cardiac contraction

Question 1

How does electrical excitability contract cardiac myocytes?

What accounts for the rise in Calcium levels in the sarcoplasm?
2

Answer 1

• Voltage at plateau phase causes the voltage gated calcium channels on the myocytes to open
  
  • This causes an influx of calcium
  • Intracellular calcium binds to the ryanodine receptor on the sarcoplasmic reticulum; this causes the ryanodine receptor to release sarcoplasmic stores of calcium into the sarcoplasm

• Rise in calcium levels occurs via:

1. Influx from the voltage gated calcium channels on the sarcomere
2. Influx from the sarcoplasmic reticulum via the ryanodine receptor (CICR)

Question 2

Describe in detail how the intracellular rise in calcium can increase contraction

Answer 2

1. Action potential depolarises T tubules and activated the voltage gated calcium channels = calcium influx
   
   2. Calcium binds to ryanodine receptor on the sarcoplasmic reticulum
   3. This causes a CICR; causing calcium to be released from sarcoplasmic reticulum storage
   4. Calcium can then bind to troponin = troponin binds to tropomyosin = allows actin and myosin to interact
   5. Myosin thick filament head binds to active site on actin
      Myosin head ATPase activity releases energy (ATP–>ADP) which slides the filaments = contraction

Question 3

Describe the interaction between actin and myosin in response to a rise in calcium ions

Answer 3

1. Binding of calcium ions changes conformation of tropomyosin to expose the binding site on actin
   
   2. The myosin binds to the actin forming a cross bridge
   3. Power stroke: ADP and phosphate are released causing the myosin head to bend
   4. A new molecule of ATP attached to the myosin head; causing it to detach from the actin
2. ATP –> ADP + Pi (hydrolysis); returning myosin to the cocked position ready to bind actin

Question 4

What are the 3 regulatory subunits of troponin?

Answer 4

Troponin T (TnT)
Troponin I (TnI)
Troponin C (TnC)

Question 5

What is the function of TnT?

Answer 5

Binds to tropomyosin

Question 6

What is the function of TnI?

Answer 6

Binds to actin filament

Question 7

What is the function of TnC?

Answer 7

Binds to calcium ions
Binding of calcium ions to TnC leads to conformational change in the shape of tropomyosin and exposure of actin binding sites

Question 8

Why can troponin be used in diagnostics?

Answer 8

TnI and TnT are important blood plasma markers for cardiac cell death (for example: following MI)

Question 9

Describe how a decrease in calcium ion concentration can cause muscular relaxation

what happens to any Ca2+ remaining in the sarcoplasm?

Answer 9

1. Action potential repolarisation due to K+ influx repolarises the t-tubules = closure of voltage gated calcium channels = < Ca2+ influx
   
   2. No calcium influx = no CICR (calcium induced calcium release)
   3. Three things happen to any calcium left in the sarcoplasm:
      A) Removal from sarcoplasm via Na+/Ca2+ exchanger (NCX)
      B) Calcium uptake into SR (sarcoplasmic reticulum) via SR membrane Ca2+ ATPase (SERCA)
      C) Calcium uptake into mitochondria
2. Reduced calcium = myosin/actin binding reduced= no contraction= chambers relaxed and can refill

Question 10

What two factors in the heart work together to affect the strength of contractility (strength of heart beat)?

Answer 10

1. Extrinsic control due to rise in calcium ions
   More calcium = higher stroke volume
   Therefore starling curve shifts upwards with increasing calcium concentrations
2. Intrinsic stretch (starling’s law)

Question 11

Some drugs are used in the medical field to increase contractility. What are the 2 main reasons they are used?

Answer 11

1. Corrects acute heart failure

2. Correct chronic heart failure

Question 12

How are drugs used to increase contractility, by which 2 mechanisms?

what is meant by a cardiac glycoside?

Answer 12

1. Increasing the voltage gated calcium channel activity
   Acts as a sympathetic memetic
   
   2. Reduces calcium ions extrusion (via Na+/Ca2+ exchanger)
      Acts as cardiac glycosides

These drugs act as positive inotropes; they increase the energy or strength of contraction

Question 13

Explain the effect of the sympathetic nervous system on cardiac contractility

Answer 13

Noradrenaline (NA) acts on beta-1 adrenoreceptors to increase contractility

Question 14

Describe in detail the mechanism and effect of NA on the strength of contractility

state what effect this has on the:
heart rate
strength of contraction

Answer 14

Beta-1 adrenoreceptors are found on the contractile cells of the heart, the atrial and ventricular cells
• NA binds to the B1-adrenoreceptor bound to a G-as protein coupled to adenylate cyclase
• Binding of NA activates adenylate cyclase; converting ATP–>cAMP
• cAMP activates PKA
• PKA phosphorylated the voltage gated calcium channel; increasing its activity
• This allows a greater influx of calcium during the plateau phase
• Increased calcium from channel along with the calcium from the SR (CICR) = increases actin-myosin interaction = increased contractility

Stronger contraction but more brief BUT heart DOES NOT pump faster

Question 15

What causes the faster heart rate?

Answer 15

Increased K+ channels opening = faster repolarisation = shorter action potential = faster heart rate

Question 16

What causes the faster relaxation of the heart?

Answer 16

Increase SR calcium ATPase = uptake of calcium into SR storage = faster relaxation

Question 17

Does the heart rate get faster in the presence of NA?

Answer 17

NO

only stronger and more brief contractions occur NOT faster
Overall stronger and faster contractions but same diastolic time to allow filling with blood and coronary perfusion

Question 18

What is a cardiac glycoside?

Answer 18

class of organic compounds that increase the output force of the heart and increases its RATE of contraction by acting as a cellular sodium-potassium ATPase pump

Question 19

What are cardiac glycosides also known as and why?

Answer 19

Inotropes because they have a positive inotropic action on the heart
they increase the strength and speed of contractility

Question 20

What is an example of a cardiac glycoside and what is it used for?

Answer 20

DIGOXIN
Increases contractility by reducing calcium extrusion

Used to treat chronic heart failure

Question 21

Describe the mechanism of action of a cardiac glycoside, such as digoxin

Answer 21

1. Digoxin inhibits the Na+/K+ ATPase pump
   
   2. This leads to an intracellular build up of sodium
   3. Intracellular increase is sodium = less calcium extrusion via the Na+/Ca2+ exchanger
   4. This leads to more calcium uptake into SR storage = more CICR

Question 22

Name 2 drugs that can be used to treat acute heart failure (hint: amine)

what receptors do these drugs stimulate?

Answer 22

1. Dobutamine
   
   2. Dopamine

These are beta-1 adrenoreceptor stimulants = more contraction

Question 23

Name a drug that can be used to treat acute heart failure, taking into consideration that the patient takes beta blocker drugs

Answer 23

Glucagon

Acts as a GPCR = stimulates Gs pathway = increased cAMP and PKA activity = more contraction

Question 24

Name a drug that can be used to increase heart contractility by acting on PDE3

Answer 24

Amrinone (only given in severe cases such as patients waiting for a heart transplant)
Phosphodiesterase inhibitor; works to inhibit PDE3 (type III phosphodiesterase which is specific to the heart)
PDE3 inhibition = build up of cAMP = cAMP activated PKA = PKA phosphorylates VGCC = increase Ca2+ influx

Question 25

What is the mechanism of action of PDE3?

Answer 25

PDE3 converts cAMP —> AMP
Decrease in cAMP = decrease in cAMP and PKA activity = reduces contraction

THEREFORE AMRINONE INHIBITS THIS BY BLOCKING THE PDE3