Cardiac contraction

Question 1

What is central to contraction?

Answer 1

Rise in concentration of calcium is central to contraction

Question 2

What is the duration of an action potential?

Answer 2

~200-500ms

Question 3

Action potential in cardiac muscles?

Answer 3

Na + channels open allowing Na + to
enter and depolarise
o K + channels open allowing K + to leave
 Thereby restoring the resting
potential

Question 4

What is force of contraction proportional to and the concentrations of Ca2+?

Answer 4

Force of contraction proportional to [Ca 2+ ]
o Diastolic [Ca 2+ ] ~ 0.1 μM
o Normal systole [Ca 2+ ] may rise ~ 1 μM
o Maximum systole [Ca 2+ ] may rise ~ 10
μm

Question 5

What is cell shortening usually less than?

Answer 5

Cell shortening usually less than maximum

Question 6

When does the Ca2+ signal and cell shortening occur?

Answer 6

Ca 2+ signal and cell shortening occur
during depolarisation “plateau” phase
of the action potential

a. When intracellular calcium
is generated

Question 7

When does cell relaxation occur?

Answer 7

Cell relaxation occurs during
repolarisation of the action potential

a. When the calcium signal is
reduced

Question 8

What are the intracellular Ca2+ levels during electrical excitability?

Answer 8

Intracellular Ca 2+ levels increase from 0.1 μM to about 10 μM

Question 9

Process of intracellular rise in Ca2+ concentration

Answer 9

1) Action potential (Na + ions) depolarises T-tubules and activates VDCCs causing a Ca 2+ influx
2) Ca 2+ binds to RyR located on SR – there is a close association with T-tubules
3) There is a release of Ca 2+ from the SR – CICR
4) Ca 2+ to troponin
a. The displacement of tropomyosin/troponin complex, exposing active sites on actin
5) Myosin thick filament heads bind to active sites
6) Myosin head ATPase activity release energy (ATP to ADP)
a. Filaments slide

Question 10

What does a rise in Ca2+ concentration cause?

Answer 10

Rise in [Ca 2+ ] causes myosin-actin interactions

Question 11

Actin myosin interaction during contraction

Answer 11

1) Myosin-actin binding sites blocked by troponin-tropomyosin complex (white star)
2) Ca 2+ displaces troponin-tropomyosin so actin-myosin binding
sites are exposed and an actin-myosin cross-bridge is
formed
3) Myosin head flexes to move actin and the Z line
towards the sarcomere centre

Question 12

What does a greater rise in Ca2+ concentration do?

Answer 12

• Greater rise in [Ca 2+ ]
  o More sites exposed
  o More cross-bridges
  o Greater contractility

Question 13

How many regulatory sub units is troponin composed of?

Answer 13

Composed of 3 regulatory subunits

Question 14

What are the three regulatory subunits?

Answer 14

o Troponin T (TnT) – binds to
tropomyosin
o Troponin I (TnI) – binds to
actin filaments
o Troponin C (TnC) – binds Ca 2+

Question 15

What does the binding of Ca2+ to TnC lead to?

Answer 15

Binding of Ca 2+ to TnC leads to conformational changes of
tropomyosin and the exposure of
actin binding sites

Question 16

Why are TnI and TnT important?

Answer 16

TnI and TnT are important blood plasma markers for cardiac cell death

Question 17

Process of decrease in Ca2+ concentration and relaxation

Answer 17

1) Action potential repolarisation (K + ions) repolarises T-tubules – closure of VGCCs,
and a decrease of Ca 2+ influx
2) No Ca 2+ influx, no CICR
3) Extrusion of Ca 2+ from cell (30%) – by Na + /Ca 2+ exchanger (NCX)
4) Ca 2+ uptake into SR via SR Ca 2+ ATPase (SERCA, 70%) – Ca 2+ in SR for next
contraction
5) Uptake of Ca 2+ in mitochondria
6) Reduction in [Ca 2+ ], myosin head ATPase activity releases energy (ATP to ADP)
7) Prevention of contraction mechanism – chambers relaxed, and can fill with blood

Question 18

Ways cardiac contractility is controlled?

Answer 18

In general, these drugs increase [Ca 2+ ]
1) Increasing VGCC activity (sympathetic mimetic)
2) Reducing Ca 2+ extrusion (cardiac glycosides)
- These are positive INOTROPES
o Increase energy/strength of contraction
- Sympathetic nervous system
o Noradrenaline (NA) acts on β 1 – adrenoreceptors to increase contractility

Question 19

Activation of beta-1 adrenoreceptors and its pathway

Answer 19

Noradrenaline stimulates the GPCR(Beta 1 adrenoreceptor)

cAMP levels increase resulting in an increase in PKA levels

PKA phosphorylates VGCC, increasing its activity

This results in a Ca2+ influx which causes CICR.

Overall concentration of Ca2+ increases

Increase in sliding filament mechanism and ultimately an increase in contractility

Question 20

What are positive inotropic effects?

Answer 20

Increased contractility of the heart

Question 21

What are positive chronotropic effects?

Answer 21

Increased heart rate

Question 22

What are positive dromotropic effects?

Answer 22

Increased conduction through AV node

Question 23

What are lusitropic effect?

Answer 23

Increased rate of relaxation, K channels & SR Ca 2+ ATPase

Question 24

What are cardiac glycosides?

Answer 24

Positive inotropic action of the heart and are therefore called inotropes

Question 25

What is digoxin and what does it do and whats it used for?

Answer 25

Digoxin is a cardiac glycoside.
Digoxin increases contractility by reducing Ca 2+ extrusion
o Used for chronic heart failure
o Not used so much now – difficult side effects
o Useful to understand contractility mechanisms

Question 26

Mechanism of action of cardiac glycosides

Answer 26

1) Digoxin inhibits Na + /K + ATPase
2) Build up of [Na + ]
3) Less Ca 2+ extrusion by Na/Ca exchanger
4) More Ca 2+ uptake into stores and greater CICR

Question 27

Dobutamine and dopamine

Inotropic agent

Answer 27

o β 1 – adrenoreceptor stimulants

 May be used in acute heart failure

Question 28

Glucagon(Inotropic agent)

Answer 28

o Acts at GPCR
o Stimulates Gs pathway, increasing cAMP and PKA activity
 Used in patients with acute heart failure who are taking β-blockers

Question 29

Amrinone(Inotropic agent)

Answer 29

o A phosphodiesterase inhibitor
o Type III phosphodiesterase (PDE3) is heart specific
o PDE converts cAMP into AMP
 Reducing cAMP and decreasing PKA activity
 Reduces contractility

o PDE inhibition leads to a build up of cAMP that activates PKA to phosphorylate
VGCCs
 An increase in calcium ions is only used in severe cases
 E.g. those waiting for heart transplants