Download CASE 5

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CASE 5
A 12-year-old girl is brought to the emergency room with difficulty in breathing. On examination she is found to have dyspnea with audible wheezes and
is diagnosed with asthma. The patient is given an inhaled medication
(albuterol), which provides immediate relief of the bronchial constrictive
symptoms.
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What autonomic nervous system (ANS) receptor does this
medication target?
What is the mechanism of action when these receptors are
stimulated?
What neurotransmitter normally activates these receptors?
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CASE FILES: PHYSIOLOGY
ANSWERS TO CASE 5: AUTONOMIC NERVOUS SYSTEM
Summary: A 12-year-old girl with an acute asthma exacerbation is given
albuterol, a β-agonist sympathomimetic agent.
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ANS receptor target: β2 receptors.
Mechanism of action: Activation of adenylyl cyclase, increase in cyclic
adenosine monophosphate (cAMP), and relaxation of bronchial smooth
muscle, leading to bronchodilation.
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Neurotransmitter: Norepinephrine (NE).
CLINICAL CORRELATION
A good understanding of the autonomic nervous system is imperative in treating many medical conditions, such as asthma. Different cells throughout the
body have different ANS receptors with differing agonist and antagonist properties, and medications targeting specific receptors can selectively relieve
symptoms in particular organs while minimizing side effects that would be
mediated by other receptors. The sympathetic β2 receptor agonist albuterol
selectively produces bronchial dilation and thus provides relief from bronchial
constrictive disorders such as asthma. However, with some receptors it is not
possible to achieve selective targeting because the same receptor is found in
diverse organs, and many commonly used drugs act on more than one receptor.
For example, propranolol, which is used to treat various cardiac and cardiovascular problems, blocks both β1 and β2 receptors. It would be contraindicated in
patients with asthma because by blocking β2 receptors, it would cause bronchial
constriction and worsening of a patient’s asthma. Many medications have side
effects involving the ANS, but these effects can be predicted if one knows the
distributions of different autonomic receptors in the body.
APPROACH TO AUTONOMIC NERVOUS SYSTEM
Objectives
1.
2.
3.
Know the organization of the autonomic nervous system (ANS).
List the major neurotransmitters of the ANS.
Know the receptor types in the ANS.
Definitions
Parasympathetic nervous system: Division of the autonomic nervous system associated with resting visceral functions (e.g., digestion), defined
anatomically by efferent preganglionic axons exiting the CNS via cranial nerves and sacral spinal nerves S2 to S4.
CLINICAL CASES
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Sympathetic nervous system: Division of the autonomic nervous system
associated with physiological responses to stress, defined anatomically
by efferent preganglionic axons exiting the CNS via thoracic and lumbar spinal nerves T1 to L3.
Enteric nervous system: Division of the autonomic nervous system associated with direct control of gastrointestinal functions, defined anatomically by embedment within the gastrointestinal tract.
DISCUSSION
Bronchial smooth muscle, like most smooth muscle, cardiac muscle, and
glands, is innervated by the ANS. The ANS mediates important homeostatic
and emergency functions in a largely involuntary manner. It has three major
divisions: the sympathetic, parasympathetic, and enteric nervous systems. The sympathetic and parasympathetic divisions have efferent (output)
systems that evoke or modulate contractile, secretory, and metabolic
responses throughout the body. The enteric division is a relatively independent nervous system embedded in the gastrointestinal (GI) tract and contains
sensory neurons, interneurons, and motor neurons. Although the enteric system can function autonomously, its activity usually is modulated by the sympathetic and parasympathetic systems. The ANS also has central integrative
components in the hypothalamus and brainstem autonomic nuclei that
receive input from visceral and somatic afferents as well as from more rostral brain regions.
In the sympathetic and parasympathetic systems, the final efferent
pathway consists of central preganglionic neurons, which synapse onto
peripheral postganglionic neurons, which then synapse onto effector cells
in target organs. In the sympathetic system, the preganglionic cell bodies
are in the intermediolateral column of the spinal cord between levels T1
and L3 (thoracolumbar). The postganglionic cell bodies are in either the
nearby paravertebral ganglia or the more distant prevertebral ganglia. Each
preganglionic sympathetic fiber synapses with many postganglionic neurons across several ganglia, often producing widespread effects. Sympathetic
postganglionic neurons usually send very long axons to effector targets. In
the parasympathetic system, the preganglionic cell bodies reside in
nuclei of the medulla, pons, midbrain, and spinal segments S2 through
S4 (craniosacral) and send long axons to synapse with relatively few postganglionic neurons in terminal ganglia, which are close to or embedded in
the walls of their target organs. Sympathetic and parasympathetic systems usually have opposite effects on visceral targets. Massive activation
of the sympathetic system enhances the capacity for immediate physical
activity (eg, exercise and fight or flight responses) and enables adaptive
responses to physiologic emergencies such as hemorrhage, whereas more
localized activation mediates discrete homeostatic reflexes. Parasympathetic
activity enhances the functions of organs active during quiescent states
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CASE FILES: PHYSIOLOGY
(rest and digest functions) and often mediates actions opposite to those of
the sympathetic system in homeostatic reflexes (eg, baroreceptor reflex,
pupillary reflex).
