LIFS 3040

Animal Physiology

EPISODE VI
Module 2: The
Heart and
Circulation of Blood
Lecture #2
Dr. Aftab Amin
aftabamin@[Link]
Presentation Content
• Introduction
• Smooth & Cardiac Muscle Similarities
• Cardiac Muscle Regulation by Ca2+
• ECG
• Feedback Mechanisms
• Systole and Diastole
• SA and AV Nodes – Heartbeat
Some Recap:

Excitation-Contraction Coupling
in Cardiac Muscle
 Cardiac and Skeletal Muscles are Similar!
(i) They both contain actin and myosin filaments organized in sarcomeres.
(ii) These INTERDIGITATE and slide closer
together during contraction and further
apart during relaxation.

(iii) Slide together in the presence of FREE Ca2+ in the cytoplasm.

(iv) Contact is made via myosin crossbridges and binding sites on the actin
filaments.
(v) Both muscle types contain T-tubules - which conduct impulses
perpendicular to the cell surface towards the interior.
(vi) Both contain a well-developed SR which:

a. Releases Ca2+ to trigger contraction.

b. *Sequesters (takes up) Ca2+ for relaxation.

(vii) Both contain TROPONIN and TROPOMYOSIN, which keep the actin and
myosin crossbridges apart in the absence of Ca2+.
Cardiac Muscle
 There are also IMPORTANT DIFFERENCES between
Cardiac and Skeletal Muscles

(i) When skeletal muscle is activated, enough Ca2+ is released into the cell
to react with NEARLY ALL the TROPONIN C - resulting in almost ALL the
myosin head BINDING SITES BECOMING AVAILABLE FOR ATTACHMENT
and almost ALL the CROSSBRIDGES BECOMING ACTIVATED.

(ii) Normally in CARDIAC muscle THIS IS NOT THE CASE.

(iii) TROPONIN-C in CARDIAC muscle is NEVER FULLY bound to Ca2+.

 Differences in Ca2+ release
In skeletal muscle normally In cardiac muscle NOT all
almost ALL Troponin Ca2+ Troponin Ca2+ binding sites are
binding sites are immediately immediately occupied on
occupied on stimulation. stimulation.

(almost)

Thus, in cardiac muscle, more Ca2+ released, more contraction!

 DIFFERENCES Continued
(iv) Regulation by Ca2+ release: This adds an extra dimension of control to cardiac
muscle contraction.
(v) Anything that increases the concentration of free Ca2+ within the cell, will
increase the number of binding sites exposed and therefore the number of
crossbridges that can bind.

(vi) This increase in the number of ACTIVE cross bridges will INCREASE the
STRENGTH OF THE CARDIAC CONTRACTION.

(vii) Thus, WHATEVER CONTROLS THE INTERNAL CONCENTRATION OF FREE Ca2+

WILL HELP CONTROL CARDIAC PERFORMANCE.
(viii) Unlike the situation in skeletal muscle, the MYOCARDIUM is not a TRUE
ANATOMICAL SYNCYTIUM.

BECAUSE…
a. Laterally, the myocardial fibers are SEPARATED FROM ADJACENT FIBRES by their
respective sarcolemmas (i.e., muscle cell plasma membranes).

b. But the ends of each fiber are separated from its neighbour by dense structures
called INTERCALATED DISCS, which are continuous with the sarcolemma.

c. Thus, although not a true anatomical syncytium, cardiac muscle FUNCTIONS as a

syncytium because of the presence of GAP JUNCTIONS.
 Development of Skeletal Muscle

Skeletal Muscle cells are a Anatomical Syncytium

true Anatomical syncytium vs. Functional Syncytium
 DIFFERENCES Continued
(ix) Another difference between cardiac and skeletal muscle, is the ABUNDANCE of
MITOCHONDRIA (or SARCOSOMES) in cardiac muscle cells.
a. Cardiac muscle, which contracts repetitively for a lifetime, is VERY RICH IN
MITOCHONDRIA - and thus requires a continuous supply of O2.

b. Skeletal muscle (especially FAST skeletal muscle) has relatively FEW mitochondria
as its function is to contract rapidly for short periods of time.

