A1258149751ITuvm

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HuBio 543September 25, 2007
Neil M. Nathanson K-536A, HSB 3-9457 nathanso_at_u.wa
shington.edu Introduction to the Sympathetic
Nervous System
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Adrenergic Innervation of Vasculature
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SYNTHESIS OF EPINEPHRINE IN THE ADRENAL MEDULLA

TH
Tyrosine
DOPA
DDC
Dopamine
PMNT
DA
NE
EPI
DßH
NE
EPI
EPI
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TERMINATION OF SYNAPTIC TRANSMISSION
NE
ACh
Re-Up
NE
ACh
Ch Ac
AdR
AChE
AChR
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Drugs that act on adrenergic terminals

• Inhibit reuptake of NE into terminal- cocaine,
  tricyclic antidepressants
• Induce release of NE from terminal- amphetamine,
  tyramine
• Inhibit uptake of DA NE into vesicle- reserpine
• Block release of NE- bretylium
• Displace NE from vesicle- guanethidine
• Inhibit TH activity- a-methyltyrosine
• Inhibit DDC activity- carbidopa
• Inhibit MAO activity- pargyline
• (Inhibit COMT activity- tolcapone)

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Presynaptic Receptors Inhibit NE Release From
Terminals
NE
ß1- AdR
NE
X
X
NE
a2- AdR
NE
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The Subtypes of Adrenergic Receptors
a EPI gt NOR gtgtISO
ß ISO gt EPI gt NE
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Beta- Adrenergic Receptors Mediate Positive
Chronotropic Effect
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Isoproterenol
Norepinephrine
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Change in HR. BPM
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0
Dose, µg/kg
0.1
100
0. 01
0.001
1
10
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Even More Subtypes of Adrenergic Receptors
a EPI gt NOR gtgtISO
ß ISO gt EPI gt NE
a1 contraction of smooth muscle (incl. VSM) a2
presynaptic receptors ( decrease NE release) ß1
in heart and juxtaglomerular cells (and
some fat cells) ß2 relaxation of smooth muscle
(and in heart) ß3 some fat cells
NOTE ON ß2 (1) mediate relaxation of skeletal
muscle vasculature (2) Pcologically
administered NE is not effective
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Specificity of Agonists at Targets and Receptors
E
NE
I
Contraction of VSM (a1-AdR)
I
Relaxation of Airways (ß2-AdR)
E
NE
I
E
NE
Increase in HR (ß1-AdR)
Concentration of Drug
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Hormone/Transmitter
Effector
GTP
BANG
GDP
Receptors G-Proteins Effectors 9 adrenergic R
20 a 4 PLC-ß 5 mAChR 5 ß 10 AC
12 g PDE ( 100?)
K channels (GIRK ) Na, Ca
channels IP3 Receptors PI-3-kinases
Rho-GEF, Ras-GEF Tyrosine Kinases
(src)
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Regulator of G-protein Signaling
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The basic functions of G-proteins
as family mediates stimulation of adenylyl
cyclase (ß-AdR) ai family mediates inhibition of
adenylyl cyclase activates GIRK (M2, M4
mAChR ?2-AdR) aq family activate certain forms
of PLC (M1, M3, M5 mAChR ?1-AdR) (and others
as well)
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Beta-adrenergic receptors stimulate adenylyl
cyclase
Norepinephrine
Adenylyl Cyclase
G-protein
ATP
(Gs)
cAMP
cAMP-dependent protein kinase (PKA)
Increased phosphorylation
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Regulation of Receptor Signaling by G-protein-
Coupled Receptor Kinase (GRK) and ß-Arrestin
Receptor is uncoupled from G-protein and targeted
for internalization and down-regulation
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Chronic Isoproterenol Decreases Cardiac Beta-AdR
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Chronic Isoproterenol Decreases Cardiac Beta-AdR
Functional Responsiveness
Increase In Contractile Force
Control
Isoproterenol, Withdrawn
(OR)
Increase In Adenylyl Cyclase
Isoproterenol Treated
Concentration of Isoproterenol
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Thyroid Hormones Increase Cardiac Beta-AdR
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Decreased number of cardiac ß-AdR in ventricles
of patients with heart failure
Controls
Heart Failure
(Receptor )
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Decreased function of cardiac ß-AdR in
ventricles of patients with heart failure
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Differential coupling of ß1 and ß2- AdR

• ß1-AdR only couple to the stimulatory G-protein
  Gs
• ß2-AdR can couple to both Gs the inhibitory
  G-protein Gi
• In heart failure, levels of ß1-AdR decrease and
  levels of Gi increase
• Therefore, ß2-AdR has less stimulatory and more
  inhibitory effects in a failing heart than in a
  non-failing heart
• Failing heart has increased expression and
  activity of GRK, which increases ß1
  desensitization and degradation and also
  increases coupling of ß2 to Gi
• The decreased level of ß1-AdR and increased
  ß2-AdR coupling to Gi both contribute to
  decreased ß-adrenergic stimulation of
  contractility in failing heart