Autonomic Nervous System

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Autonomic Nervous System and Hemodynamics Myles
Akabas Dept. of Physiology Biophysics and
Neuroscience
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Two or Three Subdivisions of the Nervous System
?
Innervates
skeletal muscle
smooth muscle cardiac muscle secretory glands
intestine controls intestinal motility
secretion absorption
Neurotransmitter
ACh
norepinephrine ACh neuropeptides
norepinephrine ACh serotonin neuropeptides
Receptors
nicotinic muscle AChR
adrenergic GPCRs muscarinic ACh GPCRs nicotinic
neuronal AChR
GPCRs
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Synaptic Connectivity Voluntary vs Autonomic
Nerves
somatic motor neuron
skeletal muscle
Principles of Neural Science, 3rd Ed. Kandel et
al., p. 762
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Synaptic Transmission in Autonomic Ganglia
Preganglionic neurons release acetylcholine
Postganglionic Cell Receptors 1) Neuronal
nicotinic acetylcholine receptors different
pharmacology from muscle nAChR different subunit
composition 2 ? 3 ? cation-selective
channel 2) Muscarinic (GPCR) receptors
http//www.pasteur.fr/recherche/banques/ LGIC/cys-
loop.html
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Subdivisions of the Autonomic Nervous System
Primary Neurotransmitter
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Focus on this synapse
autonomic ganglion
Cell body in spinal cord
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Subdivisions of the Autonomic Nervous System
Primary Neurotransmitter
norepinephrine epinephrine (20)
acetylcholine
Receptors Second Messenger Systems
Adrenergic GPCRs ?1 IP3/DAG, ?Ca2i ?PKC ?2 -
?cAMP/PKA ?1 - ?cAMP/PKA ?2 - ?cAMP/PKA ?3 -
?cAMP/PKA
Muscarinic GPCRs M1 IP3/DAG, ?Ca2i ?PKC M2
?cAMP/PKA, ?PI(3)K M3 ?cAMP/PKA,
IP3/DAG, ?Ca2i ?PKC M4 M5 IP3/DAG,
?Ca2i ?PKC
Adrenal Medulla (epinorepi8020)
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G-Protein Coupled Receptors
Rockman et al., (2002) Nature 415206-212
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Time Course of Post-Synaptic Potentials nicotini
c AChR muscarinic GPCR peptidergic GPCR
Principles of Neural Science, 3rd Ed. Kandel et
al., p. 768
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A Brief Digression on Parts of the Brain
Berne and Levy, Physiology 3rd Ed. p. 94-95
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A Brief Digression on Parts of the Brain Part 2
Berne and Levy, Physiology 3rd Ed. p. 96
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Sympathetic
Parasympathetic
brainstem cranial nerves
thoracic
lumbar
sacral
Principles of Neural Science, 3rd Ed. Kandel et
al., p. 763
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Opposing Effects of Sympathetic and
Parasympathetic Stimulation on Heart Rate
Principles of Neural Science, 3rd Ed. Kandel et
al., p. 772
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Summary of Effector Organ Responses to Autonomic
Stimulation Part I Be sure to memorize all
entries in this table
Goodman and Gilmans The Pharmacological Basis of
Therapeutics 9th Ed. p. 110-111
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Summary of Effector Organ Responses to Autonomic
Stimulation Part II This part of the table
you do not need to memorize
Goodman and Gilmans The Pharmacological Basis of
Therapeutics 9th Ed. p. 110-111
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Hemodynamics or Why Blood Flows and What
Determines How Much
Laminar vs Turbulent Flow Relation of Pressure,
Flow and Resistance Determinants of
Resistance Regulation of Blood Flow Role of Large
Vessel Elasticity in Maintaining Continuous
Flow Determinants of Blood Pressure Why do
atherosclerotic blockages reduce blood flow? How
does blood pressure change as it moves through a
resistance vessel?
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Laminar vs Turbulent Flow
Berne and Levy, Physiology 3rd Ed. p. 447
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Difference Between Flow and Velocity
Flow is a measure of volume per unit time
Velocity is a measure of distance per second
along the axis of movement
r 4
Velocity Flow/Cross sectional area
r 2
r 1
Flow
velocity
100 ml/sec
100 ml/s
radius (cm) 1 2 4 area (cm2)
(?r2) 3.14 12.56 50.24 flow
(cm3/sec) 100 100 100 fluid velocity
(cm/sec) 32 8 2
Note This assumes constant flow
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Relationship Between Velocity and Pressure
Pressure is a form of potential energy.
Differences in pressure are the driving force
for fluid movement. Kinetic energy is
proportional to (velocity)2 If we ignore
turbulence and friction, total energy (Potential
Kinetic) of the fluid is conserved and so as
velocity increases, pressure decreases
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Relationship Between Pressure, Flow and Resistance
?P QR
Change in Pressure Flow x Resistance
?V
or V IR
Similar to Ohms Law I for electricity
R
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Resistance to Fluid Flow
The preceding discussion ignored resistance to
flow in order to focus on some basic concepts.
Resistance is important in the Circulatory
System. As fluid passes through a resistance
pressure drops. A resistance dissipates energy,
so as the fluid works its way through
the resistance it must give up energy. It gives
up potential energy in the form of a drop in
pressure.
P1 gt P2
?P
QR
Pressure
distance
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Origin of Resistance in Laminar Flow
resistance arises due to 1) interactions
between the moving fluid and the stationary tube
wall 2) interactions between molecules in the
fluid (viscosity)
West, Physiological Basis of Medical Practice
11rd Ed. p. 133
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Determinants of Resistance in Laminar Flow
Poiseuilles Law