There is an abundance of mitochondria in cardiac muscle cells

Note also the capillary and red blood cell to supply cells with O2
 Regulation of Cardiac Muscle Contraction and
Relaxation by Ca2+
1. Complex and fascinating subject.
2. The complexity increases the more we discover about the physiology
and molecular biology associated with Ca2+-mediated regulation.

3. Thus, our understanding of this regulation is constantly expanding.

How is free Ca2+ regulated in Cardiac Muscle Cells?

(i) Free Ca2+ in the cytoplasm of cardiac cells is ~20,000 times LOWER that in
the EXTRACELLULAR free space surrounding a cell.
(ii) Most Ca2+ within the cell is NOT FREE. It is either:

a. Sequestered within the SR.

b. Most bound to calsequestrin.
c. Sequestered within the mitochondria.
d. Sequestered within endolysosomal vesicles.
e. Bound to proteins and other cytoskeletal components.
 Calsequestrin: Major Ca2+ binding protein
within the SR of cardiac (and skeletal) muscle cells.

Major Ca2+ storage

protein in the SR

Note: No mechanical interaction between the

DHPR (CC – calcium channel) and the RyR2.
 Calcium Binding Proteins
Most have the prefix Cal indicating they bind to Ca2+

Calsequestrin (Ca2+ storage protein in SR)

Calmodulin

Calcinurin (activates T-cells)

Q: Which important Ca2+ binding protein in cardiac and skeletal muscle cells
does not follow this “CAL” prefix convention?

A: Troponin C

(iii) Thus, in a relaxed state, Ca2+ IS POISED AT HIGHER CONCENTRATIONS

BOTH WITHIN THE SR and other organelles, as well as OUTSIDE THE CELL
waiting to enter the cytoplasm.

(iv) If it does, it will have easy access to the Troponin C and hence control the
contractile filaments.
Ca2+- mediated regulation of Contraction and Relaxation

Ca2+- release – Precise

mechanism; complex and
involves:

1) 1P3 (IP3Rs)
2) cADPR (ryanodine channels)
3) Ca2+ itself

[Ca2+]cyt [Ca2+]SR [Ca2+]o

[Ca2+]ER
 During heart activity, APs travel over surface membranes, invade T-tubules,
and come into close proximity of the SR CISTERNAE (i.e., a flattened tubule).

The precise mechanism as to how this causes the release of Ca2+ in cardiac
muscle cells is currently under intense study.
Thought to involve:

a. DHPRs in the T-tubule walls.

b. RRs in the SR membrane.
c. An additional Ca2+ releasing second messenger, IP3, and its receptor,
the IP3 Receptor (IP3R), also located in the SR membrane.

IP3: Inositol 1,4,5-trisphosphate Structure of IP3 Receptor

Many stimuli function through

PHOSPHOLIPASE C (PLC) to generate IP3.

IP3 functions to release Ca2+ from

intracellular stores, mainly the ER and SR
 IP3 signaling
from plasma
membrane to SR

PIP2 (or PIP2) :

• Phosphatidylinositol 4, 5-bisphosphate.

• It is a minor, but very important, phospholipid component of the plasma

membrane.
• Intermediate in the IP3/DAG Signaling Pathway.

• Substrate for hydrolysis by Phospholipase C.

of IP3 from PIP2
via
Phospholipase C

PIP2:
• Phosphatidylinositol 4, 5-bisphosphate.

• In addition to the Ca2+ released from the SR via RRs and IP3Rs -
SOME Ca2+ ALSO ENTERS THE CELL FROM THE OUTSIDE WITH
EACH ACTION POTENTIAL VIA VOLTAGE GATED Ca2+ CHANNELS
(DHPRs) in the cardiac muscle cell wall.
 Voltage gated Ca2+ channel in action

• = Ca2+

L-type = Long-Lasting voltage gated Ca2+ channel.

In cardiac muscle there is also another important voltage-gated Ca2+ channel:

T-type = Transient voltage gated Ca2+ channel.

T-type channels differ from the L-type Ca2+ channels due to their
ability to be activated by more negative membrane potentials.
 Ca2+ release from the SR
Role of IP3Rs and RRs in Ca2+ release in cardiac muscle cells

RyR IP3R
 Why should there be 2 types of Ca2+ release channels
in the heart?
Not exactly known!

• New evidence suggests that these two types of receptors may be

expressed in different parts of the heart.

• For example, IP3Rs have been reported to be more abundant in the

atria compared to the ventricles in the hearts of some species.

