Depression of Endothelial Nitric Oxide Synthase but Increased Expression of Endothelin-1 Immunoreactivity in Rat Thoracic Aortic Endothelium Associated With Long-term, but Not Short-term Sympathectomy

Circulation Research. 1996;79:317-323

After unilateral sympathectomy the incidence of calcified arteries on the side of operation was significantly higher than that on the contralateral side

Medial arterial calcification is frequently seen in diabetic patients with severe diabetic neuropathy. Sixty patients (19 diabetic and 41 non-diabetic) were examined radiologically for typical Monckeberg's sclerosis of feet arteries 6-8 years after uni- or bilateral lumbar sympathectomy. Fifty-five out of 60 patients (92%) revealed medial calcification. This calcification was observed in both feet of 93% of patients, who had undergone bilateral operation. After unilateral sympathectomy the incidence of calcified arteries on the side of operation was significantly higher than that on the contralateral side (88% versus 18%, p less than 0.01). Although diabetic patients showed longer
stretches of calcification than non-diabetic subjects, the difference was not significant in terms of incidence and length. Of 20 patients who had no evidence of calcinosis pre-operatively, 11 developed medial calcification after unilateral operation exclusively on the side of sympathectomy. In seven patients calcinosis was detected in both feet after bilateral operation. In conclusion, sympathetic denervation is one of the causes of Monckeberg's sclerosis regardless of diabetes mellitus.
PMID: 6873514 [PubMed - indexed for MEDLINE]
Diabetologia. 1983 May;24(5):347-50.

in the media of FAs hypercholesterolemia induces changes similar to those observed in sympathectomized rabbits in non-pathological conditions

In a previous study, we showed that after sympathectomy, the femoral (FA) but not the basilar (BA) artery from non-pathological rabbits manifests migration of adventitial fibroblasts (FBs) into the media and loss of medial smooth muscle cells (SMCs). The aim of the present study was to verify whether similar behaviour of arteries occurred in the pathological context of atherosclerosis.
Our results show that in the media of FAs hypercholesterolemia induces changes similar to those observed in sympathectomized rabbits in non-pathological conditions, i.e., migration of adventitial FBs to the media and loss of medial SMCs. These latter changes, which can be ascribed to pathological events, were accentuated after sympathectomy in the hypercholesterolemic rabbits. The present study reveals that pathological events, including migration and phenotypic modulation of vascular FBs and loss of SMCs, may be under the influence of sympathetic nerves.
Acta Histochemica; Jul2008, Vol. 110 Issue 4, p302-313, 12p

sympathectomy results in an increased collagen content in the vascular wall, suggesting a stiffening of the vessel wall

From animal experiments, it is known that long-term sympathectomy results in an increased collagen content in the vascular wall, suggesting a stiffening of the vessel wall (9). Giannattasio et al.

MEDICINE & SCIENCE IN SPORTS & EXERCISE®
Copyright © 2005 by the American College of Sports Medicine
DOI: 10.1249/01.mss.0000174890.13395.e7

hypoxic pulmonary vasoconstriction may be impaired after Sympathectomy

It is well known that hypoxic pulmonary vasoconstriction(HPV) plays an important role to protect hypoxemia during the atelectasis induced by one-lung ventilation. Thoracic sympathectomy may have effects on pulmonary vasculature(HPV) and hemodynamics during one-lung anesthesia.

Mean arterial blood pressure was decreased from 81.9+/-2.89 to 73.2+/-2.49 mmHg after thoracic sympathectomy and heart rate was decreased from 104.4+/-3.12 to 88.2+/-2.31beats/min. Arterial oxygen tension was decressed from 570.5+/-17.9 to 521.4+/-23.2mmHg after position change, and decreased to 271.1+/-28.1 mmHg under one-lung ventilation, and finally decreased to 217.0+/-18.3 mmHg after thoracic sympathectomy. With the above results, we can conclude that patients for TES should be carefully observed during and after the procedure, and hypoxic pulmonary vasoconstriction may be impaired after TES.
Korean J Anesthesiol. 1993 Aug;26(4):695-699.

Unilateral removal of the superior cervical ganglion (SCG) results in the reinnervation of the denervated cerebral vessels by sprouting nerves

Chemical sympathectomy of the mature rat rather than the neonate also leads to sensory hyperinnervation, although there are a few differences. In the lung, sympahtectomy induces a marked increase in CGRP-immunoreactive nerve density around the ariways, blood vessels, and also in the vicinity of the neuroepithelial bodies of the pulmonary epithelium.

Following transection of the preganglionic autonomic nerves or in spinal cord injury, there are marked changes in the nerves that remain. Such changes can be manifested not only as nerve growth and changes in neurotransmitter expression, but remarkably, in reorganization of nerve pathways and their function.

Since sprouting is a common response of the nerves that remain following nerve injury, the close association of the different divisions of the autonomic nervous system in the pelvic region opens up the possibility for new connections to form new pathways. Spinal cord injury can unmask spinal reflexes that are normally inhibited by input from higher centers in the brain.

