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Abnormal stress responses in patients with diseases affecting the sympathetic nervous system.

Diseases that cause malfunction of the sympathetic nervous system provide insight into how the sympathetic nerves normally modulate responses to stress. This paper discusses insight from a number of such diseases. Transection of the cervical spinal cord leads to autonomic dysreflexia. This syndrome causes episodic hypertension in quadriplegic patients from excess sympathetic activity reflexly activated by bowel or bladder distention. These patients lack cerebral control of spinal sympathetic reflexes. Radiotherapy to the neck can destroy the arterial baroreceptors that monitor blood pressure fluctuations. Patients who lack baroreceptors have exaggerated blood pressure responses to stress. They have episodes of hypertension and hypotension that cause headaches and dizziness. Diabetics and uremics often develop a peripheral sympathetic neuropathy. They have postural hypotension and diminished blood pressure responses to stress. They are often unable to tolerate heat, exercise, or fluid deprivation. Patients with heart failure deplete sympathetic neuronal norepinephrine stores. The continual stress of heart failure diminishes their ability to respond to further stresses such as standing upright or exercising. Patients with diseases of the sympathetic nervous system illustrate that everyday occurrences such as a change in posture or ambient temperature are stresses requiring a marked change in sympathetic nervous activity. Both physical and psychological stresses elicit large initial sympathetic neuronal responses that are subsequently damped by feedback inhibition from structures such as the baroreceptors. Damage to part of these feedback loops leads to exaggerated pressor responses to stress.

Autonomic Nervous System Diseases↗

Diagnosis and treatment of neurally mediated syncope.

BACKGROUND: Syncope is caused by a severe but reversible reduction in blood flow to the brain stem neurons responsible for supporting consciousness (reticular activating system). Neurally mediated syncope, also referred to as vasovagal or reflex syncope, is the most frequent cause of loss of consciousness in apparently normal subjects. REVIEW SUMMARY: Neurally mediated syncope is believed to be a reflex response with afferent, central, and efferent pathways. Characteristic autonomic changes in neurally mediated syncope are an increase in parasympathetic efferent activity causing bradycardia and a reduction in sympathetic vasoconstrictor outflow causing vasodilatation. Premonitory symptoms, such as nausea, diaphoresis, abdominal discomfort, and blurred vision, are caused by autonomic activation and are distinguishing features of neurally mediated syncope. Neurally mediated syncope frequently has a characteristic trigger, although this may not be apparent. Testing orthostatic tolerance during passive head-up tilt is the best available diagnostic procedure to evaluate patients with syncope in whom a cardiac cause has been excluded. In many cases, once the diagnosis of neurally mediated syncope is confirmed, it may suffice to reassure the patient and teach him to avoid known triggers and to recognize and act upon early warning symptoms. Because subjects with neurally mediated syncope may potentially be sodium depleted, increasing salt intake can be beneficial in improving their orthostatic intolerance. CONCLUSIONS: Neurally mediated syncope is the most common form of syncope in healthy adults. The best diagnostic tools are the clinical history and passive head-up tilt. The best treatment strategies are the avoidance of triggering factors as well as intravascular volume expansion.

Journal Article↗

Magnetism and cardiac arrhythmias.

