Which of the following nervous system activities is not an effect of norepinephrine?

SNS

SNS has evolved into the treatment of choice for patients with fecal incontinence with very few exceptions. The treatment modality expanded after a benefit on bowel control was noted in patients treated with SNS for urinary incontinence. In 2011, it secured US Food and Drug Administration approval for use in patients with fecal incontinence. Although the exact mechanism of action remains unclear, SNS via direct, low-voltage stimulation of the sacral nerve roots appears to simultaneously affect multiple levels of the complex neuromuscular pathway that controls fecal continence. The implantation is carried out in two stages, both in the outpatient setting. The first stage is considered a trial phase and involves the percutaneous placement of a wire with four leads into the S3 foramen (Fig. 4). Correct lead placement is confirmed by means of fluoroscopy (Fig. 5) and intraoperative test stimulation, which should result in a contraction of the pelvic floor musculature (Bellow’s sign) and ipsilateral great toe flexion. These leads are then connected to an external stimulator. Symptoms are tracked over 2 weeks before and after the implantation. If the stimulation results in at least a 50% reduction in fecal incontinence episodes, it is considered a success, and the patient moves on to stage 2; otherwise, the temporary lead is removed. Stage 2 procedure involves the permanent implantation of the actual stimulator in the soft tissue of the buttocks just below the iliac crest (Fig. 4).

Studies have shown that definitive implantation was associated with a greater than 50% improvement in 86% to 87% of patients and with nearly perfect control in 40% of the patients. Even in the long-term analysis, the success appeared to persist, but after 3 to 5 years, a battery change is needed. The method has a favorable safety profile, and complications (e.g., pain, infection, bleeding, paresthesia) are comparably rare.

The success of SNS has caused a major paradigm shift in the workup and treatment of patients with incontinence. It has become clear that no preoperative test, but only the trial lead placement, can predict treatment successes. Therefore, the traditional recommendation to do anophysiology and pudendal nerve testing before any surgical intervention has lost regard. SNS is now indicated following failed nonoperative management of any incontinence regardless of whether there is a sphincter defect or pudendal neuropathy. Exceptions are limited to gross congenital or acquired anatomical alterations of the sacrum and pelvic floor, local tissue infections, a predictable need for magnetic resonance imaging scans, or a failed test phase.

Sympathetic Nervous System Activity

The SNS plays an important role in the pathogenesis of hypertension in obesity. Fasting suppresses SNS activity, whereas overfeeding increases it. Obese individuals have elevated plasma levels of catecholamines. It is likely that increased SNS activity raises BP, both directly by causing vasoconstriction, and indirectly by increasing renal sodium reabsorption through activation of renal nerves. Also, obese individuals with hypertension exhibit higher sympathetic nerve activity than obese individuals without hypertension,8 which is likely due to a dysregulation of the hypothalamic-pituitary-adrenal axis and false responses to cortisol.9

Location of Damage to the Sympathetic Pathway

After the diagnosis of Horner's syndrome is made, localizing whether the damage is along the preganglionic or postganglionic sympathetic pathway helps direct imaging, if indicated. Horner's syndrome sometimes manifests so characteristically that further efforts to localize the lesion are superfluous, as with patients with cluster headaches or patients with a history of surgery or trauma along the sympathetic pathway. Localization of a sympathetic lesion is a question of considerable clinical importance because many postganglionic defects are caused by vascular headache syndromes, cavernous sinus pathology, or carotid dissections, and preganglionic lesions sometimes result from malignant tumors or strokes to the central sympathetic location in the brain. These findings can assist the radiologist in interpretation of any diagnostic imaging. Pharmacological testing with hydroxyamphetamine drops can be helpful in localizing the lesion as well.

Hydroxyamphetamine releases norepinephrine from storage vesicles in the postganglionic sympathetic nerve endings at the iris dilator muscle. When the lesion is postganglionic, the third order nerve is dead, and no norepinephrine stores are available for release at the iris. When the lesion is complete, the pupil does not dilate at all. However, the dying neurons and their stores of norepinephrine may last for almost 1 week from the onset of damage. Therefore, a hydroxyamphetamine test administered within 1 week of a postganglionic lesion may give a false preganglionic localization if some of the norepinephrine stores remain. When Horner's syndrome is caused by preganglionic or central lesions, the pupils dilate normally because the postganglionic third order neuron and its stores of norepinephrine, although disconnected, are still intact.