Receptors and their AGONISTS

ANTAGONIST: CLOSES a receptor (or channel) Antagonist: STOP!

Closed

AGONIST: OPENS a receptor (or channel) Agonist: GO!

Open
 Endogenous Agonist

IP3 cADPR
Inositol trisphosphate cyclic-ADP Ribose

IP3 Receptor RyR

Important to remember: Ca2+ itself can also modulate these receptors

Remember Skeletal Muscle Cells (Plunger Model)

Physical
Contact RR open

Get mechanical/physical interaction when stimulated.

 Cardiac Muscle Cell
NO mechanical interaction between DHPR and RR
Summary of the ways in which Ca2+ can be
released into the cytosol of a cardiac
muscle cell
 Ca2+ release channels in the SR membrane

IP3 receptors Ryanodine Receptor 1

IP3 = Inositol trisphosphate cADPR = cyclic ADP ribose

Ryanodine Receptor 2
CICR = Calcium-Induced Calcium Release
CICR
L-type or T-type
Plasma membrane Ca2+ channels
L-type or T-type

Ca2+ enters directly into the cytoplasm and

stimulates cardiac muscle to contract.

Plasma membrane Ca2+ channel

 SR/ER Ca2+ channels

Agonist = Opens channel

Antagonist = Closes channel

Ryanodine Receptor = cADPR channel or receptor

 Contraction [Ca2+]cyt RISES
From PLC ADPR cyclase
activity in PM

Other RyRs also

Ca2+ sensitive

L-type or T-type

Complex interaction between Ca2+ release mechanisms

 CICR
Although the Ca2+ entering the cardiac muscle cell via the voltage-gated
channels is NOT ENOUGH to FULLY activate the contractile mechanism,
it DOES STIMULATE THE RELEASE OF MORE Ca2+ from the INTERNAL
STORES, i.e., THE SR via RyRs and IP3Rs.

Ca2+ TRIGGERS ITS OWN RELEASE via Calcium-Induced-Calcium-

Release (CICR).

When this happens, Ca2+ levels inside the cell rise rapidly, cross bridges
are activated, and these high levels of cytosolic Ca2+ PERSIST
THROUGHOUT the PROLONGED AP.

In this example, the

1st messenger is IP3.

In some cases, the

Ca2+ signal can be
amplified.
 CICR WAVE ACROSS CARDIAC MUSCLE

During the RELAXATION of cardiac muscle, the level of

INTERNAL free Ca2+ is REDUCED PRIMARILY by an
ATP-DRIVEN Ca2+ PUMP in the membrane of the SR –
i.e., SERCA pumps.

If there is more Ca2+ in the cytosol, MORE will be loaded

BACK INTO the SR.

As a result, more Ca2+ can be potentially released at the

next heartbeat to CAUSE A MORE POWERFUL
CONTRACTION.

To act as an efficient pump,

heart muscle must RELAX as
well as CONTRACT!

Remember SERCA and PMCA

Summary: Relaxation [Ca2+]cyt FALLS

3 Na+ / Ca2+

3
 Ca2+ regulation of cardiac muscle contraction
represents an excellent example of:
(i) A complex system of control with overlapping and interacting second messengers.

(ii) A field of research that is advancing and expanding every year with each new
discovery.

(iii) An area of intense biological and biomedical investigation and importance.

(iv) The basis of crucial life saving drug development.

 The ECG and Impulse Conduction in the Heart

ELECTROCARDIOGRAM Normal ECG:

KEY FEATURES on ECG: P, QRS, T!

Only 5 components to remember!

 P-R Interval

P-R Interval: The time

from the beginning of
the P WAVE to the
beginning of the R
WAVE measures the
time taken for IMPULSE
CONDUCTION FROM
THE ATRIA to the
VENTRICLES.

(i) Although the heart APPEARS to be electrically "SILENT" during PART of this time - a
WAVE OF DEPOLARIZATION IS STILL PROPAGATED.

(ii) This time includes PASSAGE OF THE IMPULSE TO THE AV NODE.

(iii) The DELAY imposed by the AV NODE.

