CARDIOVASCULAR PHYSIOLOGY

LECTURE 1

The structure and function of the cardiovascular system.

Function and characteristics of the myocardium:

Excitability, Automatism and Conductivity

Assoc. Prof. Ana-Maria Zagrean

Physiology & Neuroscience Department

www.fiziologie.ro

The need for a competitive circulatory system

• Isolated/single cells vs. multicellular organisms

• Connection between external - internal milieu: from simple diffusion to complex, highly regulated, circulatory systems

Cardiovascular

System:

1)The heart, a dual pump,

that circulates a liquid

2) the blood,

3) through the vessels of

systemic and pulmonary

circulations

4) Integrated regulatory

system to adapt to the

changing circumstances

Circulatory System: an interplay of fast & complex

mechanisms to maintain body homeostasis and adaptive

capacity.

1. Functions of the circulatory system

The primary role of the circulatory system is the distribution

of dissolved gases and other molecules for nutrition,

growth, and repair (transport system function).

This function depends on maintaining a steep concentration gradient

from the blood to the intracellular medium for nutrients and in the

opposite direction for waste/metabolic products.

A fast blood circulation is needed between cells in the body and

circulatory areas in contact with the external milieu: lung, gut, and

kidney epithelia.

1. Circulatory system as a transport system :

- Nutrition, growth and repair

transport between all parts of the body: nutrients,

metabolic products, respiratory gases (O2, CO2):

relation CO2 pH homeostasis

- Maintenance of circulatory parameters:

cardiac output – 5L/min at rest, for an adult

! capacity to increase 5 fold during exercise

blood pressure

blood volume,

blood fluidity/viscosity

2. Functions of the circulatory system

Secondary roles:

(1) fast chemical signaling to cells by means of circulating

hormones, neurotransmitters, signaling molecules; secretory

function

(2) dissipation of heat by delivery of heat from the core to the

surface of the body

(3) mediation of inflammatory and host defense responses

against invading microorganisms:‘Channel’ for the immune response/defense mechanisms:

immune cells, antibodies, clotting proteins

3. Functions of the circulatory system

Secondary roles:

Secretory function of the circulatory system:

- Atrial Natriuretic Peptide (ANP):

released by atrial fibers as a response to heart overload

powerful vasodilator, reduce water & sodium on the circulatory

system, thereby reducing blood pressure

- Nitric oxide - NO (Endothelial Derived Relaxing Factor):

vasodilator, inhibits platelets adherence & aggregation

- Endothelial Derived Hyperpolarizing Factor

- Endothelin: vasoconstrictor on ETA, ETB2 receptors

- Prostaglandins PGE2, PGI2 (prostacyclin):

increase Na+ excretion by the kidneys, vasodilators

1. Components of the Cardiovascular System

and their function:

1. the heart consists in two pumps, operating in series, requiring

equalization of their outputs (5 L/min)

Left heart (LH) – main pump

Right heart (RH) – boost pump

2. the blood

3. a tubular system (two serial circuits):

-systemic / pulmonary circulation

-high-pressure (LV systemic capillaries)

low-pressure (systemic capillaries LA)

-vessels (arteries, veins, capillaries, lymphatics) respond with

changes in blood flow to changing metabolic demands

-angiogenesis: self-repairing / self-expanding capacity of endothelial

cells

4. an integrated regulation system to adapt to variable demands:

- intrinsic: automatism

- systemic: nervous system

endocrine system

- local/metabolic regulation

! level of activity – metabolic rate coupling

e.g., increase in muscular metabolic rate during physical activity

muscular blood perfusion - resting conditions – 4 ml/100g/min

- physical activity - 80 ml/100g/min

Components of the Cardiovascular System and

their function:

Distribution of blood flow (% Cardiac Output) at rest & during heavy exercise

Heart – morphological data:

- G = 250 - 340 g

- Longitudinal diam. =100 - 120 mm

- Transversal diam. = 80 - 100 mm

- Measurement methods:- clinical: aria of cardiac dullness- echocardiography- radiology

Morphological components of the heart

-Pericardium:thin-walled membranous cavity surrounding the heart;small volume of pericardial fluid in the space between itstwo surfaces.

