The Autonomic Nervous System and the Adrenal Medulla

The autonomic nervous system is the portion of the nervous system that controls most visceral functions of the body . This system helps to control arterial pressure, gastrointestinal motility, gastrointestinal secretion, urinary bladder emptying, sweating, body temperature, and many other activities. Some of these activities are controlled almost entirely and some only partially by the autonomic nervous system.

One of the most striking characteristics of the autonomic nervous system is the rapidity and intensity with which it can change visceral functions. For example, within 3 to 5 seconds, it can increase the heart rate to twice normal, and within 10 to 15 seconds the arterial pressure can be doubled. At the other extreme, the arterial pressure can be decreased low enough within 10 to 15 seconds to cause fainting. Sweating can begin within seconds, and the urinary bladder may empty involuntarily, also within seconds.

General Organization of the Autonomic Nervous System

The autonomic nervous system is activated mainly by centers located in the spinal cord, brain stem, and hypothalamus. In addition, portions of the cerebral cortex, especially of the limbic cortex, can transmit signals to the lower centers and in this way can influence autonomic control.

The autonomic nervous system also often operates through visceral reflexes. That is, subconscious sensory signals from visceral organs can enter the autonomic ganglia, the brain stem, or the hypothalamus and then return subconscious reflex responses directly back to the visceral organs to control their activities.

The efferent autonomic signals are transmitted to the various organs of the body through two major subdivisions called the sympathetic nervous system and the parasympathetic nervous system, the characteristics and functions of which are described in the following sections.

Physiologic Anatomy of the Sympathetic Nervous System

Figure 61-1 shows the general organization of the peripheral portions of the sympathetic nervous system. Shown specifically in the figure are (1) one of the two paravertebral sympathetic chains of ganglia that are interconnected with the spinal nerves on the side of the vertebral column, (2) prevertebral ganglia (the celiac, superior mesenteric, aorticorenal, inferior mesenteric, and hypogastric ), and (3) nerves extending from the ganglia to the different internal organs.

Figure 61-1, Sympathetic nervous system. The black lines represent postganglionic fibers, and the red lines show preganglionic fibers.

The sympathetic nerve fibers originate in the spinal cord along with spinal nerves between cord segments T1 and L2 and pass first into the sympathetic chain and then to the tissues and organs that are stimulated by the sympathetic nerves.

Preganglionic and Postganglionic Sympathetic Neurons

The sympathetic nerves are different from skeletal motor nerves in the following way. Each sympathetic pathway from the cord to the stimulated tissue is composed of two neurons, a preganglionic neuron and a postganglionic neuron, in contrast to only a single neuron in the skeletal motor pathway. The cell body of each preganglionic neuron lies in the intermediolateral horn of the spinal cord; its fiber passes through a ventral root of the cord into the corresponding spinal nerve, as shown in Figure 61-2 .

Figure 61-2, Nerve connections among the spinal cord, spinal nerves, sympathetic chain, and peripheral sympathetic nerves.

Immediately after the spinal nerve leaves the spinal canal, the preganglionic sympathetic fibers leave the spinal nerve and pass through a white ramus into one of the ganglia of the sympathetic chain. The fibers then can take one of the following three courses: (1) they can synapse with postganglionic sympathetic neurons in the ganglion that they enter; (2) they can pass upward or downward in the chain and synapse in one of the other ganglia of the chain; or (3) they can pass for variable distances through the chain and then through one of the sympathetic nerves radiating outward from the chain, finally synapsing in a peripheral sympathetic ganglion.

The postganglionic sympathetic neuron thus originates either in one of the sympathetic chain ganglia or in one of the peripheral sympathetic ganglia. From either of these two sources, the postganglionic fibers then travel to their destinations in the various organs.

Sympathetic Nerve Fibers in the Skeletal Nerves

Some of the postganglionic fibers pass back from the sympathetic chain into the spinal nerves through gray rami at all levels of the cord, as shown in Figure 61-2 . These sympathetic fibers are all very small type C fibers, and they extend to all parts of the body via the skeletal nerves. They control the blood vessels, sweat glands, and piloerector muscles of the hairs. About 8% of the fibers in the average skeletal nerve are sympathetic fibers, indicating their great importance.