All preganglionic fibers (sympathetic and parasympathetic) release acetylcholine (ACh) at synapses in autonomic ganglia; the ACh binds to nicotinic
receptors and excites postganglionic neurons. Nearly all sympathetic postganglionic neurons release NE onto effector targets. The major exceptions are the
Table 5-1
ACTIONS MEDIATED BY AUTONOMIC RECEPTORS IN SELECTED
EFFECTOR SYSTEMS*
SYMPATHETIC
ACTIVITY
PARASYMPATHETIC
ACTIVITY
EFFECTOR
ACTION
RECEPTOR
ACTION
RECEPTOR
Heart
Sinoatrial node
Contractility
Tachycardia
Increase
β1, β2
β1, β2
Bradycardia
Decrease
(atria)
M
M
Blood vessels
Skin, viscera
Skeletal muscle
Constriction
Dilation
α1, α2
β2
Secretion,
general
Secretion,
palms
M
Bronchial muscle
Relaxation
β2
Contraction
M
Eye
Radial muscle, iris
Sphincter, iris
Contraction
α1
Contraction
M
Sweat glands
α1
Gastrointestinal tract
Motility
Secretion
Decrease
Decrease
α2, β2
β2
Increase
Increase
M
M
Urinary bladder
Detrusor
Trigone, sphincter
Relaxation
Contraction
β2
α1
Contraction
Relaxation
M
M
Male sex organs
Ejaculation
α1
Erection
M
*
For a more complete list see Katzung (2004).
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sympathetic fibers innervating most sweat glands, which release ACh (binding
to muscarinic receptors), and the cells in the adrenal medulla, which are
homologous with sympathetic postganglionic neurons but release epinephrine
and some NE into the bloodstream. The major classes of receptors for NE and
epinephrine are α1 (important in blood vessels), α2 (often on presynaptic terminals of sympathetic postganglionic axons), β1 (important in the heart), and
β2 (concentrated in bronchial smooth muscle). All parasympathetic postganglionic neurons release ACh, which binds to muscarinic receptors on effector
cells. Autonomic effects are often modulatory and are mediated by second
messengers. Both muscarinic receptors and adrenergic receptors are
metabotropic receptors that often are linked positively or negatively by G proteins to adenylyl cyclase or phospholipase C, which alter cAMP or Ca2+ levels in target cells. Table 5-1 lists some of the important autonomic effectors
and the physiologic actions of each type of autonomic receptor found in them.
COMPREHENSION QUESTIONS
[5.1]
Which of the following is promoted by parasympathetic activity?
A.
B.
C.
D.
E.
[5.2]
Which type of receptor located on sinoatrial (SA) nodal cells mediate
an increase in heart rate?
A.
B.
C.
D.
[5.3]
Airway constriction
Ejaculation
Pupillary dilation
Vasoconstrictor response to hemorrhage
Secretion of sweat
α
β
Muscarinic
Nicotinic
Which of following fibers release NE?
A. Preganglionic fibers innervating the adrenal medulla
B. Postganglionic fibers causing bradycardia
C. Postganglionic fibers causing constriction of the iris
D. Postganglionic fibers causing arteriolar constriction
E. Sympathetic fibers innervating eccrine sweat glands
Answers
[5.1]
A. Parasympathetic fibers release ACh onto muscarinic receptors that
cause contraction of bronchiolar smooth muscle. All the other listed
effects are produced by sympathetic activation.
[5.2]
B. Sympathetic fibers release NE onto β1 and β2 receptors, which activate adenylyl cyclase, increasing the currents that generate the pacemaker
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potential. The other listed receptors are not present in the SA node or
decrease heart rate (muscarinic receptors).
[5.3]
D. Sympathetic fibers release NE onto α1 receptors in arterioles, which
constrict these resistance vessels. The other listed fibers all release
ACh, including sympathetic fibers that innervate eccrine sweat glands.
PHYSIOLOGY PEARLS
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The sympathetic and parasympathetic nervous systems are neural
systems controlled by integrative regions in the brain, whereas
the enteric nervous system has afferent, integrative, and efferent
components that allow it to function autonomously (the term
autonomic comes from Greek words meaning “self-governing”).
Massive activation of the sympathetic nervous system is vital for
preparing for and responding to physiologic emergencies such as
fight or flight situations and hemorrhage.
Activation of more restricted parts of the sympathetic nervous system mediates discrete autonomic reflexes such as the baroreceptor reflex and ejaculation.
The parasympathetic nervous system exerts more localized control
over visceral functions such as digestion, micturition, and many
sexual responses.
ACh is released by all preganglionic fibers (sympathetic or parasympathetic) and binds to ganglionic nicotinic receptors that rapidly
depolarize postganglionic cells.
ACh is released by parasympathetic postganglionic fibers and binds
to muscarinic receptors on effector cells, which often are coupled
through G proteins to phospholipase C (positively) or adenylyl
cyclase (negatively).
NE usually is released by sympathetic postganglionic fibers and can
bind to β1 or β2 receptors which are positively coupled to adenylyl cyclase. NE also can bind to α1 receptors, which are coupled
to phospholipase C, or to α2 receptors, which are negatively coupled to adenylyl cyclase.
REFERENCES
Katzung BG. Introduction to autonomic pharmacology. In: Katzung BG. Basic and
Clinical Pharmacology. New York: McGraw-Hill; 2004: 75-92.
Richerson GB. The autonomic nervous system. In: Boron WF, Boulpaep EL.
Medical Physiology. Philadelphia, PA: Elsevier Science; 2003: 378-398.
Weisbrodt NW. Autonomic nervous system. In: Johnson LR. Essential Medical
Physiology. San Diego, CA: Elsevier Academic Press; 2003: 145-154.