- Myocardium, cardiac conduction system, peacemaker cells

- Fibrous skeleton

- 4 intracardiac valves:

AV valves: Right (tricuspid, 3-leaflet)

Left (mitral, 2-leaflet)

Semilunar valves: Aortic & Pulmonary

- chordae tendineae

- Endocardium

- Coronary circulation

The cardiac muscle: myocardium

• Peacemaker cells

• Conductive system

• Working myocardium

-involuntary contraction-striated in appearance (sarcomeres and myofilaments similar to skeletal muscle ones); small cells, electrical and mechanical cell-to-cell communication (syncitium); -mechanical performance complex and subtle.

Myocardial cell (MC) structure

Sarcolema - T tubules & terminal cistern: continuous with the cell

membrane, carry the AP; more developed in the ventricles

Sarcoplasmic reticulum (SR):

in close proximity to the contractile elements

site of storage and release of Ca

Sarcomere: contractile unit of the MC

between 2 Z lines

contains: thin filaments - actin, troponin, tropomyosin

thick filaments – myosin

Intercalated disks: paracellular connections

hold the cells (desmosomes)

connect them electrically (gap junctions),

heart behaves as an electrical syncytium(sync, synch: informal for synchronization)

Mitochondria (> than in skeletal muscle)

Myocardial properties

1. Excitability (bathmotropia)

2. Rhythmic activity/automaticity (chronotropia)

3. Conductibility (dromotropia)

4. Contractility (inotropia)

5. Relaxation (lusitropia)

Excitability

Myocardial capacity to respond to a stimulus that has a

minimum threshold intensity

Depends on ionic gradients across the cell membrane

(polarized membrane), through the action of the membrane

ionic transport system: ionic channels, pumps, exchangers

Membrane ionic transport system

Classification according to the mechanism that mediates

the transport:

• Pore proteins (water channels, connexons of gap junctions…)

• Transporters (carriers - exchangers, pumps…)

• Channels

Properties of the transport system:

• Functional state: opened or closed

• Rate of transport (109/sec - aquaporins, 106-108/sec. - gated

channels, 102-105/sec. - transporters)

• Transport mechanism: diffusion or binding of substrates

• Saturation

• Chemical specificity

• Regulation (e.g. by ATP, phosphorylation)

Membrane Ionic Transport System

Ionic Channels

− K+ channels − fast Na+ channels, slow Na+ and Ca2+ channels− Ca2+ channels− Cl- channels− nonspecific cation channels (Na+, K+, Li+), etc...

Membrane currents in the heart

-time-dependent

-voltage-dependant

Classification

1.Na Currents (INa)

2.Ca Currents (ICa)

3.K Currents (IK)

4.Pacemaker Currents (if)

Principal ionic currents & channels that generate AP in a cardiac cell

-Na inflow through fast voltage-dependent channels:a, b1 subunits: a subunit has a phosphorylation site

for cAMP-dependent PK

1.Na Currents (INa)

-opening/activation (m activation gate) in responseto local depolarization, at ~ -55 mV (0,1- 0,2 ms)…

-closing/inactivation (h inactivation gate) to a positivepotential (~1 ms); 99% of Na channels areinactivated at the peak of the AP

-channel reset to open again after the membranebecomes repolarized below -50 mV !

- Responsible for rapid depolarization (Phase 0) ofthe AP in atrial and ventricular muscle and inPurkinje fibers.

-INa blocking: TTX, local anesthetics (lidocaine – usedas antiarrhythmic drug)

Note that during AP [Na+]i increases by only 0.02%

1. Na Currents (INa)

- activate Ca & K channels

- Ca inflow through slow L-type voltage-dependent

channels/dihydropyridine receptors (L from long lived)

- Responsible for depolarization (Phase 0) of AP inSAN, AVN and their neighboring cells

2. Ca Current (ICa)

- activation ~ 1 ms

- inactivation ~ 10-20 ms

- participate in Phase 2 (plateau phase) of AP inatrial and ventricular muscle

long refractory period of the AP

2. Ca Current (ICa)

-activates Ca-dependent Ca release from SR;

-initiates excitation-contraction coupling in myocardium

-L-type Ca channels blockers:nifedipin, verapamil, diltiazem

- Other Ca channels: T-type (transient) -activated at a lower voltage threshold(< - 30 mV), inactivated at a lower voltage…

- initiation of the AP, automatism …N-type, P/Q-type

T (transverse) tubule

Ca2+ dependent Ca2+

releasing channel

(ryanodine receptor)

Sarcoplasmic

Reticulum

L-type Ca2+ channel

(Cav1.2. dihydropiridine

receptors)

Sarcoplasmic

Reticulum (SR)