8 ? l
r
R
Q
? r4
l
length viscosity radius

• ? 3.14159 as always
• l tube length
• fluid viscosity
• r tube radius

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Some Implications of Poiseuilles Law
(
)
?(?P)
? r4
?P
r4
(?P)

Q
8 ? l
8 ? l
R
If ?P is constant, flow is very sensitive to tube
radius
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Path of Blood Flow in the Circulatory System
Heart (left ventricle) aorta arteries arterioles c
apillaries venules veins vena cava Heart (right
atrium)
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Blood Vessel Diameter and Blood Velocity
West, Physiological Basis of Medical Practice
11th Ed. p. 120
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A Brief Digression on the Cardiac Pump Cycle
Each pump cycle is subdivided into two times 1)
Diastole filling, no forward pumping (2/3) 2)
Systole forward pumping (1/3)
Blood Pressure (mm Hg) systolic /
diastolic normal BP ??? 120/80 mmHg Hypertension
gt 140/90 mm Hg
Arterial Blood Pressure
pressure (mm Hg)
Berne and Levy, Physiology 3rd Ed. p. 457
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Converting Intermittent Pumping to Continuous Flow
The heart is the pump that keeps the fluid
circulating. The heart is a pulsatile,
intermittent pump. During each pump cycle blood
flows out of the heart for only 1/3 of the
time. THE PROBLEM To maintain continuous flow
during diastole.
THE SOLUTION Large elastic arteries distend
during systole to absorb ejected volume pulse
relax during diastole maintaining arterial
pressure and flow to the periphery
volume ejected large elastic arteries
distend aortic valve closes blood flows into
periphery under pressure created by elastic
recoil of arteries while the heart fills during
diastole
Berne and Levy, Physiology 3rd Ed. p. 457
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What Can the Body Regulate to Alter Blood Flow
and Specific Tissue Perfusion?
?P Mean Arterial Pressure Mean Venous
Pressure ?P, not subject to significant short
term regulation
R Resistance
8, ?, l, ? are not subject to significant
regulation by body r4 can be regulated especially
in arterioles, resistance vessels
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Arterioles are Heavily Innervated Radius
Controlled by Autonomic Nervous System and Local
Factors
In most arterial beds sympathetic stimulation
gt norepinephrine release gt vasoconstriction of
arterioles fight or flight reflex Blood
flow redirected from internal organs to large
skeletal muscle groups. Vasoconstriction
stimulation of ? adrenergic receptors gt ? Ca2i
in vascular smooth muscle cells In some arterial
beds parasympathetic stimulation gt
acetylcholine release muscarinic receptors
causes vasodilation of arterioles
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?-Adrenergic Receptor Signal Transduction Pathways
Katzung, Basic and Clinical Pharmacology, 2001,
p. 123
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Autonomic Nervous System Regulates Distribution
of Blood Volumes in Different Parts of the
Vascular System
West, Physiological Basis of Medical Practice
11th Ed. p. 121
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Vaso-Vagal Episodes Neural Control
Lying down gt stand up quickly gt briefly feel
lightheaded
Failure of the venoconstrictor system to respond
in a timely fashion. To prevent blood pooling in
large veins must constrict veins on standing or
the rise in hydrostatic pressure will cause
veno-dilation and thus blood pooling in the large
veins of the legs and abdomen. This pooling
reduces venous return to the heart. This in turn
reduces forward cardiac output and reduces
arterial blood pressure and perfusion of the
brain. Thus, the feeling of lightheadedness.
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Local Factors in the Control of Arteriolar
Resistance
endothelial derived relaxing factor (EDRF)
nitric oxide (NO)
endothelin bradykinin
angiotensin II vasopressin, ADH
atrial naturetic peptide adenosine
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Other Local Factors in the Control of Arteriolar
Resistance
hypoxia
arteriolar vasodilation
increased tissue perfusion
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Determinants of Arterial Blood Pressure and Flow
1) Heart Cardiac Output 2) Vascular
Resistance 3) Vascular Volume (Capacitance) 4)
Blood Volume
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Factor 1 Heart Cardiac Output
Blood Pressure (Blood Flow)(Total Peripheral
Resistance) BP Q TPR
Determinants of Blood Flow (Cardiac Output)
cardiac output (heart rate) x (stroke volume)
Determinants of Stroke Volume
venous return and venous blood pressure
(preload) duration of diastole (heart
rate) ventricular wall relaxation during
diastole arterial blood pressure (afterload)
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Factor 2 Determinants of Vascular Resistance
Arterial blood pressure systole vs
diastole Perfusion pressure largely determined by
arterial blood pressure Major site of pressure
drop is in arterioles
West, Physiological Basis of Medical Practice
11th Ed. p. 120
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Fractional Drop in Pressure
Total Peripheral Resistance Rartery
Rarteriole Rcapillary Rvenule Rvein
Drop in Pressure in the arterioles
?P(Rarterioles/TPR)
?P mean arterial pressure mean venous pressure
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Factor 3 Vascular Volume - Capacitance
CNS control arterial volume by regulating vessel
diameter venous volume by regulating vessel
diameter ratio of arterial to venous
volume Examples vaso-vagal episodes shock
peripheral vasodilation drops pressure
Factor 4 Determinants of Blood Volume
Kidney Function in Lectures Coming on Wed. Nov. 3
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Mechanism of Smooth Muscle Contraction

