Neural Regulation of the HeartNeural Regulation of the Heart
Jean HardwickIthaca Collegeg
Preganglionic neuron
Target
Postganglionic neuron
Target
Target
Autonomic Nervous System
Sensory innervation
Sensory Inputs• BP• pH• pO2
Autonomic Innervation of the Heart
Parasympathetic
ACh↓ Heart Rate↓ CACh
NESympathetic
↓ Contractility↓ Cardiac Output
NENE NE↑ Heart Rate↑ Contractility↑ Cardiac Output
http://www.cvphysiology.com/Arrhythmias/SAN%20action%20potl.gif
http://www.biosbcc.net/doohan/sample/images/CO%20and%20MAP/0306pace.jpg
Cardiac Ganglion
CNS PreganglionicCNS Preganglionic Neurons
SympatheticSympathetic Postganglionic Fibers
ParasympatheticPostganglionic
NeuronsC diCardiac SensoryNeurons
Cardiac Target Cells
Parasympathetic Cardiac Ganglion
Fast synaptic transmission (excitatory)Fast synaptic transmission (excitatory)ACh (nicotinic receptors)
Other signalsOther signalsACh (muscarinic receptors)NENE NeuropeptidesLocally-generated signalsLocally generated signals
Parasympathetic Cardiac Ganglion
Preganglionic Fibers
Postganglionic Fibers
Sympathetic P t li iPostganglionicFibers
Sensory Afferents
Guinea pig cardiac ganglionp g g g
Mawe, et al (1996) Cell Tissue Res 285:281.
Neurotransmitters
NeuropeptidesNeuropeptidesSensory peptides
Substance P, CGRP,PACAP
PACAP38, PACAP27PACAP 1-27 28-38
MAP2MAP2Substance P
CGRP
PACAP 38MAP2
PACAP 27MAP2
Physiology
“puffer”containingcontainingtest substance
Preganglionic fiber
Postganglionic neuronPostganglionic neuron
Phasic Neuron Tonic NeuronPhasic Neuron Tonic Neuron
Stimulation of fiber inputs
ControlControl
0 Ca++
Wash
Substance P
Substance P
Control SP Wash
PACAP
Non-traditional Neuromodulators
Immunue mediatorsImmunue mediatorsMast cell activation
HistamineProstaglandins
Nitric Oxide
Cardiac Mast Cells
Found in high density in mammalian heartFound in high density in mammalian heartStimulated by:
Antigen exposureAntigen exposureSensory neuropeptidesChemoreceptorsChemoreceptors
pH changes, low oxygen
Upon stimulation releaseUpon stimulation, releaseHistamineProstaglandins (synthesized from phospholipids)Prostaglandins (synthesized from phospholipids)
H HH
H
H
H H
H
H
H
HH
PG’s
MAP2Histamine
Parasympathetic Cardiac Ganglion
Preganglionic Fibers
Postganglionic Fibers
Mast cells
Sympathetic P t li iPostganglionicFibers
Sensory Afferents
Sensitization
Wait
3 weeks
Collect Tissue
Apply OVA totissue to inducemast cell
Inject with OVAth d
3 weeks mast cell degranulation
every other day(3 injections total)
Mast Cell Degranulation
HYH
H Ovalbumin
HH
HH
H H
AAPGs
PLA2PGs
Response to Mast Cell Degranulation
Histamine Responses
Excitability
) 15
20 Tonic ControlTonic Histamine
z) 15
20 Phasic ControlPhasic Histamine
) 15
20Control, All cellsHistamine, Alll cells #
#
Freq
uenc
y (H
z)
10
15
Freq
uenc
y (H
z
10
15
Freq
uenc
y (H
z)
10
15
##
## #
##
# # ##
#
0 0 0 2 0 4 0 6
AP F
0
5
0 0 0 2 0 4 0 6
AP
0
5
0 0 0 2 0 4 0 6
AP F
0
5 #
##
#
Stimulus (nA)
0.0 0.2 0.4 0.6
Stimulus (nA)
