Autonomic Nervous System Author: Dr. T. Hoekman The autonomic nervous system (ANS) derives it's name from the fact that it operates quite nicely without the regulatory influence of the cerebral cortex, and in fact many of its functions will continue even when the spinal cord is disconnected from the higher centers in the brain. Hence it is "autonomous". With that "warm fuzzy" description of the nature of its function, what are the "gory details"? This subdivision of the nervous system deals with a set of afferent and efferent nerves which operate through a set of neural integration circuits to regulate activity in glands, smooth muscle, and the heart. With my usual disclaimer of anatomic illiteracy, I will use only a very functional emphasis, with a schematic approach to the anatomic issues. The higher centers for integration and control are located in the hypothalamus. This is a region of the brain, located in the brainstem, a region that is involved in a variety of "unconscious" processing operations which are out of the domain of the volitional control processes originating in the cerebral cortex. The nature of the integration of sensory inputs and resulting efferent outputs to tissues and organs is beginning to be understood, but is beyond the scope of our discussion in this course. A useful way to view the system, is as a "black box" with regulatory responses. We can look at the sensory inputs, and the efferent outputs, but in most cases not understand the mechanics of what happens in the box.

The part of the ANS which is best understood, is part of the "peripheral nervous system". This consists of parts of the nervous system with their terminal processes outside the Central Nervous System (CNS). The CNS is

defined to include the brain and spinal cord. The peripheral nervous system thus includes the peripheral part of the ANS, and the somatic nervous system, in which the afferent and efferent nerves are related to control of skeletal muscle. The peripheral ANS has two subdivisions, the Sympathetic and Parasympathetic Nervous Systems which are involved in the regulation of glands, smooth muscle and heart. These systems are defined in relation to both their anatomy and the neuro-transmitters they utilize. Both systems are organized with a neuron whose cell body is within the CNS, which emerges to form a synapse outside the CNS in a peripheral ganglion (pre-ganglionic neuron). A ganglion is a cluster of nerve cell bodies with the terminal processes of neurons from outside the ganglion entering to form synapses. There may also be lateral connectivity and possibly "interneurons" to provide the capacity for simple integrative functions. The output of the ganglion are "post-ganglionic neurons", which emerge to form connections to end organs or tissues.

Sympathetic Nervous System (SNS) The pre-ganglionic Sympathetic nerve tracts emerge from the CNS through the paravertebral ganglion chain. This is a symmetrical set of ganglia on either side of the spinal cord through which the efferent sympathetic nerves pass, and in which the pre- to post ganglionic synapse is located. The neurotransmitter in the ganglionic synapse is acetylcholine (ACh), and the neurotransmitter at the end organ can be one of several compounds. The sympathetic nervous system is sometimes called the Adrenergic Nervous System, which is a consequence of the early identification of adrenaline and nor-adrenaline as neurotransmitter which it released. We now understand that in addition to these compounds and some chemically related materials (serotonin, and dopamine), there are a number of neuropeptides and other substances such as histamines and purines which are also released by neurons of the sympathetic nervous system. As compared to the neuromuscular junction of skeletal muscle, the final efferent connection is rather diffuse. The preganglionic neuron is short and the post-ganglionic neuron is long with relatively focused innervation of the effector organ. In most instances the nerve ending releases transmitter to large groups of post synaptic cells. The sympathetic nerves innervate almost all of the organs in the viscera: heart, blood vessels, glands, and smooth muscle, as do the parasympathetic nerves. In some organs one or the other may be predominant, most are roughly balanced, and in a few sites only one side of the ANS provides input.