Tetrad: 4 L-type Ca channels

faces a single Ca release

channel on SR

Triad: T tub + 2 SR cisternae

3. K Currents

IK-repolarization currents resulting from the slow opening

(20-200 ms) of KV channels

-responsible for Phase 3 of the AP

-deactivating at the diastolic membrane voltage

Ito- early transient outward K current (A-type)

- activated by depolarization; rapidly inactivates

- contributes to Phase 1 of the AP

IK 1 inward rectifying K channel - responsible for the resting membrane potential (Phase 4)

G-protein activated inwardly-rectifying K current-vagal nerv stim. of SAN & AVN Ach muscarinicreceptor G-protein (bg subunit) GIRK K channels:outward K current hyperpolarization slows pacemaker

rate & slows AP conduction through AVN

ATP-sensitive K channels:Low probability to open at normal [ATP]~ 5 mMK currents dependent on ATP/ADP ratio; hypoxia/ischemia

ATP & ADP K channels activation & K outflow

(early repolarisation, short plateau, weak beat; possible role inelectrical regulation of contractile behavior by coupling cellularmetabolism & membrane excitability; cardioprotection…)

Note that the [K+]i changes just by 0.001% during AP.

3. K Currents

4. Pacemaker Current If

- found in SAN & AVN cells and in Purkinje fibers

- slow activation (100 ms) by hyperpolarization at the end of

Phase 3 (“f” from funny)

-Produces an inward, depolarizing current of Na+

-If through a nonspecific cation channel (permeable for Na &

K) called HCN (hyperpolarization-activated cyclic nucleotide

(AMPc, GMPc)-gated channels)

-other pacemaker currents: Ica, IK

Ionic pumps

- Na+/K+ pump: action mechanism; blockers – ouabain

- Ca2+ pumps: function, distribution, action mechanism

sarcoplasmic reticulum:

calsequestrin

Ca2+ ATPase

Ca2+

channels

Na+/Ca2+

exchanger

Na+/K+ ATPaseCa2+ ATPase

Ca2+ in myocardial fiber: transport through

channels, pumps and exchangers

- Na+/H+ antiporter

Ionic exchangers

- Cl-/HCO3- antiporter

- 1Na+/1K+/2Cl - exchanger

- K+/Cl- , Na+/Cl- symporters

- 3Na +/1Ca++ antiporter

-Na+/aa, Na+/G, H+/oligopeptidesymporters

- Na+/HCO3- symporter

Na+/Ca2+ exchanger (NCX1)

-location: sarcolema

-transport mechanism: 3Na+/1Ca2+ (net inward current)

-has an increased activity during the late part of the AP plateau phase

-functional inter-relations with Na/K pump

-[discuss the effect of cardiac glycosides (digitalis):

1. on Na/K pump & indirectly on Na/Ca exchanger

2. on Ca permeability of Na channels ]

-reverse function during injury…

Heart Excitability

• Heart is an excitable tissue capable of generating and

responding to electrical signals

Heart contains cells that generate spontaneously APs

= Pacemaker Cells (exhibits automaticity)

slow response AP induce a pace…

Working myocardium – respond to electrical stimuli

fast response AP contraction…

Action Potentials along the heart

atrium

Purkinje fb.

SANAVN

ventriclesHiss b.

Mem

bra

ne

po

ten

tia

l(m

V)

0

-50

-100

0

-50

-100

300ms

Slow response AP

Fast response AP

Transmembrane potential recorded from

a fast-response (left) and a slow-response (right) cardiac fiber

in isolated cardiac tissue immersed in an electrolyte solution.

ERP, effective refractory period;

RRP, relative refractory period.

Effect of changes in external [K+] on the transmembrane action potentials recorded from a Purkinje fiber. Stimulus artifact (St) - to the left of the upstroke of the action potential.

Fast responses may change to slow responses under certain pathological conditions (e.g., ischemia [K+] rises in the interstitial fluid because

inadequate perfusion).

atrium

Purkinje fb. ventricles

Me

mb

ran

e p

ote

ntia

l(m

V)

0

-50

-100

0

-50

-100

300 ms

• Normal atrium and ventricular myocardium

• Purkinje fibers in the specialized conductive system

Fast Action Potentials in the myocardium

Restingpotential

Mem

bra

ne p

ote

ntial(m

V)

-

+

0

depola

riza

tion

threshold

overshoot

repolarization

repola

riza

tion

posthyperpolarization

Fast Action Potentials

stimulus

AP Phases

0 50 100 150 200 250 300 ms

Mem

bra

ne P

ote

ntial(m

V)

0

-50

-100

0

21

3

4 4

AP Phases: 0- depolarization/upstroke of the AP; 1-initial repolarization; 2-plateau; 3-repolarization; 4- resting membrane potential

0 0.15 0.30

Time (sec.)