Low-level electromagnetic fields (EMFs) have been used to treat various neurologic disorders. In the present study, we applied micro Gauss (microG) levels of EMFs either to the vagosympathetic nerve trunks, dissected in the neck, or across the chest in anesthetized dogs. Based on theoretical and empiric grounds, we compared EMFs (2.87 microG at 0.043 Hz) delivered to the vagosympathetic trunks in an experimental set (n = 5) with a sham control group (n = 6). Over a period of 2 to 3 hours, heart rate decreased after an initial 5-minute EMF exposure. The maximal heart rate changes in the experimental versus control groups was 29% versus 12% (P = 0.03). The voltage applied to the autonomic nerves required to induce atrioventricular (AV) conduction block decreased by 60% in the experimental group versus a 5% increase in the control group (P = 0.005). This effect also lasted 2 to 3 hours. Another EMF setting (amplitude 0.34 microG, frequency 2 kHz) applied for 5 minutes to the vagosympathetic trunks was associated with a significant increase in the occurrence of atrial premature depolarizations (APDs), atrial tachycardia (AT), and atrial fibrillation (AF) in response to autonomic nerve stimulation compared with control states before EMF exposure. No atrial arrhythmias could be induced after propranolol and atropine, even at the highest voltage used to stimulate the autonomic nervous input to the heart (n = 11). Only 2 dogs showed no response to this EMF application. In 3 dogs in whom atrial pacing (cycle length = 250 ms) and autonomic nerve stimulation induced AF, an EMF (2.87 microG at 0.043 Hz) delivered for 35 minutes across the chest suppressed AF for up to 3 to 4 hours, after which the same protocol again induced AF. We conclude that in these preliminary experiments, specific low-level EMFs alter heart rate, AV conduction, and heart rhythm. These effects were mediated through the autonomic nervous system inputs to the heart based on adjunctive effect of autonomic nerve stimulation and the inhibitory action of autonomic blockers.

Animals↗

Neuroprotection and nerve grafts in the treatment of neurogenic erectile dysfunction.

PURPOSE: The rationale for protecting the nerve supply of the penis derives mainly from the fact that neurological injury or disease states involving this organ commonly result in erectile dysfunction. Novel directions in the management of neurogenic erectile dysfunction that pertain specifically to sustaining penile neuronal function are described. MATERIALS AND METHODS: The review constitutes a summary of neuroprotective strategies for penile erection that are under investigation at the basic science level or have been brought to clinical practice. The basic exercise consisted primarily of a literature search using the National Library of Medicine PubMed Services, with references made to such keywords as nerve grafts, nerve growth factors, neuroprotection and nerve regeneration. RESULTS: Primary advances in this field have centered on repairing structural defects and restoring the functional integrity of the cavernous nerves of the penis. In the former autologous nerve conduits, such as sural nerve grafts, have been explored and used prominently in the context of radical prostatectomy. In the latter diverse neurotrophic treatments have been investigated, with progress mostly limited to animal models of cavernous nerve injury. Basic concepts and ongoing developments in the neurobiology of axonal regeneration were identified as being applicable to this area of neurourology. CONCLUSIONS: Because neurogenic origins represent a leading categorical cause of erectile dysfunction, the importance of developing and applying treatment approaches to alleviate neuropathic effects on the erectile tissue of the penis is certain. Medical and surgical innovations for preserving and reconstituting the functional nerve supply of the penis offer great promise in the management of erectile dysfunction.

Animals↗

Development of a novel intrafascicular nerve electrode.

Artificial organs could be controlled using autonomic neural signals, because they exhibit rapid responses to physical needs similar to those of natural organs. A nerve electrode must satisfy many requirements to measure autonomous neural signals such as a long lifetime, high signal-to-noise ratio, multichannel recording, simple installation into a nerve fascicle, and good manufacturing productivity. The purpose of our study is to propose and evaluate a novel nerve electrode that satisfies these conditions, which to date has not been developed. A novel intrafascicular nerve electrode was designed, fabricated, and evaluated on autonomic nerves. Conventional extrafascicular and intrafascicular nerve electrodes were fabricated and tested for comparison to our novel intrafascicular nerve electrode. The novel intrafascicular nerve electrode had a 3-week lifetime, whereas the conventional extrafascicular nerve electrode had a 2-week lifetime. The signal-to-noise ratio was improved from 1.6 to 2.0 compared with the conventional extrafascicular nerve electrode. The novel intrafascicular nerve electrode was easier to install into a nerve fascicle and had better manufacturing productivity than the conventional intrafascicular nerve electrode. We succeeded in demonstrating the feasibility of our novel intrafascicular nerve electrode.

