Department of Physiology: ANS Physiology-Offline information

Autonomic Dysfunction: Disruption of autonomic pathways can result in specific functional deficits or more generalized loss of homeostatic function, depending on the nature of the underlying pathology. Horner syndrome is caused by disruption of the sympathetic pathway that raises the eyelid, controls pupil diameter, and regulates facial sweat gland activity. The result is a unilateral ptosis (drooping eyelid), miosis (inability to increase pupil diameter), and local anhidrosis (inability to sweat). More generalized autonomic dysfunctions are common among patients on maintenance dialysis and those with diabetes whose glucose levels are poorly controlled (diabetic autonomic neuropathy, or DAN). DAN can manifest as an inability to control blood pressure following a meal (postprandial hypotension) or upon standing (postural hypotension), gastrointestinal motility disorders (difficulty swallowing and constipation), or bladder dysfunction, among other symptoms. Tests designed to assess autonomic function include monitoring cardiac responses during changes in posture, hand immersion in ice water (the cold pressor test, designed to induce intense pain), and a Valsalva maneuver. A Valsalva maneuver involves forced expiration against a resistance, designed to cause intrathoracic pressures to rise to 40 mm Hg for 10–20 s. The pressure increase prevents venous blood from entering the thorax, so cardiac fi lling is impeded, and arterial pressure falls. In a healthy individual, a fall in arterial pressure is sensed by arterial baroreceptors, initiating a reflex increase in heart rate that is mediated by sympathetic efferents traveling in the vagus nerve. Patients with DAN may have impaired baroreceptor or vagal nerve functions and, thus, fails to respond to a Valsalva maneuver with the expected tachycardia.

Autonomic dysreflexia is a serious condition that can cause stroke, pulmonary edema, and myocardial infarction (heart attack) in people with spinal cord injuries at or above the sixth thoracic level (T6) of the spinal cord. Spinal shock may occur immediately after a spinal cord injury, especially if the cord is completely transected. At first there is a loss of spinal reflexes below the level of the injury, but after some timethe reflexes reappear in an exaggerated state. In this condition, a noxious sensory stimulus—usually from the urinary bladder or colon—can evoke a strong response from the sympathoadrenal system. Sympathetic nerves cause vasoconstriction and increased heart rate, which raise the blood pressure. Pressure receptors in arteries sense this, and sendsignals via cranial nerves IX and X to the brain. In response, the brain directs an inhibition of sympathetic activity and an increase in parasympathetic activity, which normally maintain homeostasis. However, if the person has a spinal cord injury at or above T6, the inhibition of the sympathetic (thoracolumbar) response cannot descend below the injury. High sympathetic nerve activity is maintained below the level of the injury, producing vasoconstriction that can cause dangerous hypertension as well as a cold skin and goose bumps. By contrast, sympathetic nerve activity is decreased above the level of the injury, accompanied by increased parasympathetic nerve effects. This results in bradycardia (a slow heart rate), nasal congestion, and a flushed, sweaty skin above the level of the spinal cord injury. The bradycardia is insufficient to lower the dangerously elevated blood pressure, and so autonomic dysreflexia requires efforts to eliminate the noxious stimulus that provoked it, as well as other measures.

Pharmacology of the Autonomic Nervous System Drugs That Act on Adrenergic Effector Organs—Sympathomimetic Drugs: From the foregoing discussion, it is obvious that intravenous injection of norepinephrine causes essentially the same eﬀects throughout the body as sympathetic stimulation. Therefore, norepinephrine is called a sympathomimetic or adrenergic drug. Epinephrine and methoxamine are also sympathomimetic drugs, and there are many others. They diﬀer from one another in the degree to which they stimulate diﬀerent sympathetic eﬀector organs and in their duration of action. Norepinephrine and epinephrine have actions as short as 1 to 2 minutes, whereas the actions of some other commonly used sympathomimetic drugs last for 30 minutes to 2 hours. Important drugs that stimulate specific adrenergic receptors are phenylephrine (alpha receptors), isoproterenol (beta receptors), and albuterol (only beta2 receptors).

