Autonomic Nervous Systemand

Hemodynamics

Two or “Three” Subdivisions of the Nervous System

Voluntary Autonomic Enteric

Innervates skeletal muscle smooth musclecardiac musclesecretory glands

intestinecontrols intestinal motility secretion absorption

Neurotransmitter ACh norepinephrineAChneuropeptides

norepinephrineAChserotoninneuropeptides

Receptors nicotinic muscle AChR

adrenergic GPCRsmuscarinic ACh GPCRsnicotinic neuronal AChR

GPCRs

?

Principles of Neural Science, 3rd Ed. Kandel et al., p. 762

Synaptic Connectivity – Voluntary vs Autonomic Nerves

dorsal

ventral

central nervoussystem

central nervoussystem

autonomicganglion

preganglionic fiber

postganglionicfiber

visceraleffectors

smoothmuscle

glandcells

cardiacmuscle

Autonomic motor systemSomatic motor system

skeletalmuscle

somaticmotor neuron

Synaptic Transmission in Autonomic Ganglia

Preganglionic neurons release acetylcholine

http://www.pasteur.fr/recherche/banques/LGIC/cys-loop.html

Postganglionic Cell Receptors1) Neuronal nicotinic acetylcholine receptors

different pharmacology from muscle nAChRdifferent subunit composition

2 : 3 cation-selective channel

2) Muscarinic (GPCR) receptors

Subdivisions of the Autonomic Nervous System

Sympathetic Parasympathetic

PrimaryNeurotransmitter

Cell body in spinal cord

autonomic ganglion

Focus on thissynapse

Subdivisions of the Autonomic Nervous System

Sympathetic Parasympathetic

PrimaryNeurotransmitter

norepinephrineepinephrine (~20%)

acetylcholine

Receptors&

SecondMessenger

Systems

Adrenergic GPCRs1 – IP3/DAG, [Ca2+]i PKC2 - cAMP/PKA

1 - cAMP/PKA2 - cAMP/PKA3 - cAMP/PKA

Muscarinic GPCRsM1 – IP3/DAG, [Ca2+]i PKCM2 – cAMP/PKA, PI(3)KM3 – cAMP/PKA, IP3/DAG, [Ca2+]i PKCM4 – M5 – IP3/DAG, [Ca2+]i PKC

Adrenal Medulla(epi:norepi::80:20)

Rockman et al., (2002) Nature 415:206-212

G-Protein Coupled Receptors

Principles of Neural Science, 3rd Ed. Kandel et al., p. 768

Time Course ofPost-SynapticPotentials

nicotinic AChRmuscarinic GPCRpeptidergic GPCR

Fast EPSP

Slow EPSP

Peptidergic EPSP

20 msec

10 sec

1 min

Nicotinic

Muscarinic

ACh

Peptidergic

A Brief Digression on Parts of the Brain

Berne and Levy, Physiology 3rd Ed. p. 94-95

4 parts of the brain

1) Forebrain

2) Midbrain

3) Hindbrain

4) Spinal cordcervical

thoracic

lumbar

sacral

spinal cord

Berne and Levy, Physiology 3rd Ed. p. 96

A Brief Digression on Parts of the Brain – Part 2

Principles of Neural Science, 3rd Ed. Kandel et al., p. 763

Sympathetic Parasympathetic

thoracic

lumbar

sacral

brainstemcranial nerves

Principles of Neural Science, 3rd Ed. Kandel et al., p. 772

Opposing Effects of Sympathetic and Parasympathetic Stimulation on Heart Rate

Goodman and Gilman’sThe Pharmacological Basis of Therapeutics9th Ed. p. 110-111

Summary of Effector Organ Responsesto Autonomic StimulationPart I

Be sure to memorizeall entries in this table

Goodman and Gilman’sThe Pharmacological Basis of Therapeutics9th Ed. p. 110-111

Summary of Effector Organ Responsesto Autonomic StimulationPart II

This part of the table youdo not need to memorize

Hemodynamicsor

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?

Laminar vs Turbulent Flow

Berne and Levy, Physiology 3rd Ed. p. 447

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 (cm2) (r2) 3.14 12.56 50.24

flow (cm3/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 = 1r = 2

r = 4

velocityFlow

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 = 1r = 2

r = 4

Relationship Between Pressure, Flow and Resistance

Flow = Change in Pressure

ResistanceQ =

P

R

Similar to Ohm’s Law I =for electricity

V

Ror V = IR

P = QRChange in Pressure = Flow x Resistance

Resistance to Fluid FlowThe preceding discussion ignored resistance to flow in order to focus onsome 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 theresistance it must give up energy. It gives up potential energy in the formof a drop in pressure.

