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Regulation of Cardiac Output
•  Cardiac Output = Heart Rate x Stroke Volume
•  Cardiac output is regulated by changing HR and SV
•  SV is regulated both by changes in cardiac pumping performance
(e.g. Emax), afterload (e.g. TPR) and preload (e.g. blood volume)
•  Major control of HR is via autonomic regulation of the SA node:
•  Sympathetic Nervous System (SNS) increases automaticity
(exercise, emotional stress)
•  Parasympathetic Nervous System (PSNS) decreases
automaticity (sleep)
•  HR control is typically achieved by reciprocal action of both
SNS and PSNS
Effects of Autonomic Antagonists on Heart
Rate
← Intrinsic HR
Parasympathetic tone (blocked by muscarinic receptor agonist, atropine)
normally dominates sympathetic tone (blocked by β-adrenergic receptor
blocker, propranolol) at rest
Cardiac Parasympathetic Nerve Pathways
•  Cardiac parasympathetic fibers
originate in the medulla oblongata at
the dorsal motor nucleus of the vagus
•  Efferent vagal fibers pass via neck to
synapse with postganglionic cells on
epicardium near the SAN and AVN
•  Right vagus nerve → SAN mostly,
inhibits SAN firing
•  Left vagus nerve → AVN mostly, delay
AV conduction or even cause complete
heart block
•  Neurotransmitter is ACh, but the SAN
and AVN are rich in
acetylcholinesterase
•  ACh directly activates KACh current so effects are rapid (<100 ms) because no
second messenger is needed but transient (due to ACh-esterase activity)
•  Thus vagal activity can regulate HR on a beat to beat basis
•  PSNS is faster than SNS because no second messenger is needed
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Vagal Effects on HR
•  When vagus nerves are stimulated for just a few seconds HR decreases
rapidly a reaches steady state within two beats
•  Vagal stimulation has a much greater effect than SNS stimulation because
ACh suppresses release of norepinephrine from sympathetic nerve terminals
Cardiac Sympathetic Nerve Pathways
•  Cardiac sympathetic fibers originate in
lower cervical and upper thoracic
segments of the spinal cord
•  Pre- and post-ganglionic neurons
synapse in the stellate and middle
cervical ganglia
•  SNS and PSNS nerves join to form a
mixed efferent cardiac plexus
•  SNS nerves approach along the
vessels and spread out over
epicardium of atria and ventricles,
penetrating the myocardium along the
intramural coronaries, which they also
innervate.
SNS Effects on Heart
•  Myocardial adrenergic receptors
are primarily β1, β2 and β3
agonized by isoproterenol and
blocked by propranolol
•  Left and right SNS nerves
distribute differently: Left have
more effect on contractility, right
more on HR
•  SNS stimulation effects take 15
seconds to activate and 2 min
to deactivate
•  This is because of signaling and
the fact that norepi is not
released as rapidly or
inactivated as quickly
•  PDEs take time to degrade
cAMP the main second
messenger
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SNS and PSNS Cellular Mediators
Higher Centers Affect Cardiac Function
• 
• 
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Frontal lobe, motor and pre-motor cortex,… (excitement and exercise)
Thalamus (tachycardia)
Hypothalamus (temperature responses → HR and TPR)
Stimulation of parahypoglossal region of medulla activates cardiac
SNS and inhibits PSNS pathways
•  Dorsal medulla has distinct tachycardia and bradycardia sites
(ipsilateral)
Baroreflex also Affects HR
•  The relationship between HR and MAP is mediated by reciprocal
changes in SNS and vagal firing
•  Below 100 mmHg high HR is dominated by SNS fibers
•  Above 100 mmHg vagus dominates
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Bainbridge Reflex (1915)
•  At low HR right atrial filling increases HR (blocked by cutting vagi)
•  At high HR RA filling decreases HR due to baroreflex
•  ANP is released with atrial stretch having string diuretic and
natriuretic effects on the kidneys
•  Atrial stretch sensing cells primarily in venoatrial junctions. They also
activate a neurally mediated reduction in vasopressin (ADH) from
posterior pituitary acting to increase urine volume
Heart Failure
•  Activation of renin-angiotensin-aldosterone (RAAS) system
•  Salt and water retention due to aldosterone release from
the adrenal cortex
•  Ventricular expression of ANP and increased ANP secretion
act to attenuate fluid and salt retention
•  Sympathetic activation
•  Chronic activation of beta adrenergic receptors
downregulates and desensitizes them and blunts
adrenergic responsives
Respiratory Effects on HR
•  Respiratory Sinus Arrhythmia
•  HR increases during inspiration (partial SNS effect)
•  HR decreases during expiration (increased vagal activity)
•  Vagal effects dominate
•  Thoracic pressure influences venous return and atrial filling pressure
•  Lung stretch receptors also activate cardiac vagal center in the
medulla
