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HuBio 543September 20, 2007
Neil M. NathansonK-536A, [email protected] Introduction to the Autonomic Nervous System (ANS)
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Skeletal NMJ Autonomic NS
Voluntary Involuntary
Quiescient Spontaneous Activity
Presynaptic receptors
CNS periphery
No presynaptic receptors(at least, none that we will worry about)
CNSganglia periphery
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The Sympathetic Nervous System
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Stress can activate the sympathetic nervous system
(Yosefy et al., NEJM, 350, 2315 [2004])
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Sympathetic vs. Parasympathetic ganglia
• Sympathetic ganglia:– Close to spinal cord
– One preganglionic fiber can innervate many ganglionic neurons
– can innervate many target organs
– Set up for widespread discharge
– Preganglionic fibers originate in the intermediate portion of SC
• Parasympathetic ganglia:– Close to or in target organ– One preganglionic fiber usually
innervates one ganglionic neurons
– Usually innervate one target organ
– Usually don’t have widespread discharge
– Preganglionic fibers originate in the midbrain, medulla, and the sacral portion of SC
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FromCNS
ACh NNE
Target
AdR
Most Sympathetic Ganglia:
To Target
Parasympathetic Ganglia:
FromCNS
ACh N To Target
Target
MACh
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FromCNS
ACh N
Sympathetic Innervation of Chromaffin Cells in Adrenal Medulla:
Into CirculationNE
EPI
FromCNS
ACh N To Target
Target
M
Sympathetic Innervation of Sweat Glands:
ACh
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Ganglia TargetTrans. Rec. Trans. Rec.
Symp. (most) ACh nAChR NE Adren. R
Symp. (sweat ACh nAChR ACh mAChR glands)
Parasymp. ACh nAChR ACh mAChR
Adrenal ACh nAChR Epi. Adren. RMedulla (chromaffin cells) & NE
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ORGAN EFFECTSympathetic Parasympathetic
Heart S–A Node Increased rate Decreased rate Atria Increased contractility Decreased contractility A–V Node Increased conduction
velocityDecreased conductionvelocity
Ventricles Increased contractility (no effect)Eye Iris Mydriasis (dilation) Miosis (constriction) Ciliary muscle Relaxation (for far
vision)Contraction (for nearvision)
LacrimalGlands
(no effect) Secretion
Lungs Bronchial dilation Bronchial constrictionSweat Glands Secretion (no effect)Liver Glycogen breakdown (no effect)GI Tract Inhibition of peristalsis
and secretionStimulation ofperistalsis and secretion
Colon andBladder
Inhibition of peristalsis Contraction
Salivary Glands Some secretion SecretionArterioles(exceptskeletal muscle)
Vasoconstriction (no effect)
Veins Vasoconstriction (no effect)
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Parasympathetic Stimulation Slows the Rate of Diastolic Depolarization in the S-A Node
MembranePotential
Time
Control
+ACh
mAChR increases potassium permeability in S-A node
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ACh Decreases the Duration of the Atrial Action Potential
This decreases calcium entry and thus decreases the force of contraction
MembranePotential
Time
Control
+ACh
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Positive Chronotropic Effect of Sympathetic Stimulation
Norepinephrine increases the rate of diastolic depolarization
MembranePotential
Time
Control
+NE
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Autonomic Effects on Vasculature
• Vasculature essentially only has sympathetic innervation
• Sympathetic stimulation causes constriction of most vasculature
• Sympathetic stimulation (and pharmacological administration of epinephrine) can cause dilation or constriction of skeletal muscle vasculature (due to multiple types of adrenergic receptors)
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Dual Innervation of the Iris
Constriction (Miosis)
Dilation (Mydriasis)
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Dual Innervation of the Ciliary Muscle
Parasympathetic: Contraction of Ciliary Muscle Increased curvature of the lens Accommodation for near vision
Sympathetic: Relaxation of Ciliary Muscle Decreased curvature of the lens Allows far vision
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Predominant Tone
• Predominantly sympathetic tone:– Blood vessels – sweat glands
• Predominantly parasympathetic tone:– Heart– GI and urinary tracts– Salivary glands– Eye
“Sets” the level of activity of a given target organ
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Sympathetic and parasympathetic denervation in humans
Controls Heart Transplant
Transplant, partial sympathetic reinnervation
Resting HR (bpm) 79 89* 90*
Exercise time (min) 10 6*# 8*
Peak HR (bpm) 142 121*# 143
(* diff from cont; # diff from reinnerv)
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Your brain is important… because of the autonomic reflexes
• Baroreceptors (stretch receptors) in the carotid sinus and aortic arch
• Send fibers to the CNS, to regulate activity of the ANS:
– If blood pressure is “too high”:
• decreases sympathetic activity
• increases parasympathetic activity
– If blood pressure is “too low”:
• increases sympathetic activity
• decreases parasympathetic activity
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Indicators of abnormal autonomic function associated with increased mortality:
• Resting Heart Rate > 90 beats/min
• Inability to achieve 85% of predicted maximal HR on treadmill testing
• Abnormal HR recovery (failure to decrease HR≥ 12 bpm during first minute after peak exercise)
• Abnormal HR variability (failure to change HR by ≥10 bpm during 1 minute of slow deep breaths)
(Curtis and O’Keefe, Mayo Clin Proc 77, 45 [2002])
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Pay attention: the ANS is important!Mortality as a function of recovery of heart rate 1 min after exercise:
Beat-to-beat variation in heart during 1 min. of deep breathing:
(heart rate variability)
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FromCNS
ACh
N
Synaptic Transmission Through a Sympathetic Ganglion:
To Target
M
MainPathway
ModulatoryPathway
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Synaptic Transmission in the Sympathetic Ganglia
Main Pathway: ACh acting at (excitatory) nicotinic AChRModulatory Pathway: ACh acting at (excitatory) muscarinic ACh R
Synaptic Transmission in the Parasympathetic Ganglia
Main Pathway: ACh acting at (excitatory) nicotinic AChR
Transmission in the Adrenal Medulla
Main Pathway: ACh acting at (excitatory) nicotinic AChRModulatory Pathway: ACh acting at (excitatory) muscarinic ACh R
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AChACh
ACh
AChEACh Ch +Ac
ACh
Choline + AcetylCoA
ACh + CoA
CholineAcetyltransferase
Choline
Ca++
Ca ++
AChR
Na+
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Nicotinic Ganglionic Antagonists
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Effects of nicotinic antagonists at ganglia and NMJ
C6 C10
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Effects of Ganglionic Blockade
Site Predominant Tone Effect of Blockade
Blood vessels Sympathetic VasodilationSweat Glands Sympathetic AnhidrosisHeart Parasympathetic TachycardiaIris Parasympathetic MydriasisCiliary Muscle Parasympathetic CycloplegiaG-I Tract Parasympathetic tone & motilityUrinary Tract Parasympathetic Urinary RetentionSalivary Glands Parasympathetic Xerostomia
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Therapeutic Uses of Ganglionic Blockers
• Decrease BP in emergency hypertensive crisis• Produce controlled hypotension to decrease blood loss
during surgery• Decrease symptoms of autonomic hyperreflexia
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Standing
Heart Rate
+ Mecamylamine
Recumbent
BloodPressure
+ Mecamylamine
Effects of Administration of Mecamylamine to Humans
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Nicotinic Ganglionic Agonists
* = drug list
*
*
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Effect of Ganglionic Stimulants and Blockers
+ Hexamethonium:
+ DMPP
+ DMPP
BP
BP
HR
HR