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)