•  Respiratory activity affects HR via peripheral arterial chemoreceptors
•  Decreased oxygen saturation at carotid chemoreceptors affects
HR
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Control of Contractility
• 
• 
• 
• 
• 
Frank Starling Mechanism and Anrep Effect are mediated by stretch
Extrinisic factors: circulating catecholamines, SNS
lusitropy and inotropy
Force-frequency relation
Adrenomedullary hormones
•  Epinephrine
•  Thyroid hormones increase Ca uptake and BAR sensitivity
•  Insulin-positive inotropic effect
•  Glyocogen-positive inotropic and chronotropic effects
•  Oxygen and CO2
•  Decreased pO2 and increased pCO2 decrease contractility
Autonomic Nervous System
Target
Sympathetic (adrenergic)
Parasympathetic (muscarinic)
Cardiac output
SA node: heart rate
Atrial contractility
Ventricular contractility
β1, (β2): increases
β1, (β2): increases
β1, (β2): increases
β1, (β2):
increases contractility
increases automaticity
β1:
increases conduction
increases automaticity
M2: decreases
M2: decreases
M2: decreases
---
AV node
M2:
decreases conduction
Atrioventricular block
b-adrenergic signaling and
cardiovascular disease (CVD)
•  Mediator of sympathetic autonomic
responses of the heart
•  Fight or flight “response” to stress
•  Adaptive response to impaired
function in CVD
•  Beta blockers used by 10’s of millions
• 
• 
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of Americans (5th most widely
prescribed class of medicines)
Prescribed for high blood pressure,
heart failure, cardiac arrhythmia,
coronary heart disease
Congestive heart failure affects 4.9
million Americans
Coronary heart disease affects 13
million Americans
(American Heart Association, Heart Disease and Stroke Statistics — 2005 Update)
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b-Adrenergic Regulation of ExcitationContraction Coupling
Saucerman, JJ et al., J Biol Chem 278: 47997 (2003)
Activation of cAMP-Dependent PKA
Epinephrine,
Norepinephrine
G
c
g
R
GTP
D
C
C
A
D
R
C
AC
sAC
P
Na
Ca2+
Cl
Ga
+
- K+
Ca2+
PKAR
PKAR
GDP
SOS
Raf1
Gg
ACI, V, VI
Caln
ACI
PLC
PIP2
PKC
ACIX
DAG
IP3
P
eNOS
eNOS
Signaling
VASP
RhoA
Pln
P
P
PTP
Actin Polymerization
P
Rap1
Ca2+
Rho
Kinase
CRP
4
Ras
Ga-S
Gb
CamK4
PKAC
P
Glycogen
Addu
TnnI
GSK3
DARPP32
P
cin
MyosinII/
RLC
Regulation of
Cytoskeleton
GYS
APC
Glycogen
Synthesis
Protein
Retention
P
ATF1
P
IP3R
Ca2+
ERK
P
CREM
P
CREB
CBP
P
P
C 2007-2009
SABiosciences.com
RyR
K
D
EL
R
PPtase1
MEK1,2
BRaf
Endothelial Cell
Regulation
Oncogenesis
P
GRB2
CamKs
PKAC
PHK
Myocardial
Contraction
R
T
K
C
SHC
Ga-S
PKA
Glycolysis
Growth
Factors
GTP
Lipolysis
PO
Ucn2
C
R
H
R
ACII, IV, VII
Reduction in
Rhodopsin
Phosphorylation
GRK1/7
Desensitization
A
K
A
P
HSL
Gg
Calm
P
Ucn
C
Gb
GDP
Ga-I
GTP
PDE
P
Cell Survival
Glucose-1-
N
GP
C
R
cAMP
BAD
P
PYG
N
C
Ga-S
AMP
Metabolic
Energy
14-3-3
Neurotransmitters, Hormones,
Stress, Inflammatory Stimuli
Ca2+
C
N
G
ATP
HCO 3
P
Ca2+
SCn, KCn,
ClCn, CaCn
Ga-Q,
Ga
-
Na +
Cl +
K
Netrin1
N
Gcg
N
14-3-3
NFAT
APC Regulation
NF-kB
P
Gene
Expression
Cell Survival
Elk1
P
b-Adrenergic Regulation of
E-C Coupling in Rabbit
Model
[Ca]i
Experiments
Iso
Ctrl
Ginsburg KS, Bers DM
J Physiol. 556:463 (2004)
VM
Ctrl
Iso
APD90 ↓10%:
Sanguinetti MC, et al.
Circ Res. 68:77 (1991)
Base model: Puglisi JL, Bers DM.
AJP 281:C2049 (2001)
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Modulation of Calcium Transients
1 µM Isoproterenol @ 10 sec
Increased inotropy and lusitropy
with PKA phosphorylation of LCC,
PLB, RyR, and TnI.
Saucerman JJ and McCulloch AD (2004) Prog
Biophys Mol Biol, 85:261-78
Experimental data from: Xiao, R. P. et al.
J Biol Chem 269, 19151-6 (1994).
In silico KO’s reveal functional roles of
PKA targets
Single target phosphodisruption
• PLB disruption does not restore t80
• PLB and LCC anti-cooperative for t80
• No sig. role for TnI in Ca dynamics
Single target phosphorylation
• Big contractility increase from
PLB, LCC phosphorylation
• No increase in systolic Ca for
RyR phosphorylation
• Apparent increased relaxation w/
LCC phosphorylation
Saucerman and McCulloch, Prog Biophys Mol Bio 85: 261 (2004)
Congestive Heart Failure
Control
CHF
Sham
β1-AR: -75%
8 wk
16 wk
SERCA: -30%
CHF Sham
Oudit, G. Y., et al. (2003). Circulation 108(17): 2147-52.
Zarain-Herzberg, et al. (1996). Mol Cell Biochem 163-164: 285-90.
Sjaastad, I., et al. (2002). Acta Physiol Scand 175(4): 261-9.
NCX: +55%
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Congestive Heart Failure
Normal
7e-4
5e-4
4e-4
3e-4
2e-4
0.1
300
6e-4
Calcium (mM)
Calcium (mM)
Ca2+
(mM)
CHF
7e-4
6e-4
Systolic Calcium
(% of control)
0.7
5e-4
4e-4
3e-4
250
Normal
HF
200
150
100
2e-4
50
1.E-04
1e-4
1e-4
25
26
27
28
Time (sec)
29
30
25
26
27
28
29
30
Time (sec)
1.E-03
1.E-02
1.E-01
1.E+00
Isoproterenol (µM)
Holt, ET et al. (1998) J Mol Cell Cardiol 30(8): 1581-93
Xiao RP et al. (2003) Circulation 108(13): 1633-9
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