Animals↗

Complex genetic alterations in gastrointestinal stromal tumors with autonomic nerve differentiation.

Gastrointestinal stromal tumors (GISTs) with neurogenic differentiation, also referred to as "gastrointestinal autonomic nerve tumors (GANTs)," form an ultrastructurally distinctive subgroup of mesenchymal neoplasms of gastrointestinal tract. Cytogenetic and molecular data of these tumors are limited. In the current study, c-KIT gene sequenc-ing analysis, comparative genomic hybridization (CGH), and interphase fluorescence in situ hybrid- ization (FISH) analysis, utilizing chromosome 14- and 22-specific probes, were performed on five primary ultrastructurally confirmed GANTs. FISH and CGH analysis revealed loss of a whole or part of chromosome 14q in two tumors and of chromo- some 22q, with the common overlapping area of loss at q13, in all five tumors evaluated. c-KIT mu- tations were found in all cases; three tumors carried point mutation and/or deletions of exon 11, and in two tumors, insertion in exon 9 was found. These findings suggest that accumulated genetic changes contribute to the pathogenesis of GANTs and that 22q13 loss may be a characteristic feature of these tumors.

Adult↗

Skin hemodynamics during change from supine to lateral position.

The purpose of this study was to identify the skin hemodynamics during the position change from supine to lateral in patients with neurodegenerative diseases. The participants were 19 patients with neurodegenerative diseases and 12 healthy volunteers. The alteration in the total concentration of oxyhemoglobin and deoxyhemoglobin, indicative of change in blood volume, was measured in the skin of the left flank by using a portable noninvasive tissue oxygen monitor by near-infrared spectroscopy. The positions were changed from the left and right lateral with a return to the supine between each procedure. In healthy volunteers, total hemoglobin concentration (skin blood volume) increased when the position changed from supine to left lateral and decreased when changed from supine to right lateral. The decreased skin blood volume gradually recovered after a change from the supine to the right lateral position in healthy volunteers. However, it did not recover in three sporadic olivopontocerebellar atrophy (OPCA) patients with marked autonomic dysfunction and one Parkinsonian patient with severe orthostatic hypotension. Our study identified that the intracutaneous blood was changing dynamically during the position change from supine to lateral and was regulated by autonomic nerve function.

Autonomic Pathways↗

Genes, lineages and the neural crest: a speculative review.

Sensory and sympathetic neurons are generated from the trunk neural crest. The prevailing view has been that these two classes of neurons are derived from a common neural crest-derived progenitor that chooses between neuronal fates only after migrating to sites of peripheral ganglion formation. Here I reconsider this view in the light of new molecular and genetic data on the differentiation of sensory and autonomic neurons. These data raise several paradoxes when taken in the context of classical studies of the timing and spatial patterning of sensory and autonomic ganglion formation. These paradoxes can be most easily resolved by assuming that the restriction of neural crest cells to either sensory or autonomic lineages occurs at a very early stage, either before and/or shortly after they exit the neural tube.

Animals↗

A new Arabidopsis gene, FLK, encodes an RNA binding protein with K homology motifs and regulates flowering time via FLOWERING LOCUS C.

Posttranscriptional RNA metabolism plays versatile roles in the regulation of gene expression during eukaryotic growth and development. It is mediated by a group of RNA binding proteins with distinct conserved motifs. In this study, an Arabidopsis (Arabidopsis thaliana) gene, designated FLK, was identified and shown to encode a putative RNA binding protein with K homology motifs. A mutant in which FLK was inactivated by T-DNA insertion exhibited a severe late flowering phenotype both in long and short days. The late flowering phenotype was reversed by gibberellin and vernalization treatments. The FLOWERING LOCUS C (FLC) transcription was greatly upregulated, whereas those of FLOWERING LOCUS T and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 decreased in the mutant. These observations demonstrate that FLK regulates the autonomous flowering pathway via FLC. It is now evident that a battery of different RNA binding proteins are involved in the posttranscriptional regulation of flowering time in Arabidopsis.