Segmental Distribution of the Sympathetic Nerve Fibers

The sympathetic pathways that originate in the different segments of the spinal cord are not necessarily distributed to the same part of the body as the somatic spinal nerve fibers from the same segments. Instead, the sympathetic fibers from cord segment T1 generally pass as follows: (1) up the sympathetic chain to terminate in the head; (2) from T2 to terminate in the neck; (3) from T3, T4, T5, and T6 into the thorax; (4) from T7, T8, T9, T10, and T11 into the abdomen; and (5) from T12, L1, and L2 into the legs. This distribution is only approximate and overlaps greatly.

The distribution of sympathetic nerves to each organ is determined partly by the locus in the embryo from which the organ originated. For example, the heart receives many sympathetic nerve fibers from the neck portion of the sympathetic chain because the heart originated in the neck of the embryo before translocating into the thorax. Likewise, the abdominal organs receive most of their sympathetic innervation from the lower thoracic spinal cord segments because most of the primitive gut originated in this area.

Special Sympathetic Nerve Endings in the Adrenal Medullae

Preganglionic sympathetic nerve fibers pass, without synapsing, all the way from the intermediolateral horn cells of the spinal cord, through the sympathetic chains, then through the splanchnic nerves, and finally into the two adrenal medullae. There they end directly on modified neuronal cells that secrete epinephrine and norepinephrine into the blood stream. These secretory cells embryologically are derived from nervous tissue and are actually postganglionic neurons; indeed, they even have rudimentary nerve fibers, and it is the endings of these fibers that secrete the adrenal hormones epinephrine and norepinephrine.

Physiological Anatomy of the Parasympathetic Nervous System

The parasympathetic nervous system is shown in Figure 61-3 , which demonstrates that parasympathetic fibers leave the central nervous system through cranial nerves III, VII, IX, and X; additional parasympathetic fibers leave the lowermost part of the spinal cord through the second and third sacral spinal nerves and occasionally the first and fourth sacral nerves. About 75% of all parasympathetic nerve fibers are in the vagus nerves (cranial nerve X), passing to the entire thoracic and abdominal regions of the body. The vagus nerves supply parasympathetic nerves to the heart, lungs, esophagus, stomach, entire small intestine, proximal half of the colon, liver, gallbladder, pancreas, kidneys, and upper portions of the ureters.

Figure 61-3, The parasympathetic nervous system. The blue lines represent preganglionic fibers and the black lines show postganglionic fibers.

Parasympathetic fibers in the third cranial nerve go to the pupillary sphincter and ciliary muscle of the eye. Fibers from the seventh cranial nerve pass to the lacrimal, nasal, and submandibular glands, and fibers from the ninth cranial nerve go to the parotid gland.

The sacral parasympathetic fibers are in the pelvic nerves, which pass through the spinal nerve sacral plexus on each side of the cord at the S2 and S3 levels. These fibers then distribute to the descending colon, rectum, urinary bladder, and lower portions of the ureters. Also, this sacral group of parasympathetics supplies nerve signals to the external genitalia to cause erection.

Preganglionic and Postganglionic Parasympathetic Neurons

The parasympathetic system, like the sympathetic system, has both preganglionic and postganglionic neurons. However, except in the case of a few cranial parasympathetic nerves, the preganglionic fibers pass uninterrupted all the way to the organ that is to be controlled. The postganglionic neurons are located in the wall of the organ . The preganglionic fibers synapse with these neurons, and extremely short postganglionic fibers, a fraction of a millimeter to several centimeters in length, leave the neurons to innervate the tissues of the organ. This location of the parasympathetic postganglionic neurons in the visceral organ is quite different from the arrangement of the sympathetic ganglia because the cell bodies of the sympathetic postganglionic neurons are almost always located in the ganglia of the sympathetic chain or in various other discrete ganglia in the abdomen, rather than in the excited organ.