0.0 0.2 0.4 0.6
Stimulus (nA)
0.0 0.2 0.4 0.6
Nitric Oxide in the Heart
Nitric Oxide
NOS
NONO
Ca++
NONO
GuanylateCyclasecGMP
Physiological Actions of NO
Electrophysiological recordings from theElectrophysiological recordings from the cardiac plexus
AChPreganglionic fiber
Intracardiac neuron
Nitric Oxide
SNP
Control
20 mV
50 msec
Regulation of neuronal firingPreganglionic fibers
ACh fast depolarization AP generationACh - fast depolarization, AP generationPACAP – slow, long lasting depolarization, increase in excitabilityincrease in excitability
Sensory afferent fibersSP slow depolarization increase in excitabilitySP – slow depolarization, increase in excitability
Mast cellsHistamine depolarization increase in excitabilityHistamine – depolarization, increase in excitability
Intracardiac neuronsNO ti i i EPSP lit dNO – presynaptic increase in EPSP amplitude
Chronic Heart Disease and Neuronal Regulation
Horackova, M. et al. (2004) Am J Physiol Heart Circ Physiol 287: H1599-H1608
Copyright ©2004 American Physiological Society
Models of Heart Disease
Myocardial infarctionMyocardial infarctionLigate left ventricular coronary artery6-9 weeks recovery6 9 weeks recovery
Pressure OverloadBand descending dorsal aortaBand descending dorsal aortaProduces left ventricular hypertrophy8-10 weeks recovery8 10 weeks recovery
Sham surgery
Regulation of NOS levels
Control Chronic MIControl Chronic MInNOSand
MAP2
Regulation of NOS levels
25
Control
20
Control CMI Sham surgery CPO
##
NO
S c
ells 15
%nN
5
10
0
5
Mast Cell Density
C t l CMIControl CMI
Mast Cells
2.0
mm
2 )
1.5
Control MI PO * #
nsity
(cel
ls/m
1.0*
ast C
ell D
en
0.5
M
0.0
Physiological Changes with Chronic MI
Physiological Changes with Disease
18
20
ControlH
z) 14
16
18Control with HistaminePO with HistamineMI with Histamine
Freq
uenc
y (
8
10
12
AP
2
4
6
Stimulus Intensity (nA)
0.0 0.2 0.4 0.60
2
y ( )
Physiological Changes with Diseasey g g
25z)
20ControlControl with PACAPPO with PACAPMI with PACAP
requ
ency
(Hz
10
15
AP F
r
5
10
0.0 0.2 0.4 0.60
Stimulus Intensity (nA)
PreganglionicInputs
SensoryInputsp Inputs
PACAP
Mast Cells
ACh PACAP
HistamineNO
SPCGRPSensory
Inputs
T t C llTarget Cells
Acknowledgements
National Institutes of HealthNational Institutes of HealthHeart Lung and Blood Institute
Jeffrey Ardell – ETSUMarie Southerland, DVM – ETSU Rodney Parsons – UVM
Student CollaboratorsSeth DePuy (’99) Melanie Powers (’01) Beth Peterson (’01) Gina DiMasi (’02) ( ) ( )Kristen Sager (’02) Zach Goldsmith (’02)Greg Jelson (’02) Martha Morin (’03)Bekke Mapes (’03) Brenna Corbett (’03)Bekke Mapes ( 03) Brenna Corbett ( 03)Amy Kotarski (’05) Jay Sellers (’05)Danielle Federico (’05) Abby Wilkes (’06)Andrew Kelley (’05) Megan McManus (’06)Robert Janelli (’07) Nancy Andersen (’07)Ryan Bochacki (’07) Amber Contrastan (’09)y ( ) ( )Caitlin Baran (’09) Lauren Houdek (’10)Noah Mishkin (‘11) Alison Girasole (’11)
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