Drugs That Cause Release of Norepinephrine From Nerve Endings: Certain drugs have an indirect sympathomimetic action instead of directly exciting adrenergic eﬀector organs. These drugs include ephedrine, tyramine, and amphetamine. Their eﬀect is to cause release of norepinephrine from its storage vesicles in the sympathetic nerve endings. Te released norepinephrine in turn causes the sympathetic eﬀects.

Drugs That Block Adrenergic Activity: Adrenergic activity can be blocked at several points in the stimulatory process, as follows: 1. The synthesis and storage of norepinephrine in the sympathetic nerve endings can be prevented. The best-known drug that causes this eﬀect is reserpine. 2. Release of norepinephrine from the sympathetic endings can be blocked. Tis eﬀect can be caused by guanethidine. 3. The sympathetic alpha receptors can be blocked. Two drugs that block both alpha1 and alpha2 adrenergic receptors are phenoxybenzamine and phentolamine. Selective alpha1 adrenergic blockers include prazosin and terazosin, whereas yohimbine blocks alpha2 receptors. 4. The sympathetic beta receptors can be blocked. A drug that blocks beta1 and beta2 receptors is propranolol. Drugs that block mainly beta1 receptors are atenolol, nebivolol, and metoprolol. 5. Sympathetic activity can be blocked by drugs that block transmission of nerve impulses through the autonomic ganglia. They are discussed in a later section, but an important drug for blockade of both sympathetic and parasympathetic transmission through the ganglia is hexamethonium.

Drugs That Act on Cholinergic Effector Organs Parasympathomimetic Drugs (Cholinergic Drugs): Acetylcholine injected intravenously usually does not cause exactly the same eﬀects throughout the body as parasympathetic stimulation because most of the acetylcholine is destroyed by cholinesterase in the blood and body ﬂuids before it can reach all the eﬀector organs. Yet a number of other drugs that are not so rapidly destroyed can produce typical widespread parasympathetic eﬀects; they are called parasympathomimetic drugs. Two commonly used parasympathomimetic drugs are pilocarpine and methacholine. They act directly on the muscarinic type of cholinergic receptors.

Drugs That Have a Parasympathetic Potentiating Effect—Anticholinesterase Drugs: Some drugs do not have a direct eﬀect on parasympathetic eﬀector organs but do potentiate the eﬀects of the naturally secreted acetylcholine at the parasympathetic endings. Tey are the same drugs as those discussed in Chapter 7 that potentiate the eﬀect of acetylcholine at the neuromuscular junction. Tese drugs include neostigmine, pyridostigmine, and ambenonium. Tey inhibit acetylcholinesterase, thus preventing rapid destruction of the acetylcholine liberated at parasympathetic nerve endings. As a consequence, the quantity of acetylcholine increases with successive stimuli, and the degree of action also increases.

Drugs That Block Cholinergic Activity at Effector Organs—Antimuscarinic Drugs: Atropine and similar drugs, such as homatropine and scopolamine, block the action of acetylcholine on the muscarinic type of cholinergic eﬀector organs. These drugs do not aﬀect the nicotinic action of acetylcholine on the postganglionic neurons or on skeletal muscle.

Drugs That Stimulate or Block Sympathetic and Parasympathetic Postganglionic Neurons Drugs That Stimulate Autonomic Postganglionic Neurons: The preganglionic neurons of both the parasympathetic and the sympathetic nervous systems secrete acetylcholine at their endings, and the acetylcholine in turn stimulates the postganglionic neurons. Furthermore, injected acetylcholine can also stimulate the postganglionic neurons of both systems, thereby causing at the same time both sympathetic and parasympathetic eﬀects throughout the body. Nicotine is another drug that can stimulate postganglionic neurons in the same manner as acetylcholine because the membranes of these neurons all contain the nicotinic type of acetylcholine receptor. Therefore, drugs that cause autonomic eﬀects by stimulating postganglionic neurons are called nicotinic drugs. Some other drugs, such as methacholine, have both nicotinic and muscarinic actions, whereas pilocarpine has only muscarinic actions. Nicotine excites both the sympathetic and parasympathetic postganglionic neurons at the same time, resulting in strong sympathetic vasoconstriction in the abdominal organs and limbs but at the same time resulting in parasympathetic eﬀects such as increased gastrointestinal activity.