Mem

bra

ne

Pote

nti

al

(mV

)

0

-50

-100

10

1.0

0.1

PNa+

PK+

PCa2+

AP

Name

Voltage

(V)-Gated

or Ligand

(L)-Gated Functional Role

Voltage-gated Na+

channel (fast, INa)

V Phase 0 of action potential (permits influx of Na+)

Voltage-gated Ca2+

channel (slow, ICa)

V Contributes to phase 2 of action potential (permits influx of Ca++

when membrane is depolarized); β-adrenergic agents increase

the probability of channel opening and raise Ca2+ influx;

Acetylcholine (ACh) lowers the probability of channel opening

Inward rectifying K+

channel (IK1)

V Maintains resting membrane potential (phase 4) by permitting

outflux of K+ at highly negative membrane potentials

Outward (transient)

rectifying K+

channel (Ito)

V Contributes briefly to phase 1 by transiently permitting outflow of

K+ at positive membrane potentials

Outward (delayed)

rectifying K+

channels (iKr, iKs)

V Cause phase 3 of action potential by permitting outflow of K+

after a delay when membrane depolarizes; IKr channel is also

called HERG channel (‘r’ for rapid, ‘s’ for slow).

G protein–activated

K+ channel (iK.G,

iK.ACh, iK.ado)

L G protein–operated channel, opened by ACh and adenosine

(ado); this channel hyperpolarizes membrane during phase 4

and shortens phase 2

Major Ion Channels Involved in Purkinje and Ventricular

Myocyte Membrane Potentials

Events associated with the

ventricular action potential

0 50 100 150 200 250 300 ms

Mem

bra

ne

Pote

nti

al(m

V)

0

-50

-100

ERPRRP

Refractory periods

ERP/ARP-effective/absolute refractory period;

RRP-relative refractory period

Changes in action potential amplitude and slope of the upstroke as premature (P) action potentials are initiated at different stages of the relative refractory period of the preceding excitation in a fast-response fiber (bar = 100 msec).

Premature contraction

P

early

delayed

AP – electrical activity

Contraction – mechanical activity

P- premature contraction

Compensatory pause

Myocardial Properties

Excitability (bathmotropia)

Rhythmic activity /automaticity (chronotropia)

Conductibility (dromotropia)

Contractility (inotropia)

Relaxation (lusitropia)

Cardiac muscle cells contract without nervous stimulation

- 1% from the myocardium: pacemaker/autorhythmic cells

(99% contractile cells)

- Pacemaker cells: organized in a specialized excitatory & conductive system

- anatomically distinct

smaller, contain few contractile fibers

- electrogenic system: EXCITABILITY, CHRONOTROPISM generate AP spontaneously, rhythmically

- set the rate of the heart beat: CONDUCTIVITY

rapidly conduct APs throughout the heart generate rhythmical contraction

Specialized excitatory & conductive system

1. S-A Node: pacemaker of the heart in normal conditions;

- exhibits automaticity: generate AP at a higher rate than the AV node andHis-Purkinje system (latent pace-makers);

- located in the superior posterolat. wall of the RA; ellipsoid shape: 15/3/1 mm

- P cells: do not have a constant resting potential; membrane permeability to

Na and Ca during diastole; inward Ca current during upstroke of AP.

2. Internodal & interatrial pathways

3. A–V Node: inward Ca current during upstroke of AP;

here an AP delay of 0.1 sec (role!)

4. AV bundle (His-Purkinje)

- intercalated disks, gap junctions

- left & right branches of the AV bundle

5. Purkinje fibres: distribute to the endocardium, causes ventricles

to contract, from bottom up, pushing blood out top of heart

Action Potential (AP) in pacemaker cells

Phases of SAN action potential.

The records in this figure are idealized. IK, INa, ICa,

and If are currents through K+, Na+, Ca2+, and

nonselective cation channels, respectively.