To perform the hydroxyamphetamine test, the pupil diameters are measured before and 60 minutes after hydroxyamphetamine drops have been placed in both eyes. The change in anisocoria in room light is noted. If the affected pupil—the smaller one—dilates less compared with the normal pupil, an increase in anisocoria occurs, and the lesion is in the postganglionic neuron. If the smaller pupil now dilates so much that it becomes the larger pupil, the lesion is preganglionic and the postganglionic neuron is intact. The examiner must wait at least 48 hours after cocaine has been used before the administration of hydroxyamphetamine; cocaine inhibits the uptake of hydroxyamphetamine into the presynaptic sympathetic nerve terminal and seems to block its effectiveness. In general, if the anisocoria increases by at least 0.5 mm after hydroxyamphetamine administration, the lesion is most likely postganglionic. A decrease in anisocoria points toward a preganglionic location of the lesion. However, hydroxyamphetamine is no longer commercially available, and there are rare reports of false localization with hydroxyamphetamine. For these reasons, many clinicians forgo further localizing with hydroxyamphetamine and image the entire sympathetic pathway unless history or associated signs and symptoms clearly localize the lesion. For instance, acute Horner's syndrome with associated ipsilateral neck or facial pain requires urgent imaging of the neck for evaluation of a carotid dissection.

Sympathetic nervous system

Sympathetic nervous system activation has been shown to influence muscle spindle activity directly.32 Animal studies have shown that experimental activation of the cervical sympathetic nerve depresses the discharge rate of cervical muscle spindle afferents and affects the sensitivity of changes in muscle length. This was independent of changes in blood flow and inflammatory responses.32 A recent review discussed possible links between pain, stress, and activation of the sympathetic nervous system and the effect that this may have on muscle spindle activation. This could be another factor to consider as a cause of altered modulation of cervical somatosensory information in those with neck pain.11

Adrenal Medullary Sympathetic Hormone Excess: Pheochromocytoma

Less than 0.1% of all cases of hypertension are caused by pheochromocytomas, or catecholamine-producing tumors derived from chromaffin tissue.54 Nevertheless, these tumors are clearly important to the anesthesiologist as previously 25% to 50% of hospital deaths in patients with pheochromocytoma occurred during induction of anesthesia or during operative procedures for other causes.55 This high mortality has been reduced with the improvements in anesthesia management during our current era.55a Although usually found in the adrenal medulla, these vascular tumors can occur anywhere (referred to as paragangliomas), with a proportion of up to 20%.55b Malignant spread, which occurs in less than 15% of pheochromocytomas, usually proceeds to venous and lymphatic channels with a predisposition for the liver. This tumor is occasionally familial or part of the multiglandular-neoplastic syndrome known as multiple endocrine adenoma type IIa or type IIb, and is manifested as an autosomal dominant trait. Type IIa consists of medullary carcinoma of the thyroid, parathyroid adenoma or hyperplasia, and pheochromocytoma. What used to be called type IIb is now often called pheochromocytoma in association with phakomatoses such as von Recklinghausen neurofibromatosis and von Hippel–Lindau disease with cerebellar hemangioblastoma. Frequently, bilateral tumors are found in the familial form. Localization of tumors can be achieved by MRI or CT, metaiodobenzylguanidine nuclear scanning, ultrasonography, or intravenous pyelography (in decreasing order of combined sensitivity and specificity).

Symptoms and signs that may be solicited before surgery or procedures and are suggestive of pheochromocytoma are as follows: excessive sweating; headache; hypertension; orthostatic hypotension; previous hypertensive or arrhythmic response to induction of anesthesia or to abdominal examination; paroxysmal attacks of sweating, headache, tachycardia, and hypertension; glucose intolerance; polycythemia; weight loss; and psychological abnormalities. In fact, the occurrence of combined symptoms of paroxysmal headache, sweating, and hypertension is probably a more sensitive and specific indicator than any one biochemical test for pheochromocytoma (Table 32.4).

The value of preoperative and preprocedure adrenergic receptor blocking drugs probably justifies their use as these drugs may reduce the perioperative complications of hypertensive crisis, the wide arterial blood pressure fluctuations during tumor manipulation (especially until venous drainage is obliterated), and the myocardial dysfunction. Mortality is decreased with resection of pheochromocytoma (from 40% to 60% to the current 0% to 6%) when adrenergic receptor blockade is introduced as preoperative and preprocedure preparatory therapy for such patients.56-60