(iv) Passage through the AV BUNDLE (the BUNDLE OF HIS), BUNDLE BRANCHES, and
into the PURKINJE NETWORK.
QRS COMPLEX: This corresponds to the INVASION of the
VENTRICULAR MUSCULATURE by EXCITORY IMPULSES.
(i) It is recorded as a bigger deflection than the P WAVE because the
VENTRICULAR MASS is MUCH LARGER than the ATRIAL MASS.

(ii) The duration of the QRS Complex is shorter than the P WAVE because
impulse conduction through the ventricles (partly via the PURKINJE
NETWORK) is VERY RAPID.

S-T SEGMENT: During the interval between S and T, the ECG registers ZERO
- all of the ventricular muscle is in the same DEPOLARIZED STATE (recall
the long plateau of the action potential of ventricular fibers) - as a result,
THERE ARE NO DIFFERENCES TO RECORD.

T WAVE: This results from ventricular REPOLARIZATION as different parts

of the ventricle REPOLARIZE AT DIFFERENT TIMES.

These are only the BARE RUDIMENTS of the information buried in an ECG.
Atrial Repolarization hidden by QRS complex

Normal ECG wave

 The Nodes!
SA NODE is composed of specialist cardiac myocytes and
although they do posses some contractile filaments,
they do not contract – considered to be the heart’s pacemaker.

SA = Sinoatrial

AV NODE is also a region of

specialized heart tissue
Located between the atria Purkinje system
and ventricle and serves to
conduct normal electrical
impulses from the atria to ◄ Bundle of His
the ventricles

AV = Atrioventricular

Purkinje system
 Normal Cell – Land Animal

CHANNELS
Ions flow down
concentration gradients.
High Low
(FREE) Ca2+

PUMPS
Have to work to move
them against
concentration gradients.
Low High
(WORK – ATP)
 AP in Skeletal Muscle or
Nerve Cells, and most
Heart Muscle cells.

First, rapid depolarization.

Followed by repolarization.

On repolarization always
get some overshoot.

Level Resting Potential

 In all three cases - NERVE,
SKELETAL MUSCLE and MOST
CARDIAC MUSCLE - the opening
of the Na+ channel is caused by
MEMBRANE DEPOLARIZATION:
This also activates a POSITIVE
FEEDBACK.

Positive feedback:
Once one Na+ channel opens
other Na+ channels open
 In NERVE and SKELETAL
MUSCLE, this is followed by an
INACTIVATION of the Na+
channels together with an Negative Positive
OPENING of the K+ CHANNEL - feedback feedback
which REPOLARIZES THE
MEMBRANE VERY QUICKLY.

Negative feedback: Positive Negative

closes the Na+ channel. feedback feedback

Positive feedback:
acts on the opening
more K+ channels.

ALL types of Cardiac Muscle

cell are also REPOLARIZED by
opening K+ channels.
CARDIAC PURKINJE muscle cell is DIFFERENT:
(i) Its Na+ channels do activate and inactivate in a similar way.
(ii) But the opening of its K+ channels IS DELAYED.

(iii) During this delay, the membrane potential is HELD IN A SUSPENDED

PLATEAU by SMALL AMOUNTS OF Ca2+ FLOWING THROUGH Ca2+ CHANNELS
that have opened in RESPONSE TO MEMBRANE DEPOLARIZATION.

(iv) The small amounts of Ca2+ that enter the cell JUST BALANCE the small
amounts of K+ that are leaking out. This leads to the AP plateau.

Plateau: Flat region at the peak of a curve

(v) Finally, after a 0.2 to 0.3 sec (200 to 300 msec) DELAY, MORE K+
CHANNELS OPEN, the Ca2+ channels CLOSE, and the membrane is rapidly
REPOLARIZED.

(vi) The membrane potential falls to a minimum and then begins to rise towards
the THRESHOLD as the CYCLE REPEATS.
Purkinje fiber

Skeletal
muscle fiber
 Two New Terms
Systole: When the heart muscle contract.

Hence terms such as “Systolic pressure” or “Systolic potential.”

Diastole: When the heart muscles relax.

Hence terms such as “Diastolic pressure” or “Diastolic potential.”

Systole and Diastole and the ECG Trace

The SLOWLY RISING DIASTOLIC* POTENTIAL is due to the CLOSING of the
K+ channel so that the small resting flow of Na+ leaking inwards becomes
more and more effective in balancing the K+ outflow.

This drives the potential towards the threshold and depolarization.