Ganglionic Blocking Drugs: Drugs that block impulse transmission from the autonomic preganglionic neurons to the postganglionic neurons include tetraethyl ammonium ion, hexamethonium ion, and pentolinium. Tese drugs block acetylcholine stimulation of the postganglionic neurons in both the sympathetic and the parasympathetic systems simultaneously. Tey are often used for blocking sympathetic activity but seldom for blocking parasympathetic activity because their eﬀects of sympathetic blockade usually far overshadow the eﬀects of parasympathetic blockade. The ganglionic blocking drugs especially can reduce the arterial pressure rapidly, but they are not very useful clinically because their eﬀects are difficult to control.

Effects of Sympathetic Activation: The sympathetic division can change the activities of tissues and organs by releasing NE at peripheral synapses, and by distributing E and NE throughout the body in the bloodstream. The visceral motor fibers that target specific effectors, such as smooth muscle fibers in blood vessels of the skin, can be activated in reflexes that do not involve other visceral effectors. In a crisis, however, the entire division responds. This event, called sympathetic activation, is controlled by sympathetic centers in the hypothalamus. The effects are not limited to peripheral tissues; sympathetic activation also alters CNS activity. During sympathetic activation, the following changes occur in an individual:

• Increased alertness via stimulation of the reticular activating system, causing the individual to feel “on edge.”

• A feeling of energy, often associated with a disregard for danger and a temporary insensitivity to painful stimuli.

• Increased activity in the cardiovascular and respiratory centers of the pons and medulla oblongata, leading to elevations in blood pressure, heart rate, breathing rate, and depth of respiration.

• A general elevation in muscle tone, so the person looks tense and may begin to shiver. • The mobilization of energy reserves, through the accelerated breakdown of glycogen in muscle and liver cells and the release of lipids by adipose tissues. These changes, plus the peripheral changes already noted, complete the preparations necessary for the individual to cope with a stressful situation.

The sympathetic nervous system mass discharge: When large portions of the sympathetic nervous system discharge at the same time—that is, a mass discharge— this action increases the ability of the body to perform vigorous muscle activity in many ways, as summarized in the following list:

1. Increased arterial pressure

2. Increased blood ﬂow to active muscles concurrent with decreased blood ﬂow to organs such as the gastrointestinal tract and the kidneys that are not needed for rapid motor activity

3. Increased rates of cellular metabolism throughout the body

4. Increased blood glucose concentration

5. Increased glycolysis in the liver and in muscle

6. Increased muscle strength

7. Increased mental activity

8. Increased rate of blood coagulation

The sum of these eﬀects permits a person to perform far more strenuous physical activity than would otherwise be possible. Because either mental or physical stress can excite the sympathetic system, it is frequently said that the purpose of the sympathetic system is to provide extra activation of the body in states of stress, which is called the sympathetic stress response. The sympathetic system is especially strongly activated in many emotional states. For instance, in the state of rage, which is elicited to a great extent by stimulating the hypothalamus, signals are transmitted downward through the reticular formation of the brain stem and into the spinal cord to cause massive sympathetic discharge; most aforementioned sympathetic events ensue immediately. This is called the sympathetic alarm reaction. It is also called the fight-or-ﬂight reaction because an animal in this state decides almost instantly whether to stand and fight or to run. In either event, the sympathetic alarm reaction makes the animal’s subsequent activities vigorous

Effects of Parasympathetic Stimulation: Under normal conditions, the entire parasympathetic division— unlike the sympathetic division—is neither controlled nor activated as a whole. Although it is active continuously, the activities are reflex responses to conditions within specific structures or regions. Examples of the major effects produced by the parasympathetic division include the following:

• Constriction of the pupils (to restrict the amount of light that enters the eyes) and focusing of the lenses of the eyes on nearby objects.