• The Contractile Event of Smooth Muscle
• A scheme for smooth muscle contraction is shown
  on next slide. Contraction is initiated
• by the increase of Ca2 in the myoplasm this
  happens in the following ways
• Ca2 may enter from the extracellular fluid
  through channels in the plasmalemma.
• These channels open, when the muscle is
  electrically stimulated depolarizing the
• plasmalemma.
• 2. Due to agonist induced receptor activation,
  Ca2 may be released from the
• sarcoplasmic reticulum (SR). In this pathway, the
  activated receptor interacts with
• a G-protein (G) which in turn activates
  phospholipase C (PLC). The activated PLC
• hydrolyzes phosphatidyl inositol bisphosphate
  one product of the hydrolysis is
• inositol 1,4,5-trisphosphate (IP3). IP3 binds to
  its receptor on the surface of SR,
• this opens Ca2 channels and Ca2 from SR is
  entering the myoplasm.
• 3. Ca2 combines with calmodulin (CaM) and the
  Ca2 -CaM complex activates
• myosin light chain kinase (MLCK), which in turn
  phosphorylates myosin LC. The
• phosphorylated myosin filament combines with the
  actin filament and the
• muscle contracts.

http//www.uic.edu/classes/phyb/phyb516/smoothmusc
leu3.htmcontractile
http//www.uic.edu/classes/phyb/phyb516/
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A Simplified View of Smooth Muscle Contraction
CaM Calmodulin
MLCK myosin light chain kinase IP3 inositol
trisphosphate
Bárány, K. and Bárány, M. (1996). Myosin light
chains. In Biochemistry of Smooth Muscle
Contraction (M. Bárány , Ed.), pp. 21-35,
Academic Press.
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Smooth Muscle Contraction A More Complicated View
http//www.neuro.wustl.edu/neuromuscular/pathol/di
agrams/smmusccont.htm