Parasympathetic Nervous System (PNS) Whereas the nerves of the SNS emanate from the spinal cord along almost its entire length, the outflow in the PNS is restricted to the cranial nerves (e.g. nerves which emerge directly from the brain) and from the spinal cord near its end in the sacral region. More specifically, it is found in cranial

nerves 3, 7, 9, and 10 as well as in sacral spinal segments 2,3,4, and 5. The nerve trunk formed by the neurons emerging from the 10th cranial nerve is known as the vagus (Latin for wanderer), it has a bilateral pair of vagii that course down from the head parallel to the carotid arteries, and "visit" most of the tissues and organs in the chest and abdomen. The nerves emerging from the sacral segments connect to the large intestine, bladder, and genital organs. This is separate from the vagus. The nerves of the PNS have a long pre-ganglionic neuron, and a very short post-ganglionic neuron. In general the ganglion occurs virtually on the surface of the end organ. The ganglionic synapse also uses ACh as its neurotransmitter. The receptors in ganglion are very similar in both sympathetic and parasympathetic systems, responding very similarly to drugs which interact with them. The post-ganglionic synapse in the PNS also releases ACh, but the post-synaptic receptor is quite different from the receptor in the ganglion.

Parasympathetic Neurotransmitters Acetylcholine Acetylcholine is the neurotransmitter which is used at Neuromuscular Junction (NMJ) of the somatic nervous system, the ganglionic synapse, and the end organ synapse of the PNS. These constitute 3 distinct classes of postsynaptic receptors with distinctive physiologic and pharmacologic properties. The unifying property is the chemistry of ACh, its synthesis and disposition at the various sites. In all three of these synapses ACh is synthesized presynaptically from its precursors choline and acetate mediated by the action of the enzyme choline acetyl tranferase. The ACh is then sequestered in membrane vesicles in the nerve terminal. When the nerve terminal is invaded by a propagated action potential, an influx of Ca++ ions causes many of these vesicles to fuse with the terminal membrane, and open to the extracellular space, releasing their contents into the synaptic cleft. The ACh diffuses across this narrow gap 200-300 A and attaches to a post-synaptic receptor. When this occurs the membrane permeability to all ions is dramatically increased in the local region of the synapse and the membrane potential which is normally about -90 mV, depolarizes toward 0 mV, and initiates an action

potential or produces a local response in the effector organ e.g. muscle contraction or glandular secretion. This effectively activates the post-synaptic cell(s), but in most instances a useful response is a brief period of activity with a return to the resting or baseline state, so there must be a means for quickly terminating the receptor activation. This occurs with ACh by two mechanisms: 1.Diffusion: The release of ACh is a brief event limited by the duration of the presynaptic action potential, and the high concentration of ACh rapidly diffuses away from the synaptic cleft. This reduces the number of receptors activated, because receptor attachment behaves with a simple Mass Action relationship. The final result is a restoration of membrane state to the pre-stimulated state. 2.Enzymatic Breakdown: The "passive" inactivation is further facilitated by the presence of a post-synaptically localized enzyme, Acetylcholinesterase (AchE), which rapidly hydrolyzes the ACh to its constituent parts acetate and choline. Acetate has no capacity to activate the receptor, and while choline activates some ACh receptors, is at least 1000-fold less effective than ACh. The synaptic enzyme is highly specific to ACh, but there is another non-specific cholinesterase which is has limited distribution in the synapse but has very high concentrations in the plasma. This enzyme will hydrolyze a wide variety of "esters" including ACh as it diffuses away from the synaptic cleft, thus blood levels of ACh usually remain very low.

This represents the scheme for synthesis, release and inactivation of ACh which is an accurate description of events at skeletal muscle (somatic nervous system) ganglionic synapses and many parasympathetic effector organ synapses. ACh release at the neuromuscular junction, probably the best characterized synapse in the body, is excitatory. This does not mean all ACh synapses are excitatory. In fact looking at the autonomic nervous system, depending on tissue and site, any of the major neurotransmitters can shift its role between "excitation" and "inhibition". The final activity is determined by the process which is coupled to the receptor.