• Secretion by digestive glands, including salivary glands, gastric glands, duodenal glands, intestinal glands, the pancreas (exocrine and endocrine), and the liver.

• Secretion of hormones that promote the absorption and utilization of nutrients by peripheral cells.

• Changes in blood flow and glandular activity associated with sexual arousal.

• Increased smooth muscle activity along the digestive tract.

• Stimulation and coordination of defecation.

• Contraction of the urinary bladder during urination.

• Constriction of the respiratory passageways.

• Reduction in heart rate and in the force of contraction.

These functions center on relaxation, food processing, and energy absorption. Stimulation of the parasympathetic division leads to a general increase in the nutrient content of the blood. Cells throughout the body respond to this increase by absorbing nutrients and using them to support anabolic activities such as growth, cell division, and the creation of energy reserves in the form of lipids or glycogen.

Effects of Sympathetic and Parasympathetic Stimulation on Specific Organs:

1. Eyes. Two functions of the eyes are controlled by the autonomic nervous system: (1) the pupillary opening and (2) the focus of the lens. Sympathetic stimulation contracts the meridional fbers of the iris that dilate the pupil, whereas parasympathetic stimulation contracts the circular muscle of the iris to constrict the pupil. The parasympathetics that control the pupil are reﬂexly stimulated when excess light enters the eyes; this reﬂex reduces the pupillary opening and decreases the amount of light that strikes the retina. Conversely, the sympathetics become stimulated during periods of excitement and increase pupillary opening at these times. Focusing of the lens is controlled almost entirely by the parasympathetic nervous system. The lens is normally held in a ﬂattened state by intrinsic elastic tension of its radial ligaments. Parasympathetic excitation contracts the ciliary muscle, which is a ringlike body of smooth muscle fibers that encircles the outside ends of the lens radial ligaments. This contraction releases the tension on the ligaments and allows the lens to become more convex, causing the eye to focus on objects near at hand.

2. Glands of the Body. The nasal, lacrimal, salivary, and many gastrointestinal glands are strongly stimulated by the parasympathetic nervous system, usually resulting in copious quantities of watery secretion. The glands of the alimentary tract most strongly stimulated by the parasympathetics are those of the upper tract, especially those of the mouth and stomach. On the other hand, the glands of the small and large intestines are controlled principally by local factors in the intestinal tract itself and by the intestinal enteric nervous system; they are controlled much less by the autonomic nerves. Sympathetic stimulation has a direct eﬀect on most alimentary gland cells to cause formation of a concentrated secretion that contains high percentages of enzymes and mucus. However, it also causes vasoconstriction of the blood vessels that supply the glands and in this way sometimes reduces their rates of secretion. The sweat glands secrete large quantities of sweat when the sympathetic nerves are stimulated, but no eﬀect is caused by stimulating the parasympathetic nerves. However, the sympathetic fibers to most sweat glands are cholinergic (except for a few adrenergic fibers to the palms and soles), in contrast to almost all other sympathetic fibers, which are adrenergic. Furthermore, the sweat glands are stimulated primarily by centers in the hypothalamus that are usually considered to be parasympathetic centers. Therefore, sweating could be called a parasympathetic function, even though it is controlled by nerve fibers that anatomically are distributed through the sympathetic nervous system. The apocrine glands in the axillae secrete a thick, odoriferous secretion as a result of sympathetic stimulation, but they do not respond to parasympathetic stimulation. This secretion actually functions as a lubricant to allow easy sliding motion of the inside surfaces under the shoulder joint. The apocrine glands, despite their close embryological relation to sweat glands, are activated by adrenergic fibers rather than by cholinergic fibers and are also controlled by the sympathetic centers of the central nervous system rather than by the parasympathetic centers.