Handbook of the autonomic nervous system in health and disease

By Liana Bolis, J. Licinio, Stefano GovoniInforma Health Care, 2003 - Medical - 677 pages

depletion of brain noradrenaline levels causes a disturbance in cerebral microvascular tone

A hypertensive condition at a mean arterial pressure of about 160 mm Hg was maintained for 1 hour by intravenous infusion of phenylephrine. In the 6-hydroxydopamine-treated group, CBF increased significantly after the elevation of systemic blood pressure compared with that in the control group, and cerebral autoregulation was impaired. After a 1-hour study, the specific gravity of the cerebral tissue in the treated group significantly decreased; electron microscopic studies at that time revealed brain edema.It is suggested that depletion of brain noradrenaline levels causes a disturbance in cerebral microvascular tone and renders the cerebral blood vessels more vulnerable to hypertension.

Journal of Neurosurgery, December 1991 Volume 75, Number 6

cerebral edema is worsened by sympathectomy, which causes increased cerebral blood flow

Although excessive SNS activity may be globally harmful, catecholamines and sympathetic nerves may also have organ-protective effects via reflex arteriolar constriction, which may protect the capillaries of the brain and kidney from surges in SBP. A baroprotective role of cerebral sympathetic nerves was uncovered by Heistad et al., who unilaterally denervated the cerebral vasculature in stroke-prone rats and found that fatal stroke occurred rapidly in the hemisphere ipsilateral to the sympathetic denervation. In the syndrome of malignant hypertension, cerebral edema is worsened by sympathectomy, which causes increased cerebral blood flow.

Role of hte Hypothalamus in Integration of behavior and Cardiovascular Responses (p. 60)

Hypertension: a companion to Brenner and Rector's the kidney

By Suzanne Oparil, Michael A. Weber
Elsevier Health Sciences, 2005 - Medical - 872 pages

Spinal Cord Infarction caused by sympathectomy

Uncommon causes include decompression sickness, which has a predilection for spinal ischemic damage; complications of abdominal surgery, particularly sympathectomy; circulatory failure as a result of cardiac arrest or prolonged hypotension; and vascular steal in the presence of an arteriovenous malformation.

Author: Thomas F Scott, MD, Professor, Program Director, Department of Neurology, Drexel University College of Medicine; Director, Allegheny MS Treatment Center
Contributor Information and Disclosures

Updated: Aug 21, 2009

sympathectomy per se may sensitize peripheral nociceptors and lead to neuralgia

Interestingly, while is used for the treatment of some chronic pain conditions, sympathectomy per se may sensitize peripheral nociceptors to circulating norephinephrine, and this sensitization may lead to post-sympathectomy neuralgia. (p.287)

Peripheral Receptor Targets for Analgesia: Novel Approaches to Pain Management

By Brian E. Cairns
John Wiley and Sons, 2009 - Medical

we conclude that the sympathetic nervous system influences the metabolic activity of the aorta

The effect of chemical sympathectomy with 6-hydroxydopamine (6-OH-DA) on collagen formation in the aortic wall was investigated in rabbits and rats. Eight weeks after 6-OH-DA treatment of rabbits, there was a significant increase an collagen content in aortas and histologic changes in the elastic elements within the media. The possibility of a direct effect of 6-OH-DA on connective tissue formation was investigated in a subsequent experiment in rats. The rates of collagen synthesis and prolyl hydroxylase activity (PHA) were determined in aortas and in the fibrotic granuloma around subcutaneously implanted polyvinylalcohol sponges. Rates of collagen synthesis and PHA were significantly increased in the aortas of 6-OH-DA treated rats, but not in fibrotic granuloma, confirming the changes seen in the aorta of rabbits and suggesting that 6-OH-DA does not directly affect collagen synthesis. We conclude that the sympathetic nervous system influences the metabolic activity of the aorta. Our data indicate that when the aortic wall is deprived of adrenergic nervous stimulation, changes occur which resemble those seen in natural aging of the aorta. It is plausible to assume that such a metabolic derangement in the vessel wall will make these vessels more vulnerable to additional stresses.

Experimental and Molecular Pathology
Volume 28, Issue 3, June 1978, Pages 279-289

a significant impairment of the heart rate to workload relationship was consistently observed following sympathectomy

Several reports also demonstrate significantly lower heart rate increases during exercise in subjects who have undergone bilateral ISS [9–12] compared to pre-surgical levels. In spite of this high occurrence, recent reviews on the usual collateral effects of thoracic sympathectomy still do not include these possible cardiac consequences [6].
The aim of the present prospective study was to confirm that a significant impairment of the heart rate to workload relationship was consistently observed following unilateral and/or bilateral surgery.
Eur J Cardiothorac Surg 2001;20:1095-1100
http://ejcts.ctsnetjourna...i/content/full/20/6/1095

slowing of the heart rate usually occurs on the second to fourth day after sympathectomy

The rate fell to a level between 40 and 6o per minute, the maximal slowing usually occurring on the second to fourth day after operation. Consistent slowing of the rate was not observed after a unilateral thoracic sympathectomy of either side. While there was some recovery from the maximum brady-
cardia with the passage of time in most patients, relatively slow resting cardiac rates and failure of tachycardia to develop with postural hypotension or exercise persisted in all patients.



