Cardiac contraction

Question 1

Length of cardiomyocytes

Answer 1

60-140μm

Question 2

Diameter of cardiomyocytes

Answer 2

17-25μm

Question 3

Myocytes

Answer 3

Made up of myofibrils that are composed of sarcomeres

Question 4

T-tubules

Answer 4

Invaginations of sarcolemma that penetrate the center of cardiac muscle cells

Question 5

Function of cardiomyocyte

Answer 5

• T-tubules have Ca2+ channels - ensure Ca2+ delivered deep into the cell close to the sarcomere
• Ca2+ enters via calcium channel that open in response to the wave of depolarization that travels along the sarcolemma where they trigger the release of more calcium from the SR and initiate contraction.
• The varying actin-myosin overlap is shown for systole, when [Ca2+] is maximal, and diastole, when [Ca2+] is minimal.
• Eventually the Ca2+ that has entered the cell leaves predominantly through an Na+/Ca2+ exchanger.

Question 6

What occurs at point 0 on a membrane potential time graph

Answer 6

Na+ channels open allowing Na+ to enter and depolarise the cell

Question 7

What occurs at point 2 on a membrane potential time graph

Answer 7

Plateau phase Ca2+, CICR

Force of contraction is proportional to intracellular Ca2+

Question 8

What occurs at point 3 on a membrane potential time graph

Answer 8

Ca2+ channels close and K+ channels open fully allowing K+ to leave and repolarise the cell
Muscle relaxation occurs

Question 9

What occurs at point 4 on a membrane potential time graph

Answer 9

Stable - Na+/K+ pump

3Na+ out and 2K+ in

Question 10

Describe the steps for the intra-cellular rise in [Ca2+]

Answer 10

1) Action potential (Na+) depolarises t-tubules and activates VGCCs causing Ca2+ influx
2) Ca2+ binds to RyR located on SR - close association with T-tubules
3) Release of Ca2+ from SR - Ca induced Ca release (CICR)
4) Ca2+ to troponin, 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) slides filaments

Question 11

How does a rise in [Ca2+] initiate contraction

Answer 11

1) Calcium binds to troponin C exposing actin binding sites
2) Hydrolysis of ATP causes myosin to extend and bind head to actin forming cross bridges
3) Power stroke moves actin filament relative to myosin. ADP + Pi released from myosin head
4) Myosin remains attached to actin until a new molecule of ATP binds. Myosin heads then cocked back ready to make further crosslinks
5) Cycle continues until cellular calcium levels decrease allowing calcium to dissociate from troponin which returns to original conformation which blocks actin binding site

Question 12

List the 3 regulatory sub-units on Troponin

Answer 12

Troponin T
Troponin I
Troponin C

Question 13

Troponin T

Answer 13

Binds to tropomyosin

Question 14

Troponin I

Answer 14

Binds to actin filaments

Question 15

Troponin C

Answer 15

Binds to Ca2+

Leads to a conformational changes of tropomyosin and exposure of actin binding sites

Question 16

Describe the steps for a decrease in [Ca2+] and relaxation

Answer 16

1) Action potential repolarisation (K+ ions influx) repolarises T-tubules – closure of VGCCs, and lowers Ca2+ influx.
2) No Ca2+ influx, no CICR.
3) Extrusion of Ca2+ from cell (30%)- by Na+/Ca2+ exchanger (NCX).
4) Ca2+ uptake into SR via SR membrane Ca2+ATPase (sarco/endoplasmic reticulum ATPase - SERCA, 70%) – Ca2+ in SR for next contraction, even relaxation requires energy (ATP).
5) Uptake of Ca2+ in mitochondria.

Question 17

How factors can increase intracellular Ca2+

Answer 17

Increasing VGCC activity

Reducing Ca2+ extrusion

Question 18

How does the sympathetic nervous system lead to an increase in Ca2+

Answer 18

Noraderenaline act on β1 adrenoreceptors to increase contractility by phosphorylating calcium channels

Question 19

What does increased PKA lead to

Sympathetic stimulation

Answer 19

1) Increased Ca2+ channels so higher Ca2+ levels and greater contraction
2) Increased K+ channel opening so faster repolarisation and shorter action potential leads to faster heart rate
3) Increased sarcoplasmic reticulum Ca2+ ATPase, so uptake of Ca2+ into storage by SR allowing faster relaxation
4) Overall stronger faster contractions but same diastolic time to allow for filling with blood and coronary perfusion

Question 20

What increases in sympathetic stimulation

Answer 20

Ca2+ influx
Force of contraction
K+ channels so increase repolarisation
SR Ca2+ATPase
Ca2+ uptake
Relaxation
Heart rate and conduction

Question 21

What does digoxin do

Answer 21

Increase contractility by reducing Ca2+ extrusion

Question 22

What is digoxin used for

Answer 22

Chronic heart failure

Question 23

Mechanism of digoxin

Answer 23

1) Digoxin inhibits Na+/K+ ATPase
2) Build up of [Na+] lowers concentration gradient (which normally powers Na/Ca exchanger)
3) Less Ca2+ extrusion by Na/Ca exchanger
4) More Ca2+ uptake into stores and greater CICR

Question 24

Inotropic agent

Answer 24

Modifies the force or speed of contraction

Question 25

Positive inotrope

Answer 25

Increase energy/strength of contraction

Question 26

What do Dobutamine and dopamine stimulate

Answer 26

β1 adrenoreceptor stimulants

Question 27

What can dobutamine and dopamine be used for

Answer 27

Acute heart failure

Question 28

What does glucagon stimulate

Answer 28

G protein coupled receptor

Stimulates Gs pathway - increase cAMP and PKA activity

Question 29

What can glucagon be used for

Answer 29

Acute heart failure. Used by patients who are taking β blockers

Question 30

What is amrinone

Answer 30

Is a phosphodiesterase inhibitor

Question 31

The mechanism of amrinone

Answer 31

Type III phosphodiesterase (PD3) is heart specific. Converts cAMP to AMP
Reduces cAMP and PKA activity

Question 32

What does phosphodiesterase inhibition lead to

Answer 32

Build up of cAMP that activates PKA to phosphorylate VGCCs and increase Ca2+ influx

Question 33

When is amrinone used

Answer 33

Only in severe cases e.g. those waiting for heart transplants