3. Intramural Nerve Plexus of the Gastrointestinal System. The gastrointestinal system has its own intrinsic set of nerves known as the intramural plexus or the intestinal enteric nervous system, located in the walls of the gut. Also, both parasympathetic and sympathetic stimulation originating in the brain can aﬀect gastrointestinal activity mainly by increasing or decreasing specific actions in the gastrointestinal intramural plexus. Parasympathetic stimulation, in general, increases the overall degree of activity of the gastrointestinal tract by promoting peristalsis and relaxing the sphincters, thus allowing rapid propulsion of contents along the tract. This propulsive eﬀect is associated with simultaneous increases in rates of secretion by many of the gastrointestinal glands, described earlier. Normal motility functions of the gastrointestinal tract are not very dependent on sympathetic stimulation. However, strong sympathetic stimulation inhibits peristalsis and increases the tone of the sphincters. The net result is greatly slowed propulsion of food through the tract and sometimes decreased secretion as well—even to the extent of sometimes causing constipation.

4. Heart. In general, sympathetic stimulation increases the overall activity of the heart. This eﬀect is accomplished by increasing both the rate and force of heart contraction. Parasympathetic stimulation causes mainly opposite eﬀects—decreased heart rate and strength of contraction. To express these eﬀects in another way, sympathetic stimulation increases the eﬀectiveness of the heart as a pump, as required during heavy exercise, whereas parasympathetic stimulation decreases heart pumping, allowing the heart to rest between bouts of strenuous activity.

5. Systemic Blood Vessels. Most systemic blood vessels, especially those of the abdominal viscera and skin of the limbs, are constricted by sympathetic stimulation. Parasympathetic stimulation has almost no eﬀects on most blood vessels. Under some conditions, the beta function of the sympathetics causes vascular dilation instead of the usual sympathetic vascular constriction, but this dilation occurs rarely except after drugs have paralyzed the sympathetic alpha vasoconstrictor eﬀects, which, in most blood vessels, are usually far dominant over the beta eﬀects.

6. Effect of Sympathetic and Parasympathetic Stimulation on Arterial Pressure. The arterial pressure is determined by two factors: propulsion of blood by the heart and resistance to ﬂow of blood through the peripheral blood vessels. Sympathetic stimulation increases both propulsion by the heart and resistance to ﬂow, which usually causes a marked acute increase in arterial pressure but often very little change in long-term pressure unless the sympathetics also stimulate the kidneys to retain salt and water at the same time. Conversely, moderate parasympathetic stimulation via the vagal nerves decreases pumping by the heart but has virtually no eﬀect on vascular peripheral resistance. Therefore, the usual eﬀect is a slight decrease in arterial pressure. However, very strong vagal parasympathetic stimulation can almost stop or occasionally actually stop the heart entirely for a few seconds and cause temporary loss of all or most arterial pressure.

7. Effects of Sympathetic and Parasympathetic Stimulation on Other Functions of the Body. Because of the great importance of the sympathetic and parasympathetic control systems, they are discussed many times in this text in relation to multiple body functions. In general, most of the entodermal structures, such as the ducts of the liver, gallbladder, ureter, urinary bladder, and bronchi, are inhibited by sympathetic stimulation but excited by parasympathetic stimulation. Sympathetic stimulation also has multiple metabolic eﬀects such as release of glucose from the liver and an increase in blood glucose concentration, glycogenolysis in both liver and muscle, skeletal muscle strength, basal metabolic rate, and mental activity. Finally, the sympathetics and parasympathetics are involved in execution of the male and female sexual acts. Penile erection is mediated by parasympathetic nervous system while ejaculation is mediated by sympathetic nervous system.

Comparison of the Autonomic and the Somatic Nervous System (see Table)