You can dissolve an embryonic heart into its individual cell types with

trypsin, an enzyme that destroys the protein glue between the cells. Plate

these cells in a dish and you will see some cells - called myocytes - that

beat independently, some faster, some slower, as long as they do not touch

one another. The cells shown here are from the chick embryo.

http://www.cellsalive.com/myocyte.htm

Autorhythmic cells exhibit PACEMAKER POTENTIALS

Modulation of pacemaker activity

to decrease the heart rate:

A. Prolonged slow depolarization

B. Hyperpolarization (a more negative

resting potential)

C. Threshold shift towards a more

positive value

Myocardial Properties

Excitability (bathmotropia)

Rhythmic activity /automaticity (chronotropia)

Conductibility (dromotropia)

Contractility (inotropia)

Relaxation (lusitropia)

Myocardial conductivity = DROMOTROPIAin a dish… in the heart…

After two or three days in vitro, the myocytes form interconnected sheets of

cells (monolayers) that beat in unison. Pores (gap junctions) open between

adjacent touching cells, making their cytoplasms interconnected. These gap

junctions ensure the synchronous activity of the connected cells.

Myocardial conductivity = DROMOTROPIA

1. S-A Node area

2. Internodal & interatrial pathways

3. A–V Node:

inward Ca current duringupstroke of AP; AP delay 0.1 s

4. AV bundle (His-Purkinje)- intercalated disks, gapjunctions- split into left & right branches

5. Purkinje fibres: causes ventricles to contract, from bottom up, pushing blood out top of heart

1. Atria contraction precedes ventricles contraction, because of AV nodal delay:

- the impulse travels rather slowly through AV node (0.09 sec) & penetrating part of the

AV bundle (0,04 sec) (cause of the delay: less gap junctions…)

2. Both atria and ventricles should contract as a unit

-the impulse spreads so rapidly through the conducting system that all myocardial cells in

the atria and ventricles, respectively, contract at about the same time.

The myocardial conductivity is needed for an efficient pumping

The AV node

• composed of three functional regions:

1. the AN region - the transitional zone between the atrium and the remainder of the node;

2. the N region - the middle part of the AV node

3. the NH region, in which the nodal fibers gradually merge with the bundle of His

• normally, the AV node and bundle of His are the only pathways along which the cardiac impulse travels from atria to ventricles

- accessory AV pathways - reentry loops

Organization of the A-V node. The numbers represent the interval of time (sec) from the origin of the impulse in the sinus node.

Conduction velocity• Reflects the time required for excitation to spread from SAN

to the entire cardiac tissue

• Fastest in the Purkinje system, slowest in AVN (important for ventricular filling…)

– 0.02 to 0.1 m/sec in SA & AV nodes

– 1 m/sec. in internodal & interatrial anterior pathways

– 0.3-0.5 m/sec in A & V muscle

– 1.5 - 4 m/sec in Purkinje fibers

longer fibers, distributed in 1/3 of ventricular volume

gap junctions (no., permeability…),

direct connection with myocytes

fast Na currents, “regenerative spread of conducted AP”

rapid conduction of cardiac impulse

Atrioventricular and ventricular conduction system. Purkinje network distribution.

Conduction velocity

SAN / AVN: 0.02 to 0.1 m/sec

Internodal&interatrial anterior

pathways: 1m/sec.

AV delay: ~ 0.1 sec

AV bundle

Purkinje fibers: 1.5 - 4 m/sec

EndocardiumEpicardium

(in A&V mm): 0.3-0.5 m/sec

Transmission of the cardiac impulse through theheart, showing the time of appearance (infractions of a second after initial appearance atthe sinoatrial node) in different parts of the heart.

Spreading of excitation from S-A N to the entire cardiac tissue

Chronotropic effect:

on the firing rate of SAN;

positive/negative

Dromotropic effects:

on conduction velocity, especially in AVN;

positive/negative

Distribution of the nervous fibers

Modulation of the heart rate by the autonomic nervous system

PS vagal innervation Ach mediated

Muscarinic receptors on SAN, atria, AVN

Negative chronotropic effect: ↓ If , delayed slow depolarization↓ heart rate (sinus bradycardia)

Negative dromotropic effect: ↓ inward Ca current

↓ conduction velocity through AVN

AP are conducted more slowly from A to V

S innervationnorepinephrine mediated (also epinephrine - adrenal medulla)

b1 receptors

Positive chronotropic effect: ↑ If , ↑ heart rate (sinus tachycardia)

Positive dromotropic effect: ↑ inward Ca current↑ conduction velocity through AVN

! ventricular filling

Autonomic effects on automatism and

conduction velocity