Amino Acid Motifs↗

The FLF MADS box gene: a repressor of flowering in Arabidopsis regulated by vernalization and methylation.

A MADS box gene, FLF (for FLOWERING LOCUS F ), isolated from a late-flowering, T-DNA-tagged Arabidopsis mutant, is a semidominant gene encoding a repressor of flowering. The FLF gene appears to integrate the vernalization-dependent and autonomous flowering pathways because its expression is regulated by genes in both pathways. The level of FLF mRNA is downregulated by vernalization and by a decrease in genomic DNA methylation, which is consistent with our previous suggestion that vernalization acts to induce flowering through changes in gene activity that are mediated through a reduction in DNA methylation. The flf-1 mutant requires a greater than normal amount of an exogenous gibberellin (GA3) to decrease flowering time compared with the wild type or with vernalization-responsive late-flowering mutants, suggesting that the FLF gene product may block the promotion of flowering by GAs. FLF maps to a region on chromosome 5 near the FLOWERING LOCUS C gene, which is a semidominant repressor of flowering in late-flowering ecotypes of Arabidopsis.

Arabidopsis↗

Long-term modulation by postnatal oxytocin of the alpha 2-adrenoceptor agonist binding sites in central autonomic regions and the role of prenatal stress.

The aim of this work was to evaluate whether oxytocin administered in male rats subcutaneously early in life in the absence or presence of food restriction during pregnancy has life-long effects on the alpha(2)-agonist binding sites in the nucleus of the solitarii tract (NTS), in the hypothalamus and the amygdala, as evaluated by quantitative receptor autoradiography. Maternal food restriction alone increased the affinity of the alpha(2)-agonist [(3)H]UK14.304 binding sites exclusively in the NTS. In offspring from ad libitum fed dams, oxytocin treatment significantly increased the density of alpha(2)-agonist binding sites in the NTS and in the hypothalamus. The K(d) value of the alpha(2)-agonist binding sites in the hypothalamus of these rats, but not in the other regions studied, was also significantly increased. In offspring from food-restricted dams, oxytocin treatment produced a significant increase of the B(max) values in the hypothalamus and the amygdala and the K(d) value of the alpha(2)-agonist binding sites in the NTS of these rats also was selectively and significantly increased. These results suggest that a postnatal, oxytocin-induced increase of regional alpha(2)-adrenoceptor function can be seen in adulthood by a persistent, regionally selective increase in the density of central alpha(2)-adrenoceptor agonist binding sites, in the absence of an affinity change in the NTS. Such a regional increase of alpha(2)-adrenoceptor signalling in adulthood may contribute to the anti-stress action of postnatal oxytocin. By contrast, after prenatal stress, the potential increase in alpha(2)-adrenoceptor signalling takes place via selective increases of density with no changes of affinity of the alpha(2)-agonist binding sites in the hypothalamus and the amygdala.

Adrenergic alpha-2 Receptor Agonists↗

Sympatho-adrenal and pituitary hormone responses during and immediately after thoracic surgery--modulation by four different pain treatments.

Four different pain treatments (single intercostal block with bupivacaine, repeated intercostal block, epidural morphine and epidural bupivacaine infusions) were compared in 39 patients subjected to lung surgery under general anaesthesia. The patients' own estimate of the postoperative pain was not significantly different between the groups, but the epidurally treated patients required fewer doses of supplementary analgesic than those given just a single dose of intercostal bupivacaine. Bupivacaine levels in blood were below the toxic range in all groups. The concentration of antidiuretic hormone in blood was increased early during the operation, and had only partly returned to normal on the first postoperative morning. Growth hormone in plasma was increased only at the end of the operation. Catecholamine levels in blood increased gradually, reaching their peak postoperatively. There were only slight differences between the groups in these posterior and anterior pituitary and sympatho-adrenal responses to surgical stress. Thus, neither repeated intercostal blockade nor epidural administration of morphine or bupivacaine could prevent the endocrine responses to thoracic surgery, in spite of significant, albeit incomplete, pain relief. This was probably caused in part by residual pain, and also by poor access of the extradural medications to the autonomic afferent pathways mediating nociceptive signals from thoracic organs and tissues.