Basic Characteristics of Sympathetic and Parasympathetic Function

Cholinergic and Adrenergic Fibers—Secretion of Acetylcholine or Norepinephrine

The sympathetic and parasympathetic nerve fibers secrete mainly one or the other of two synaptic transmitter substances, acetylcholine or norepinephrine. The fibers that secrete acetylcholine are said to be cholinergic. Those that secrete norepinephrine are said to be adrenergic, a term derived from adrenalin, which is an alternate name for epinephrine.

All preganglionic neurons are cholinergic in both the sympathetic and the parasympathetic nervous systems ( Figure 61-4 ). Acetylcholine or acetylcholine-like substances, when applied to the ganglia, will excite both sympathetic and parasympathetic postganglionic neurons. Either all or almost all of the postganglionic neurons of the parasympathetic system are also cholinergic . In contrast, most of the postganglionic sympathetic neurons are adrenergic . However, the postganglionic sympathetic nerve fibers to the sweat glands and perhaps to a very few blood vessels are cholinergic.

Figure 61-4, Preganglionic sympathetic and parasympathetic axons are both lightly myelinated, and both use acetylcholine (Ach) as the neurotransmitter. Postganglionic axons are unmyelinated. Most sympathetic postganglionic axons store norepinephrine (NE) in their varicosities and release this neurotransmitter over the surface of the target tissue. Postganglionic parasympathetic axons store Ach in varicosities and release Ach onto the target tissue surface.

Thus, the terminal nerve endings of the parasympathetic system all or virtually all secrete acetylcholine. Almost all of the sympathetic nerve endings secrete norepinephrine, but a few secrete acetylcholine. These neurotransmitters in turn act on the different organs to cause respective parasympathetic or sympathetic effects. Therefore, acetylcholine is called a parasympathetic transmitter and norepinephrine is called a sympathetic transmitter.

The molecular structures of acetylcholine and norepinephrine are as follows:

Mechanisms of Transmitter Secretion and Removal at Postganglionic Endings

Secretion of Acetylcholine and Norepinephrine by Postganglionic Nerve Endings

A few of the postganglionic autonomic nerve endings, especially those of the parasympathetic nerves, are similar to but much smaller than those of the skeletal neuromuscular junction. However, many of the parasympathetic nerve fibers and almost all the sympathetic fibers merely touch the effector cells of the organs that they innervate as they pass by, or in some cases, they terminate in connective tissue located adjacent to the cells that are to be stimulated. Where these filaments touch or pass over or near the cells to be stimulated, they usually have bulbous enlargements called varicosities (see Figure 61-4 ). It is in these varicosities that the transmitter vesicles of acetylcholine or norepinephrine are synthesized and stored. Also in the varicosities are large numbers of mitochondria that supply adenosine triphosphate, which is required to energize acetylcholine or norepinephrine synthesis.

When an action potential spreads over the terminal fibers, the depolarization process increases the permeability of the fiber membrane to calcium ions, allowing these ions to diffuse into the nerve terminals or nerve varicosities. The calcium ions in turn cause the terminals or varicosities to empty their contents to the exterior. Thus, the transmitter substance is secreted.

Synthesis of Acetylcholine, Its Destruction After Secretion, and Its Duration of Action

Acetylcholine is synthesized in the terminal endings and varicosities of the cholinergic nerve fibers, where it is stored in vesicles in highly concentrated form until it is released. The basic chemical reaction of this synthesis is the following (CoA = coenzyme A):

Acetyl - CoA + Choline - \overset{Choline acetyltransfer}{\to} acetylcholine

$Acetyl - CoA + Choline - \overset{Choline acetyltransfer}{\to} acetylcholine$

Once acetylcholine is secreted into a tissue by a cholinergic nerve ending, it persists in the tissue for a few seconds while it performs its nerve signal transmitter function. Then it is split into an acetate ion and choline, catalyzed by the enzyme acetylcholinesterase, which is bound with collagen and glycosaminoglycans in the local connective tissue. This mechanism is the same as that for acetylcholine signal transmission and subsequent acetylcholine destruction that occurs at the neuromuscular junctions of skeletal nerve fibers. The choline that is formed is then transported back into the terminal nerve ending, where it is used again and again for synthesis of new acetylcholine.