Fluid flow

resistance

P1 P2P1 > P2

Pressure

distance

P = QR

Origin of Resistance in Laminar Flow

resistance arises due to 1) interactions between the moving fluid and the stationary tube wall2) interactions between molecules in the fluid (viscosity)

West, Physiological Basis of Medical Practice 11rd Ed. p. 133

} r

l

lengthviscosityradius

Q

Determinants of Resistance in Laminar Flow – Poiseuille’s Law

R =8 l

r4

= 3.14159 as alwaysl = tube length= fluid viscosityr = tube radius

8 l

r4

(P)Q = P

R=

Some Implications of Poiseuille’s Law

If P is constant, flow is very sensitive to tube radius

8 l

r4

(P) =Q = P

R=

r (10 - r/10)*100 Q/X [1 - (Q/Qr=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 l

(P) r4( )

8 l

(P) X =

Path of Blood Flow in the Circulatory System

Heart (left ventricle)

aorta

arteries

arterioles

capillaries

venules

veins

vena cava

Heart (right atrium)

West, Physiological Basis of Medical Practice 11th Ed. p. 120

Blood Vessel Diameter and Blood Velocity

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 / diastolicnormal BP ??? 120/80 mmHg Hypertension > 140/90 mm Hg

Berne and Levy, Physiology 3rd Ed. p. 457

pre

ssu

re (

mm

Hg)

Arterial Blood Pressure

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 arterieswhile the heart fills during diastole

Berne and Levy, Physiology 3rd Ed. p. 457

What Can the Body Regulate to Alter Blood Flow and Specific Tissue Perfusion?

8 l

r4

(P)Q = P

R=

P = Mean Arterial Pressure – Mean Venous Pressure

P, not subject to significant short term regulation

R = Resistance R =8 l

r4

8, , l, are not subject to significant regulation by body

r4 can be regulated especially in arterioles, resistance vessels

Arterioles are Heavily InnervatedRadius 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 adrenergic receptors > [Ca2+]i in vascular smooth muscle cells

In some arterial beds parasympathetic stimulation > acetylcholine release muscarinic receptors causes vasodilation of arterioles

Katzung, Basic and Clinical Pharmacology, 2001, p. 123

-Adrenergic Receptor Signal Transduction Pathways

West, Physiological Basis of Medical Practice 11th Ed. p. 121

Autonomic Nervous System Regulates Distribution ofBlood Volumes in Different Parts of the Vascular System

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.

Local Factors in the Control of Arteriolar Resistance

endothelial derived relaxing factor (EDRF) – nitric oxide (NO)

cGMP

NO

Ca++

GTP

GMP

IntracellularCa++ Stores

Ca++

Ca++

Arginine

+Citrulline GTP

NO

PDE

Membrane BoundGuanylate Cyclase

SolubleGuanylate Cyclase

C.M.

Ion ChannelscGMP-Dependent PK

PDEase Activity

NO Synthetase

endothelinbradykinin

angiotensin IIvasopressin, ADH

atrial naturetic peptideadenosine

hypoxia

Other Local Factors in the Control of Arteriolar Resistance

arteriolar vasodilation

increased tissue perfusion

Determinants of Arterial Blood Pressure and Flow

1) Heart – Cardiac Output

2) Vascular Resistance

3) Vascular Volume (Capacitance)

4) Blood Volume

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 diastolearterial blood pressure (afterload)

Determinants of Blood Flow (Cardiac Output)

cardiac output = (heart rate) x (stroke volume)

Determinants of Stroke Volume

West, Physiological Basis of Medical Practice 11th Ed. p. 120

Arterial blood pressure – systole vs diastolePerfusion pressure largely determined by arterial blood pressureMajor site of pressure drop is in arterioles

Factor #2: Determinants of Vascular Resistance

Fractional Drop in Pressure

Total Peripheral Resistance = Rartery + Rarteriole + Rcapillary + Rvenule + Rvein

P = mean arterial pressure – mean venous pressure

Drop in Pressure in the arterioles = P*(Rarterioles/TPR)

Factor #3: Vascular Volume - Capacitance

CNS controlarterial volume by regulating vessel diametervenous volume by regulating vessel diameterratio of arterial to venous volume

Examplesvaso-vagal episodesshock – peripheral vasodilation drops pressure

Factor #4: Determinants of Blood Volume

Kidney Function in Lectures Coming on Wed. Nov. 3

The Contractile Event of Smooth Muscle

A scheme for smooth muscle contraction is shown on next slide. Contraction is initiated

by the increase of Ca2+ in the myoplasm; this happens in the following ways:

1. Ca2+ 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, Ca2+ 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 (IP3). IP3 binds to its receptor on the surface of SR,

this opens Ca2+ channels and Ca2+ from SR is entering the myoplasm.

3. Ca2+ combines with calmodulin (CaM) and the Ca2+ -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

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 kinaseIP3 = inositol trisphosphate

A Simplified View of Smooth Muscle Contraction

SR

actin

myosin

GPCR

phospholipase C

heterotrimeric G-protein

myosin light chain

http://www.neuro.wustl.edu/neuromuscular/pathol/diagrams/smmusccont.htm

Smooth Muscle Contraction: A More Complicated View