Autonomic Nervous System and Hemodynamics

1. Autonomic Nervous System
and
Hemodynamics

2. Two or “Three” Subdivisions of the Nervous System
Voluntary Autonomic
Enteric
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
?

3. Principles of Neural Science, 3
rd
Ed. Kandel et al., p. 762
Synaptic Connectivity – Voluntary vs Autonomic Nerves
dorsal
ventral
central nervous
system
central nervous
system
autonomic
ganglion
preganglionic
fiber
postganglionic
fiber
visceral
effectors
smooth
muscle
gland
cells
cardiac
muscle
Autonomic motor systemSomatic motor system
skeletal
muscle
somatic
motor neuron

4. Synaptic Transmission in Autonomic Ganglia
Preganglionic neurons release acetylcholine
http://www.pasteur.fr/recherche/banques/
LGIC/cys-loop.html
Postganglionic Cell Receptors
1) Neuronal nicotinic acetylcholine receptors
different pharmacology from muscle nAChR
different subunit composition
2 a: 3 b
cation-selective channel
2) Muscarinic (GPCR) receptors

5. Subdivisions of the Autonomic Nervous System
Sympathetic Parasympathetic
Primary
Neurotransmitter

6. Cell body in spinal cord
autonomic ganglion
Focus on this
synapse

7. Subdivisions of the Autonomic Nervous System
Sympathetic Parasympathetic
Primary
Neurotransmitter
norepinephrine
epinephrine (~20%)
acetylcholine
Receptors
&
Second
Messenger
Systems
Adrenergic GPCRs
a
1
– IP
3
/DAG, ­[Ca
2+
]
i
­PKC
a
2
- ¯cAMP/PKA
b
1
- ­cAMP/PKA
b
2
- ­cAMP/PKA
b
3
- ­cAMP/PKA
Muscarinic GPCRs
M
1
– IP
3
/DAG, ­[Ca
2+
]
i
­PKC
M
2
– ¯cAMP/PKA, ­PI(3)K
M
3
– ¯cAMP/PKA,
IP
3
/DAG, ­[Ca
2+
]
i
­PKC
M
4
–
M
5
– IP
3
/DAG, ­[Ca
2+
]
i
­PKC
Adrenal Medulla
(epi:norepi::80:20)

8. Rockman et al., (2002) Nature 415:206-212
G-Protein Coupled Receptors

9. Principles of Neural Science, 3
rd
Ed.
Kandel et al., p. 768
Time Course of
Post-Synaptic
Potentials
nicotinic AChR
muscarinic GPCR
peptidergic GPCR
Fast EPSP
Slow EPSP
Peptidergic EPSP
20 msec
10 sec
1 min
Nicotinic
Muscarinic
ACh
Peptidergic

10. A Brief Digression on Parts of the Brain
Berne and Levy, Physiology 3
rd
Ed. p. 94-95
4 parts of the brain
2)Forebrain
3)Midbrain
4)Hindbrain
5)Spinal cord
cervical
thoracic
lumbar
sacral
spinal cord

11. Berne and Levy, Physiology 3
rd
Ed. p. 96
A Brief Digression on Parts of the Brain – Part 2

12. Principles of Neural Science, 3
rd
Ed. Kandel et al., p. 763
Sympathetic Parasympathetic
thoracic
lumbar
sacral
brainstem
cranial
nerves

13. Principles of Neural Science, 3
rd
Ed. Kandel et al., p. 772
Opposing Effects of Sympathetic and Parasympathetic
Stimulation on Heart Rate

14. Goodman and Gilman’s
The Pharmacological Basis of Therapeutics
9
th
Ed. p. 110-111
Summary of
Effector Organ Responses
to Autonomic Stimulation
Part I
Be sure to memorize
all entries in this table

15. Goodman and Gilman’s
The Pharmacological Basis of Therapeutics
9
th
Ed. p. 110-111
Summary of
Effector Organ Responses
to Autonomic Stimulation
Part II
This part of the table you
do not need to memorize

16. 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?

17. Laminar vs Turbulent Flow
Berne and Levy, Physiology 3
rd
Ed. p. 447

18. 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
radius (cm) 1 2 4
area (cm
2
) (pr
2
) 3.14 12.56 50.24
flow (cm
3
/sec) 100 100 100
fluid velocity (cm/sec)32 8 2
100 ml/sec
100 ml/s
Velocity = Flow/Cross sectional area
Note: This assumes constant flow
r = 1
r = 2
r = 4
velocityFlow

19. 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
100 ml/sec
100 ml/s
ASSUMES CONSTANT FLOW
velocityFlow
Pressure P(r = 4) > P(r = 2) > P(r = 1)
r = 1
r = 2
r = 4

20. Relationship Between Pressure, Flow and Resistance
Flow =
Change in Pressure
Resistance
Q =
DP
R
Similar to Ohm’s Law I =
for electricity
DV
R
or V = IR
DP = QRChange in Pressure = Flow x Resistance

21. 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.
Fluid flow
resistance
P
1
P
2
P
1
> P
2
Pressure
distance
DP = QR

22. 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 11
rd
Ed. p. 133

23. }r
l
length
viscosity
radius
Q
Determinants of Resistance in Laminar Flow – Poiseuille’s Law
R =
8 h l
p r
4
p = 3.14159 as always
l = tube length
h= fluid viscosity
r = tube radius
8 h l
p r
4
(DP)
Q =
DP
R
=