This is illustrated by an example of PNS end organ response at the sinoatrial node of the heart, where ACh release acts as a modulator of the primary pacemaker potential. In this specialized bit of tissue in the right atrium, a spontaneous periodic depolarization occurs, to set the rate of the heart-beat. If you insert a microelectrode into a cell of the S-A node, you will see a pattern like that in the next illustration. As you will note, after each action potential repolarizes, the membrane potential does not remain constant, but begins to creep back upward toward the threshold. When it reaches threshold, another action potential is initiated. These three records are taken from different cells in the atrium, the first is called the primary pacemaker, because it is the cell whose depolarization triggers the action potential which spreads through all the other cells of the heart it has the fastest rate of depolarization. The second trace is from a secondary pacemaker, so-called because if the primary pace maker cell is damaged it is the next slowest in rate of depolarization and will take over the pacemaker function for the entire heart. There is a whole series of secondary pacemakers with progressively slower rates of depolarization, located in the A-V node, the Bundle of His, and finally the slowest in the ventricle itself. Most of the non-specialized fibers in the atrium and the ventricle however, are non-pacemaker cells as in the third record, whose resting membrane potential remains very stable between excitation events. What then is going on in the pacemaker cell to produce this slow depolarization? It appears that these cells are very leaky with respect to sodium during the resting phase, and have a relatively low conductance for potassium, thus they depolarized. The rate of depolarization has been shown to depend on the ratio between the gK and gCa/gNa. Thus, as Calcium-sodium permeability is increased rate of depolarization and heart rate is increased, as potassium permeability is increased, rate of depolarization and heart rate decrease. The SA node is innervated by both cholinergic and adrenergic nerve endings, and we

will see in the section on the sympathetic nervous system how its action is complementary to that of ACh in regulating the activity of the S-A node. If cholinergic nerves (vagus) are stimulated, it results in a decrease in pacemaker rate, which is directly related to hyperpolarization of the interspike RMP and a decrease in the rate of pacemaker depolarization. This is the influence of acetylcholine on the S-A node, but at the neuromuscular junction, ganglionic synapse, and other end organs in the autonomic nervous system, it acts as an excitatory transmitter with a postsynaptic depolarization response. Quite separately from the excitatory or inhibitory properties of a synapse, the ACh receptor at the site can be classified into two broad categories according to subtle differences in their functional characteristics. Hence we speak of a synapse which has Nicotinic or Muscarinic ACh receptors. This are pharmacologic distinctions based upon their characteristic response to certain drugs.

Nicotinic Receptors Historically, the nicotinic receptor response was first characterized by the British physiologist Langely. He noted that when certain synapses were exposed to nicotine, that at low concentrations it stimulated activity and at higher concentrations blocked synaptic transmission. These synapses have since been shown to operate using ACh receptors, and are now defined has having Nicotinic ACh receptors. They are found at the NMJ in the somatic nervous system and at the ganglionic synapse of the autonomic nervous system. There are also nicotinic ACh receptors in the central nervous system. Ganglionic Nicotinic receptors can be distinguished from Neuromuscular ganglionic receptors, again by pharmacology. Neuromuscular blockers such as dtubocurare interfere with synaptic transmission in the NMJ, but have little effect at the ganglion. Conversely a ganglionic blocker such as hexamethonium, interferes with transmission at the ganglion, but has a negligible effect at the NMJ. Neither of these set of compounds have significant blocking effect at muscarinic receptors.

Muscarinic Receptors Later experiments examined the compound Muscarine, extracted from the poisonous mushroom Amanita muscaria. This showed a similar response for a second set of ACh receptors, hence they are designated as Muscarinic ACh receptors. These include all the post-ganglionic end organ synapses of the parasympathetic nervous system, and sympathetic end organ synapses at the sweat glands and in some blood vessels in muscle and skin. Muscarinic receptors can be blocked by atropine, but not by d-tubocurarine or hexamethonium at doses where these have their effects at NMJ and ganglionic synapses respectively.