*Diastolic Potential = Resting Potential

Action potentials recorded from other areas of the ventricle are similar -
EXCEPT that the resting potential REMAINS LEVEL.

These other cells DO NOT show the same SPONTANEOUS ACTIVITY as

Purkinje Fibers.
1. Atrium wall
2. Ventricle wall
3. SA node (pacemaker)
4. AV node
5. AV bundle
6. Purkinje system
- Left and right bundle branches
- Purkinje fibers

1, 2, and 5 =
level resting
potentials
3, 4, and 6 =
rising resting
potentials
APs in various regions of the heart
AP in Purkinje Fiber - Slowly rising resting potential explained by:-
opening and closing of channels

Dynamic Ion Exchange

Shape of curve
explained by the
relationship between
K+ moving OUT
and Na+ moving IN
SINOATRIAL NODE (SA NODE) and the ATRIOVENTRICULAR NODE (AV NODE):

(i) Action potentials recorded from the SA and AV nodes are DIFFERENT from Purkinje
Fibers and other heart muscle cells.

(ii) Instead of Na+ channels, Ca2+ channels are ACTIVATED by membrane depolarization.

(iii) Thus, the inward flow of Ca2+ is responsible for the rising phase of the AP.

Remember: All muscle cells are

repolarized by an efflux of K+
AP in SA
Node (iv) The RISE in DIASTOLIC POTENTIAL
(or RESTING POTENTIAL) is RAPID and
reaches threshold VERY QUICKLY.

(v) Isolated cells for the SA and AV NODE

DO show SPONTANEOUS ACTIVITY.

(vi) Isolated SA node cells BEAT at FAST

RATES - FASTER THAN ISOLATED AV
NODE CELLS - which in turn BEAT
FASTER THAN PURKINJE FIBERS.
 SA and AV Node Cells:

Why use Ca2+ instead of Na+?

It depolarizes the plasma

membrane very rapidly.
 Cells from the SA NODE (PACEMAKER) set the rhythm for the entire heart.

(i) These rapidly beating cells become excited first, then TRANSMIT THEIR
EXCITATION to the other cells of the heart.
(ii) Although many other heart cells are capable of beating at their own (slower) rate,
they never do so because they are DRIVEN AT THE FASTER RATE by impulses
ORIGINATING AT THE SA NODE.

To initiate a COORDINATED BEAT - there has to be a mechanism for RAPID IMPULSE

CONDUCTION TO ALL PARTS OF THE HEART.

It is ALSO important that the ATRIA

and VENTRICLES of the heart DO
NOT beat at the same time.

ATRIA AND VENTRICLES are

separated by a band of
CONNECTIVE TISSUE that DOES
NOT conduct impulses very well.
Bachman’s Bundle: Impulse conduction across the Atria
 Impulse conduction from the Atria to the Ventricles
1. SA Node

2. AV Node

3. AV Bundle or
Bundle of His

4. Left and Right

Bundle Branches

5. Bundle Branches (Purkinjie Fibers)

It takes about 0.04 sec for an impulse to travel from the SA node to the AV node.

But by the time the impulse finally leaves the AV node to emerge in the
ATRIOVENTRICULAR BUNDLE (AV BUNDLE or BUNDLE of HIS), there is an
ADDITIONAL DELAY of about 0.11 sec.
This AV DELAY PROVIDES TIME for the ATRIA to COMPLETE
THEIR BEAT BEFORE the VENTRICLES BEGIN TO CONTRACT.
Once past the AV node, the impulse is RAPIDLY CONVEYED VIA THE
PURKINJE NETWORK to ALL parts of the ventricle, ensuring that ALL
PARTS BEAT IN UNISON (i.e., TOGETHER) to impart the maximal thrust to
the blood.
This delay in passing on the wave of depolarization, and hence contraction,
is crucial as it ensures that the atria have ejected their blood BEFORE the
ventricles contract!

Remember – VERY Important !

The ECG trace that you record DOES NOT represent
the electrical activity of a SINGLE CELL.

It represents the electrical activity of the WHOLE

HEART, i.e., many thousands of cells. These lie in
different orientations and are active at different times.

Thus, the ECG shows the ‘BIG PICTURE’ of the

heart’s electrical activity.
 1. Heart Arrhythmia

2. Artificial Pacemaker
A pacemaker is a device used to control
an irregular heart rhythm.

Thank
You!