Synthesis of Norepinephrine, Its Removal, and Its Duration of Action

Synthesis of norepinephrine begins in the axoplasm of the terminal nerve endings of adrenergic nerve fibers but is completed inside the secretory vesicles. The basic steps are the following:

Tyrosine \overset{Hydroxylation}{\to} Dopa

$Tyrosine \overset{Hydroxylation}{\to} Dopa$

Dopa \overset{Decarboxylation}{\to} Dopamine

$Dopa \overset{Decarboxylation}{\to} Dopamine$

3.
Transport of dopamine into the vesicles

Dopamine \overset{Hydroxylation}{\to} Norepinephrine

$Dopamine \overset{Hydroxylation}{\to} Norepinephrine$

In the adrenal medulla, this reaction goes still one step further to transform about 80% of the norepinephrine into epinephrine, as follows:

Norapinephrine \overset{Methylation}{\to} Epinephrine

$Norapinephrine \overset{Methylation}{\to} Epinephrine$

After secretion of norepinephrine by the terminal nerve endings, it is removed from the secretory site in three ways: (1) reuptake into the adrenergic nerve endings by an active transport process, accounting for removal of 50% to 80% of the secreted norepinephrine; (2) diffusion away from the nerve endings into the surrounding body fluids and then into the blood, accounting for removal of most of the remaining norepinephrine; and (3) destruction of small amounts by tissue enzymes. One of these enzymes is monoamine oxidase, which is found in the nerve endings, and another is catechol-O-methyl transferase, which is present diffusely in the tissues.

Ordinarily, the norepinephrine secreted directly into a tissue remains active for only a few seconds, demonstrating that its reuptake and diffusion away from the tissue are rapid. However, the norepinephrine and epinephrine secreted into the blood by the adrenal medullae remain active until they diffuse into some tissue, where they can be destroyed by catechol- O -methyl transferase; this action occurs mainly in the liver. Therefore, when secreted into the blood, both norepinephrine and epinephrine remain active for 10 to 30 seconds, but their activity declines to extinction over 1 minute to several minutes.

Receptors on the Effector Organs

Before acetylcholine, norepinephrine, or epinephrine secreted at an autonomic nerve ending can stimulate an effector organ, it must first bind with specific receptors on the effector cells. The receptor is on the outside of the cell membrane, bound as a prosthetic group to a protein molecule that penetrates all the way through the cell membrane. Binding of the transmitter substance with the receptor causes a conformational change in the structure of the protein molecule. In turn, the altered protein molecule excites or inhibits the cell, most often by (1) causing a change in cell membrane permeability to one or more ions or (2) activating or inactivating an enzyme attached to the other end of the receptor protein, where it protrudes into the interior of the cell.

Excitation or Inhibition of the Effector Cell by Changing Its Membrane Permeability

Because the receptor protein is an integral part of the cell membrane, a conformational change in structure of the receptor protein often opens or closes an ion channel through the interstices of the protein molecule, thus altering the permeability of the cell membrane to various ions. For example, sodium and/or calcium ion channels frequently become opened and allow rapid influx of the respective ions into the cell, usually depolarizing the cell membrane and exciting the cell. At other times, potassium channels are opened, allowing potassium ions to diffuse out of the cell, which usually inhibits the cell because loss of electropositive potassium ions creates hypernegativity inside the cell. In some cells, the changed intracellular ion environment will cause an internal cell action, such as a direct effect of calcium ions to promote smooth muscle contraction.