24. Some Implications of Poiseuille’s Law
If DP is constant, flow is very sensitive to tube radius
8 h l
p r
4
(DP) =
Q =
DP
R
=
r (10 - r/10)*100 Q/X [1 - (Q/Q
r=10
)]*100
10 0% 10,000 0%
9 10% 6,561 35%
5 50% 625 94%
1 90% 1 99.99%
% decrease in flow
% decrease in radius
8 h l
p(DP)
r
4
()
8 h l
p(DP)
X =

25. Path of Blood Flow in the Circulatory System
Heart (left ventricle)
aorta
arteries
arterioles
capillaries
venules
veins
vena cava
Heart (right atrium)

26. West, Physiological Basis of Medical Practice 11
th
Ed. p. 120
Blood Vessel Diameter and Blood Velocity

27. 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 > 140/90 mm Hg
Berne and Levy, Physiology 3
rd
Ed. p. 457
pressure (mm Hg)
Arterial Blood Pressure

28. 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.
Converting Intermittent Pumping to Continuous Flow
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 3
rd
Ed. p. 457

29. What Can the Body Regulate to Alter Blood Flow
and Specific Tissue Perfusion?
8 h l
p r
4
(DP)
Q =
DP
R
=
DP = Mean Arterial Pressure – Mean Venous Pressure
DP, not subject to significant short term regulation
R = ResistanceR =
8 h l
p r
4
8, h, l, p are not subject to significant regulation by body
r
4
can be regulated especially in arterioles, resistance vessels

30. Arterioles are Heavily Innervated
Radius Controlled by Autonomic Nervous System and Local Factors
In most arterial beds
sympathetic stimulation > norepinephrine release > vasoconstriction of arterioles
“fight or flight” reflex
Blood flow redirected from internal organs to large skeletal muscle groups.
Vasoconstriction
stimulation of a adrenergic receptors > ­ [Ca
2+
]
i in vascular smooth muscle cells
In some arterial beds
parasympathetic stimulation > acetylcholine release
muscarinic receptors causes vasodilation of arterioles

31. Katzung, Basic and Clinical Pharmacology, 2001, p. 123
a-Adrenergic Receptor Signal Transduction Pathways

32. West, Physiological Basis of Medical Practice 11
th
Ed. p. 121
Autonomic Nervous System Regulates Distribution of
Blood Volumes in Different Parts of the Vascular System

33. Vaso-Vagal Episodes – Neural Control
Lying down > stand up quickly > 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.

34. Local Factors in the Control of Arteriolar Resistance
endothelial derived relaxing factor (EDRF) – nitric oxide (NO)
cGMP
NO
Ca
++
GTP
GMP
Intracellular
Ca
++
Stores
Ca
++
Ca
++
Arginine
+
CitrullineGTP
NO
PDE
Membrane Bound
Guanylate Cyclase
Soluble
Guanylate Cyclase
C.M.
Ion Channels
cGMP-Dependent PK
PDEase Activity
NO
Synthetase
endothelin
bradykinin
angiotensin II
vasopressin, ADH
atrial naturetic peptide
adenosine

35. hypoxia
Other Local Factors in the Control of Arteriolar Resistance
arteriolar vasodilation
increased tissue perfusion

36. Determinants of Arterial Blood Pressure and Flow
1) Heart – Cardiac Output
2) Vascular Resistance
3) Vascular Volume (Capacitance)
4) Blood Volume

37. Factor #1: Heart – Cardiac Output
Blood Pressure = (Blood Flow)*(Total Peripheral Resistance)
BP = Q * TPR
venous return and venous blood pressure (preload)
duration of diastole (heart rate)
ventricular wall relaxation during diastole
arterial blood pressure (afterload)
Determinants of Blood Flow (Cardiac Output)
cardiac output = (heart rate) x (stroke volume)
Determinants of Stroke Volume

38. West, Physiological Basis of Medical Practice 11
th
Ed. p. 120
Arterial blood pressure – systole vs diastole
Perfusion pressure largely determined by arterial blood pressure
Major site of pressure drop is in arterioles
Factor #2: Determinants of Vascular Resistance

39. Fractional Drop in Pressure
Total Peripheral Resistance = R
artery
+ R
arteriole
+ R
capillary
+ R
venule
+ R
vein
DP = mean arterial pressure – mean venous pressure
Drop in Pressure in the arterioles = DP*(R
arterioles
/TPR)

40. 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

43. The Contractile Event of Smooth Muscle
A scheme for smooth muscle contraction is shown on next slide. Contraction is initiated
by the increase of Ca
2+
in the myoplasm; this happens in the following ways:
•Ca
2+
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, Ca
2+
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 (IP
3
). IP
3
binds to its receptor on the surface of SR,
this opens Ca
2+
channels and Ca
2+
from SR is entering the myoplasm.
3.Ca
2+
combines with calmodulin (CaM) and the Ca
2+
-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/smoothmuscleu3.htm#contractile
http://www.uic.edu/classes/phyb/phyb516/
Mechanism of Smooth Muscle Contraction

44. Bárány, K. and Bárány, M. (1996). Myosin light chains.
In Biochemistry of Smooth Muscle Contraction (M. Bárány , Ed.), pp. 21-35, Academic Press.
CaM = Calmodulin MLCK = myosin light chain kinase
IP
3 = inositol trisphosphate
A Simplified View of Smooth Muscle Contraction
SR
actin
myosin
GPCR
phospholipase C
heterotrimeric G-protein
myosin light chain

45. http://www.neuro.wustl.edu/neuromuscular/pathol/diagrams/smmusccont.htm
Smooth Muscle Contraction: A More Complicated View