Skoog's12 work has shown that there are marked differences in the number and precise location of the accessory ganglion cells in the cervical region in different patients and on the two sides in the same patient.

Even when a single midthoracic paravertebral ganglion is left in place in an otherwise total sympathectomy the thoracic dermatome supplied by the ganglion appears for several days or weeks to be sympathectomized also. Then, sweating begins to appear, and it increases gradually in amount until the skin of that dermatome may be dripping. This phenomenon more than any other meets the
objection of those who maintain that if residual pathways do exist, the evidence of their presence should be manifest immediately after operation.
Annals of Surgery, 1949 October
Volume 130 Number 4

sympathectomy must somehow quiet the contralateral spread of spinal cord hyperexcitability underlying mirror-image pain

Blocking sympathetic function, whether by surgical sympathectomy, systemic phentolamine, or systemic guanethidine, relieves partial nerve injury-induced neuropathic pain in laboratory animal models as well as humans (8, 35, 146, 239, 278). Indeed, sympathectomy does not just relieve pathological pain in the body region ipsilateral to the CRPS-initiating event; rather, it also relieves pain arising from anatomically impossible mirror-image sites, that is, the identical body region contralateral to the initiating event (278). Thus sympathectomy must somehow quiet the contralateral spread of spinal cord hyperexcitability underlying mirror-image pain. 

Alterations in sympathetic fibers rapidly follow peripheral nerve injury. This occurs as sprouting of sympathetic fibers, creating aberrant communication pathways from the new sympathetic terminals to sensory neurons (35). Sympathetic sprouting has been documented in the region of peripheral terminal fields of sensory neurons (262), at the site of nerve trauma (57), and within the dorsal root ganglia (DRG) containing cell bodies of sensory neurons (248, 343). Each of these sites develops spontaneous activity and sensitivity for catecholamines and sympathetic activation (8, 53). 

The clearest evidence that immune activation participates in sympathetic sprouting comes from studies of the DRG. DRG cells receive signals that peripheral nerve injury has occurred via retrograde axonal transport from the trauma site. These retrogradely transported signals trigger sympathetic nerve sprouting into DRG (205, 308). As a result of nerve damage-induced retrogradely transported signals, glial cells within the DRG (called satellite cells) proliferate (248) and become activated (343); macrophages are recruited to the DRG as well (63, 176). In turn, the activated satellite glial cells (and, presumably, the macrophages) release proinflammatory cytokines and a variety of growth factors into the extracellular fluid of the DRG (206, 246 –248, 258, 277, 308, 358). These substances stimulate and direct the growth of sympathetic fibers, which form basket-like terminals around the satellite cells that, in turn, surround neuronal cell bodies (247, 248, 343). 

Until recently, the sympathetic sprouting, rather than the glial (satellite cell) activation, has attracted the attention of pain researchers. The satellite cells were ignored as they were thought to be irrelevant to the creation of exaggerated pain states. However, it may be speculated that the satellite cells, rather than the sympathetic sprouts, have the most impact on pain.

Physiol Rev • VOL 82 • OCTOBER 2002 • www.prv.org

Beyond Neurons: Evidence That Immune and Glial Cells 

Contribute to Pathological Pain States 

LINDA R. WATKINS AND STEVEN F. MAIER 

Department of Psychology and the Center for Neuroscience, 

University of Colorado at Boulder, Boulder, Colorado 

Chronic pain can occur after peripheral nerve injury, infection, or inflammation

Chronic pain can occur after peripheral nerve injury, infection, or inflammation. Under such neuropathic pain conditions, sensory processing in the affected body region becomes grossly abnormal. Despite decades of research, currently available drugs largely fail to control such pain. This review explores the possibility that the reason for this failure lies in the fact that such drugs were designed to target neurons rather than immune or glial cells. It describes how immune cells are a natural and inextricable part of skin, peripheral nerves, dorsal root ganglia, and spinal cord. It then examines how immune and glial activation may participate in the etiology and symptomatology of diverse pathological pain states in both humans and laboratory animals. Of the variety of substances released by activated immune and glial cells, 

proinflammatory cytokines (tumor necrosis factor, interleukin-1, interleukin-6) appear to be of special importance in the creation of peripheral nerve and neuronal hyperexcitability.

Although this review focuses on immune modulation of pain, the implications are pervasive. Indeed, all nerves and neurons regardless of modality or function are likely affected by immune and glial activation in the ways described for pain.

Physiol Rev   82: 981–1011, 2002; 10.1152/physrev.00011.2002.