Sympathetic Nervous System

The SNS is a crucial regulator of arterial pressure and vital organ perfusion during the myriad of daily activities such as exercise, eating, and changing body posture.47 In heart failure, the SNS is activated at an early stage82 in response to reduced carotid and aortic baroreceptor sensitivity and altered arterial compliance.83 Changes in SNS activity in heart failure produce a dramatic reduction in regional blood flow to the skin, gut, and kidney while maintaining vital flow to coronary, cerebral, and skeletal muscle circulations.47 The SNS also contributes to the pathophysiology of heart failure through its stimulation of renin release.84 Increased sympathetic activation in heart failure can be documented by elevated plasma or urinary catecholamines; by increased NE spillover from the heart, kidney, brain, and skeletal muscle; or by increased common peroneal nerve sympathetic nerve traffic from microneurographic recordings. However it is documented, this activation correlates with the severity of LV dysfunction and predicts survival.2,82,85 While increased SNS activity in established systolic heart failure acts to maintain blood flow to vital organs, long-term and intense overactivation can have harmful effects through direct toxicity to myocardium, an adverse increase in LV afterloading (as a consequence of peripheral vasoconstriction), and LV hypertrophy (LVH) and subsequent dilatation.75

The pathophysiological importance of SNS activation and the benefit of β-adrenergic receptor blockade in systolic heart failure is clearly established.14,15,86 SNS activation is generally considered to be also important in primary (essential) hypertension87–90 and reflects increased sympathetic neuronal firing and decreased NE uptake.88 SNS activation is further augmented in hypertensive patients with heart failure, possibly through impaired baroreceptor function.91 There are, however, limited data regarding the degree of SNS activation in heart failure with preserved LVEF. Nevertheless, plasma NE levels do appear to rise in diastolic heart failure, but not to the extent seen in systolic heart failure.39,40 In animal models, the SNS appears to have a significant role in the development of LVH, LV remodeling, and heart failure due to pressure overload. Dopamine beta-hydroxylase knockout mice do not develop LVH during aortic banding, suggesting an important requirement for the SNS in activation of signaling pathways and the development of hypertrophy and heart failure, at least in this model.92

Modulation of sympathetic activity may be one important mechanism of effective antihypertensive therapy and prevention of heart failure. Therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers, both of which reverse LVH and reduce heart failure events in high-risk or hypertensive subjects, also suppresses cardiac efferent sympathetic activity.93,94 The role of β-adrenergic receptor blockade as first-line therapy for hypertension has, however, been questioned recently.95 First-line treatment with the alpha-adrenergic blocker doxazosin was reportedly associated with increased heart failure events compared with treatment with chlorthalidone, lisinopril, or amlodipine,96 although the accuracy of the diagnosis of heart failure has been questioned. Whereas the therapeutic efficacy of selected β-adrenergic receptor blockers in patients with all grades of systolic heart failure is not in question, the place of these drugs in the treatment of established diastolic heart failure remains unclear. Treatment with carvedilol has been shown to have beneficial effects on LV diastolic function in the setting of heart failure with preserved EF,97,98 but the effect on clinical outcomes is also uncertain.

Sympathetic Nervous System Activation and Its Role in the Pathogenesis of Heart Failure

Activation of the SNS (eg, after MI, for long-standing hypertension), much like increases in RAS activity, contributes to the pathophysiology of HF. SNS activation leads to pathologic LV growth and remodeling. Myocytes thicken and elongate, with eccentric hypertrophy and increases in sphericity. Wall stress is increased by this architecture, promoting subendocardial ischemia, cell death, and contractile dysfunction. The activated SNS can also harm myocytes directly through programmed cell death. As myocytes are replaced by fibroblasts, heart function deteriorates from this remodeling. The threshold for arrhythmias may also be lowered, contributing in a deteriorating cycle.

Sympathetic Nervous System

The sympathetic nervous system is responsible for the fight-or-flight response. This reaction is mediated by catecholamines, including epinephrine and norepinephrine. The term adrenergic refers to synapses in which epinephrine is used, although noradrenergic refers to synapses in which norepinephrine is used. Another neurotransmitter important for the sympathetic nervous system and CRPS is substance P, which is responsible for transmission of pain from certain sensory neurons to the CNS and aids in controlling relaxation of the vasculature and lowering blood pressure.

These catecholamine neurotransmitters stimulate α and β receptors. The stimulation of α receptors results in elevated heart rate and blood pressure, piloerection, and skin vasoconstriction. The stimulation of β receptors results in increased heart rate, muscle vasodilation, and bronchial dilation.172

Sympathetic nerve fibers originate inside the vertebral column at the first thoracic segment and extend to the third lumbar segment. Because the cells begin in both the thoracic and lumbar regions of the spinal cord, the sympathetic nervous system has a thoracolumbar outflow. Axons of these nerves leave the spinal cord and pass near the spinal ganglion.

