hubio 543 september 20, 2007 neil m. nathanson k-536a, hsb 3-9457 nathanso@u.washington.edu...

HuBio 543September 20, 2007

Neil M. NathansonK-536A, HSB3-9457nathanso@u.washington.edu Introduction to the Autonomic Nervous System (ANS)

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

The Sympathetic Nervous System

Stress can activate the sympathetic nervous system

(Yosefy et al., NEJM, 350, 2315 [2004])

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

FromCNS

ACh NNE

Target

AdR

Most Sympathetic Ganglia:

To Target

Parasympathetic Ganglia:

FromCNS

ACh N To Target

Target

MACh

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

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

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)

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

ACh Decreases the Duration of the Atrial Action Potential

This decreases calcium entry and thus decreases the force of contraction

MembranePotential

Time

Control

+ACh

Positive Chronotropic Effect of Sympathetic Stimulation

Norepinephrine increases the rate of diastolic depolarization

MembranePotential

Time

Control

+NE

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)

Dual Innervation of the Iris

Constriction (Miosis)

Dilation (Mydriasis)

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

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

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)

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

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])

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)

FromCNS

ACh

N

Synaptic Transmission Through a Sympathetic Ganglion:

To Target

M

MainPathway

ModulatoryPathway

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

AChACh

ACh

AChEACh Ch +Ac

ACh

Choline + AcetylCoA

ACh + CoA

CholineAcetyltransferase

Choline

Ca++

Ca ++

AChR

Na+

Nicotinic Ganglionic Antagonists

Effects of nicotinic antagonists at ganglia and NMJ

C6 C10

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

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

Standing

Heart Rate

+ Mecamylamine

Recumbent

BloodPressure

+ Mecamylamine

Effects of Administration of Mecamylamine to Humans

Nicotinic Ganglionic Agonists

* = drug list

*

*

Effect of Ganglionic Stimulants and Blockers

+ Hexamethonium:

+ DMPP

+ DMPP

BP

BP

HR

HR