Receptor Action by Altering Intracellular “Second Messenger” Enzymes

Another way a receptor often functions is to activate or inactivate an enzyme (or other intracellular chemical) inside the cell. The enzyme often is attached to the receptor protein where the receptor protrudes into the interior of the cell. For example, binding of norepinephrine with its receptor on the outside of many cells increases the activity of the enzyme adenylyl cyclase on the inside of the cell, which causes formation of cyclic adenosine monophosphate (cAMP). The cAMP in turn can initiate any one of many different intracellular actions, with the exact effect depending on the specific effector cell and its chemical machinery.

It is easy to understand how an autonomic transmitter substance can cause inhibition in some organs or excitation in others. This is usually determined by the nature of the receptor protein in the cell membrane and the effect of receptor binding on its conformational state. In each organ, the resulting effects are likely to be different from those in other organs.

Two Principal Types of Acetylcholine Receptors—Muscarinic and Nicotinic Receptors

Acetylcholine activates mainly two types of receptors, which are called muscarinic and nicotinic receptors. The reason for these names is that muscarine, a poison from toadstools, activates only muscarinic receptors and will not activate nicotinic receptors, whereas nicotine activates only nicotinic receptors. Acetylcholine activates both of them.

Muscarinic receptors, which use G proteins as their signaling mechanism, are found on all effector cells that are stimulated by the postganglionic cholinergic neurons of either the parasympathetic nervous system or the sympathetic system.

Nicotinic receptors are ligand-gated ion channels found in autonomic ganglia at the synapses between the preganglionic and postganglionic neurons of both the sympathetic and parasympathetic systems. (Nicotinic receptors are also present at many nonautonomic nerve endings—for example, at the neuromuscular junctions in skeletal muscle, discussed in Chapter 7 .)

An understanding of the two types of receptors is especially important because specific drugs are frequently used as medicine to stimulate or block one or the other of the two types of receptors.

Alpha and Beta Adrenergic Receptors

Two major classes of adrenergic receptors also exist; they are called alpha receptors and beta receptors. There are two major types of alpha receptors, alpha ₁ and alpha ₂ , which are linked to different G proteins. The beta receptors are divided into beta ₁ , beta ₂ , and beta ₃ receptors because certain chemicals affect only certain beta receptors. The beta receptors also use G proteins for signaling.

Norepinephrine and epinephrine, both of which are secreted into the blood by the adrenal medulla, have slightly different effects in exciting the alpha and beta receptors. Norepinephrine excites mainly alpha receptors but excites the beta receptors to a lesser extent as well. Epinephrine excites both types of receptors approximately equally. Therefore, the relative effects of norepinephrine and epinephrine on different effector organs are determined by the types of receptors in the organs. If they are all beta receptors, epinephrine will be the more effective excitant.

Table 61-1 lists the distribution of alpha and beta receptors in some of the organs and systems controlled by the sympathetic nerves. Note that certain alpha functions are excitatory, whereas others are inhibitory. Likewise, certain beta functions are excitatory and others are inhibitory. Therefore, alpha and beta receptors are not necessarily associated with excitation or inhibition but simply with the affinity of the hormone for the receptors in the given effector organ.

Table 61-1

Adrenergic Receptors and Function

Alpha Receptor	Beta Receptor
Vasoconstriction	Vasodilation (β ₂ )
Iris dilation	Cardioacceleration (β ₁ )
Intestinal relaxation	Increased myocardial strength (β ₁ )
Intestinal sphincter contraction	Intestinal relaxation (β ₂ ) Uterus relaxation (β ₂ )
Pilomotor contraction	Bronchodilation (β ₂ )
Bladder sphincter contraction	Calorigenesis (β ₂ )
Inhibits neurotransmitter release (α ₂ )	Glycogenolysis (β ₂ ) Lipolysis (β ₁ ) Bladder wall relaxation (β ₂ ) Thermogenesis (β ₃ )

As discussed later in the chapter, several sympathomimetic drugs have been developed that mimic the actions of the endogenous catecholamines, norepinephrine and epinephrine. Some of these compounds selectively activate alpha or beta adrenergic receptors. For example, a synthetic drug chemically similar to epinephrine and norepinephrine, isoprenaline (isoproterenol), has an extremely strong action on beta receptors but essentially no action on alpha receptors.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here