The paravertebral ganglia, also termed the sympathetic chain or trunk, are a series of paired chains of ganglia that lie parallel to the vertebral bodies of the spinal column. The ganglia are interconnected to each other by nerve fibers and extend from the base of the skull down to the coccyx. There are three sympathetic chain ganglia located at the cervical level. The most inferior of these is the stellate ganglion which is believed to the supply the majority of the sympathetic innervation to the upper extremities. In the lower extremities, the sympathetic innervation is carried through lumbar paravertebral ganglia.107

All preganglionic motor neurons originate within the spinal cord and postganglionic fibers always originate in the PNS within a ganglion. There are 22 to 23 pairs of sympathetic chain ganglia. The interaction of nerve fibers begins at the spinal cord where they arise at the thoracolumbar region (T1-L2) and emerge via the ventral nerve root. They enter the sympathetic chain through the white rami communicans.

There are three options available to the preganglionic neurons in the sympathetic ganglion: (1) synapse with postganglionic neurons, (2) pass up and down the sympathetic chain, and (3) leave the ganglion using a cord that leads to a special ganglia in the viscera. It is this ability to move superiorly and inferiorly along the chain that results in the mass response to the sympathetic nervous system. A preganglionic fiber may synapse to 15 to 20 postganglionic fibers. Sympathetic postganglionics from the chain enter the gray rami communicans and go back to the spinal nerves to be distributed to somatic tissues of the limbs and body walls.

The sympathetic nervous system innervates all vascular smooth muscle (vasomotor function for blood pressure control and distribution control), all sweat glands (sudomotor control: core temperature control), and all arrector pili smooth muscle of hair follicles (pilomotor function: temperature control). Stimulation of the sympathetic nervous system results in:

Dilation of pupils

Stimulation of sweat glands

Accelerated heart rate

Increased blood pressure

Increased blood glucose levels

Relaxed bronchial muscles

Reduction of saliva and mucus

Reduction digestive activity, urine secretion

There is a dual innervation of most organs of the body by the sympathetic and parasympathetic divisions. In these cases, one will inhibit and the other will excite, providing the opposite effect such as speeding or slowing of heart rate.

Acute Mental Stress and Blood Pressure

The SNS stimulation that occurs repeatedly throughout the day as a result of mental stress and activity causes transitory increases in NE production and BP. Among the most important of these stimuli is physical activity. Although exercise raises BP, physical conditioning overrides this stimulatory effect and leads to effective reduction in basal and stimulated SNS activity and BP,137,138 as well as cardiovascular risk.139 Another important SNS stimulant is cigarette smoking.140 Even though the effects of smoking are transient and BP is only increased for a short time, the repetitive nature of smoking causes an increase in average daily BP. Major stressors that cause acute hypertension are burns, brain injury, surgical interventions such as cardiopulmonary bypass, and general anesthesia, each of which results in marked SNS activation.140 Exposure to cold and withdrawal from drugs such as opiates and central sympatholytics also acutely activate the SNS. Such episodes are transient, however, and are not associated with chronic hypertension.

1.2.5 Sympathetic Nervous System

The sympathetic nervous system regulates niche components through binding of the neurotransmitter norepinephrine to the β3- and β2-adrenergic receptors expressed on MSCs and osteoblasts (Asada et al., 2013; Mendez-Ferrer, Lucas, Battista, & Frenette, 2008). Trafficking of HSCs from the BM to the bloodstream is a consequence of rhythmic downregulation of CXCL12 expression regulated by the molecular clock genes through circadian noradrenaline secretion by the sympathetic nervous system (Mendez-Ferrer et al., 2008). Casanova-Acebes et al. demonstrated that this circadian release is regulated by rhythmic elimination of neutrophils by BM-resident macrophages (Casanova-Acebes et al., 2013). The migration of aged neutrophils is CXCR4-dependent and disrupts the HSC niche by reducing CAR cells, thereby reducing CXCL12 protein expression. Nonmyelinating Schwann cells that ensheath and protect sympathetic nerve fibers are positive for Nestin, like some perivascular MSCs. These glial cells maintain HSC dormancy by releasing active TGFB1, which triggers signaling pathways required for HSC quiescence (Yamazaki et al., 2009, 2011). Therefore, the sympathetic nervous system together with its glial cells regulates HSC trafficking and proliferation through modulation of niche components.