decreases in muscle sympathetic nerve activity (MSNA). Patients with chronic kidney disease (CKD) have high MSNA. Bilateral nephrectomy, but not renal transplantation normalizes MSNA indicating central sympathoexcitatory effects by renal afferents. The objective of this study was to assess to what extent is HTN driven by central sympathetic hyperactivity in patients with diabetic CKD, OSA, and resistant HTN. Thirteen patients (age 62.2±7.4 years) with diabetic CKD, resistant HTN defined as SBP on 24-hr ABPM above 135 mmHg while on 3 or more BP lowering drugs (including diuretic) with OSA, were randomized to therapeutic CPAP or non-therapeutic CPAP for one months. 24-hr ABPM, plasma catecholamines, aldosterone, and renin, and MSNA were assessed before and 1 months after randomization. Our results show (Table) that in contrast to sham CPAP, therapeutic CPAP decreased daytime and nighttime BP. In contrast, neither therapeutic nor sham CPAP caused any changes in MSNA and plasma catecholamines. In conclusion, decreases in BP in response to CPAP in patients with in diabetic CKD, despite maintained high MSNA, indicate other mechanism contributing to HTN in these patients as well as other central sympathoexcitatory pathways activated.


1994 ◽  
Vol 77 (3) ◽  
pp. 1366-1374 ◽  
Author(s):  
A. V. Ng ◽  
R. Callister ◽  
D. G. Johnson ◽  
D. R. Seals

We tested the hypothesis that endurance training is associated with altered basal levels of muscle sympathetic nerve activity (MSNA) and responses to acute stress in healthy older adults. MSNA (peroneal microneurography) and plasma norepinephrine (NE) concentrations were measured during supine rest, a cold pressor test, and isometric handgrip (40% maximal voluntary force to exhaustion) in 16 older masters endurance athletes [10 men, 6 women; 66 +/- 1 (SE) yr] and 15 healthy normotensive untrained control subjects (9 men, 6 women; 65 +/- 1 yr). The athletes had higher levels of estimated daily energy expenditure and maximal oxygen uptake and lower levels of resting heart rate and body fat than the control subjects (all P < 0.05). MSNA during supine rest was elevated in the athletes whether expressed as burst frequency (43 +/- 2 vs. 32 +/- 3 bursts/min, respectively; P < 0.05) or burst incidence (75 +/- 4 vs. 52 +/- 5 bursts/100 heartbeats, respectively; P < 0.01). These whole group differences were due primarily to markedly higher levels of MSNA in the athletic vs. untrained women (48 +/- 4 vs. 25 +/- 3 bursts/min, 82 +/- 3 vs. 38 +/- 3 bursts/100 heartbeats, respectively, P < 0.001). In contrast, basal plasma NE concentrations were not significantly different in the athletes vs. control subjects. The MSNA and plasma NE responses to acute stress tended to be greater in the athletes. These findings indicate that vigorous regular aerobic exercise is associated with an elevated level of MSNA at rest and a tendency for an enhanced response to acute stress in healthy normotensive older humans.


2005 ◽  
Vol 13 (2) ◽  
pp. 167-170 ◽  
Author(s):  
Y Mikami ◽  
T Ogura ◽  
T Kubo ◽  
Y Kira ◽  
S Aramaki

Purpose. To examine whether the activity of peripheral sympathetic nerves in animals with spinal cord injury can be controlled using therapeutic electrical stimulation. Methods. The spinal cords of 6 Wistar rats were severed at T12/T13 disk level and were given continuous therapeutic electrical stimulation. Microneurography was used to record sympathetic nerve activity at 24, 48, and 72 hours after severing the spinal cord. Results. Integrated values of muscle sympathetic nerve activity after 72 hours of therapeutic electrical stimulation revealed significantly larger potentials on the stimulated side than the non-stimulated side. Skin sympathetic nerve activity showed no difference between the 2 sides. Conclusion. Therapeutic electrical stimulation was found to have a facilitatory effect on the muscle sympathetic nerve activity, whereas regulatory function was activated by the sympathetic nerves.


2010 ◽  
Vol 41 (01) ◽  
Author(s):  
M Knosalla ◽  
CA Haensch ◽  
J Wehe ◽  
H Lerch ◽  
J Weis ◽  
...  

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