Aged↗

Supramedullary modulation of sympathetic vasomotor function.

1. Supramedullary structures including the ventral medial prefrontal cortex (MPFC) and the midbrain cuneiform nucleus (CnF) project directly and indirectly to premotor sympatho-excitatory neurons of the rostral ventrolateral medulla (RVLM) that are critically involved in the generation of sympathetic vasomotor tone. 2. Electrophysiological studies have demonstrated that activation of depressor sites within the MPFC is associated with splanchnic sympathetic vasomotor inhibition and inhibition of the activity of RVLM sympathoexcitatory neurons. 3. Antidromic mapping and anatomical studies support the notion that a relay in the nucleus tractus solitarius is involved in the cardiovascular response to MPFC stimulation. 4. The midbrain CnF, which lies adjacent to the midbrain periaqueductal grey, is a sympathoexcitatory region of the midbrain reticular formation. Sympathoexcitatory responses evoked from the CnF are associated with short-latency excitation of RVLM neurons. 5. Cuneiform nucleus stimulation induces the expression of mRNA for the immediate early genes c-fos and NGFI-A in mid-brain, pontine and hypothalamic structures. 6. The MPFC and CnF are supramedullary structures with opposing modulatory influences on sympathetic vasomotor drive, whose roles in cardiovascular control mechanisms warrant further investigation.

Animals↗

Autonomic and respiratory responses to microinjection of ATP into the intermediate or caudal nucleus tractus solitarius in the working heart-brainstem preparation of the rat.

1. Activation of peripheral chemoreceptors with KCN in the working heart-brainstem preparation from young male Wistar rats (70-90 g) increases phrenic (PNA; +105 +/- 18%) and thoracic (tSNA; +44 +/- 6%) sympathetic nerve activity compared with baseline and reduces heart rate (HR; from 377 +/- 27 to 83 +/- 6 b.p.m.). 2. Microinjections of increasing doses of ATP (1, 5, 25, 100 and 500 mmol/L; n = 7) into the intermediate nucleus tractus solitarius (NTS) produced a dose-dependent reduction in PNA (from -6 +/- 3 to -82 +/- 1%) and in HR (from -12 +/- 4 to -179 +/- 47 b.p.m.). Microinjections of ATP into the intermediate NTS also produced a reduction in tSNA (from -3 +/- 3 to -26 +/- 5%), which was not dose dependent. 3. Microinjections of ATP into the caudal NTS (n = 5) produced a dose-dependent increase in PNA (from 0.2 +/- 3 to 115 +/- 27%) and minor changes in HR and tSNA, which were not dose dependent. 4. The data show that microinjection of ATP into distinct subregions of the NTS produces different respiratory and autonomic responses and suggest that ATP in the caudal NTS is involved in the respiratory but not in the sympathoexcitatory component of the chemoreflex.

Adenosine Triphosphate↗

Sexual function after rectal excision.

BACKGROUND: Rectal excision is associated with a risk of autonomic nerve damage and associated sexual dysfunction (SD). The evolution of our understanding of the anatomy and physiology of sexual function together with continual refinement of surgery for both benign and malignant disease has led to a decrease in the incidence of SD after rectal surgery. A knowledge of the degree of risk of postoperative SD is important both for the patient and as a benchmark for audit of individual colorectal practice. METHODS: The available literature on the anatomy, physiology and surgical aspects of this topic has been researched through the Medline database. The more recently available data are reviewed in the context of the historical evolution of surgery for benign and malignant rectal disease. RESULTS AND CONCLUSIONS: In the best hands, permanent impotence occurs in less than 2% of patients following restorative proctocolectomy and at a similarly low rate after proctocolectomy and ileostomy. Isolated ejaculatory dysfunction is also numerically a minor problem post operation for benign disease. Patient age is the most important predictor of SD after surgery for rectal cancer. The incidence of permanent impotence remains high (>40%) after abdomino-perineal excision of the rectum (APE) but the continued decline in the use of this operation in favour of low anterior resection (LAR), which carries about half the risk of impotence compared to sphincter ablating surgery, is likely to have resulted in a fall in the absolute number of patients rendered impotent as a result of rectal cancer surgery. Anatomical dissection of the pelvis with preservation of the named autonomic fibres results in a low and predictable rate of sexual morbidity. Surgeons could profitably spend more time with their patients discussing the possible effects of surgery on sexual function. Further research is required to determine the effects of adjuvant therapy for rectal cancer on sexual function.

Autonomic Nervous System Diseases↗

New method to prevent bladder dysfunction after radical hysterectomy for uterine cervical cancer.

OBJECTIVE: The purpose was to improve the surgical procedures to prevent bladder dysfunction after radical hysterectomy. METHODS: Twelve patients with stage Ib cervical cancer underwent intraoperative electrical stimulation to identify the vesical branches of the pelvic nerves. Autonomic nerve localization in the vesicouterine ligament was examined in 10 patients immunohistochemically. According to the results of the above studies a new method to preserve the vesical branches was developed. Grades of postoperative bladder dysfunction were compared between new (n = 19) and conventional methods (n = 18). RESULTS: Electrical stimulation on the outer surface of the posterior sheath of the vesicouterine ligament caused the increase of intravesical pressure. S-100 protein localized also on this area. Postoperative compliance of the detrusor in cases with the new method demonstrated less decrement from preoperative values than in cases with the conventional method. The new method required significantly fewer days to achieve residual urine volumes less than 50 ml after surgery. CONCLUSIONS: The new method significantly reduces bladder dysfunction after radical hysterectomy.

Autonomic Pathways↗

Persistent cerebrovascular effects of MDMA and acute responses to the drug.

Acutely, 3,4,-methylenedioxymethamphetamine (MDMA) induces cerebrovascular dysfunction [Quate et al., (2004)Psychopharmacol., 173, 287-295]. In the longer term the same single dose results in depletion of 5-hydroxytrptamine (5-HT) nerve terminals. In this study we examined the cerebrovascular consequences of this persistent neurodegeneration, and the acute effects of subsequent MDMA exposure, upon the relationship that normally exists between local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu). Dark agouti (DA) rats were pre-treated with 15 mg/kg i.p. MDMA or saline. Three weeks later, rats from each pre-treatment group were treated with an acute dose of MDMA (15 mg/kg i.p.) or saline. Quantitative autoradiographic imaging was used to measure LCBF or LCMRglu with [(14)C]-iodoantipyrine and [(14)C]-2-deoxyglucose, respectively. Serotonergic terminal depletion was assessed using radioligand binding with [(3)H]-paroxetine and immunohistochemistry. Three weeks after MDMA pre-treatment there were significant reductions in densities of 5-HT transporter (SERT)-positive fibres (-46%) and [(3)H]-paroxetine binding (-47%). In animals pre-treated with MDMA there were widespread significant decreases in LCMRglu, but no change in LCBF indicating a persistent loss of cerebrovascular constrictor tone. In both pre-treatment groups, acute MDMA produced significant increases in LCMRglu, while LCBF was significantly decreased. In 50% of MDMA-pre-treated rats, random areas of focal hyperaemia indicated a loss of autoregulatory capacity in response to MDMA-induced hypertension. These results suggest that cerebrovascular regulatory dysfunction resulting from acute exposure to MDMA is not diminished by previous exposure, despite a significant depletion in 5-HT terminals. However, there may be a sub-population, or individual circumstances, in which this dysfunction develops into a condition that might predispose to stroke.

Acute Disease↗