Heart Contractility and the Ionotropic Effect

Question 1

What’s the relationship between Ca2+ and contractility?

How does action potential upstroke lead to contraction?

How does more Ca2+ lead to more contraction?

LOOK AT DIAGRAM!

Answer 1

• ↑[Ca2+] = ↑Contractility
• 1. AP UPSTROKE depolarises the T-tubules to activate the VGCCs = Ca2+ influx.
     
     2. Ca2+ binds to RyR on SR for CICR to occur = ↑[Ca2+] in cell.
     3. Ca2+ binds to Troponin → change complex shape to expose binding sites.
     4. Myosin heads bind using ATP and then unbind = Contraction
• ↑Ca = ↑Exposed binding sites = ↑Cross-bridge = ↑Contractility.

Question 2

How does the Troponin-Tropomyosin complex work for contraction?

What are TnI and TnT important blood markers for?

LOOK AT DIAGRAM!

Answer 2

• Troponin composed of 3 regulatory subunits:
  1. TnT - bind to tropomyosin
  2. TnI - bind to actin to hold tropomyosin in place
  3. TnC - binds to Ca2+

When Ca2+ binds to TnC, it displaces the TnI and Tropomyosin to expose the binding sites.

• NSTEMI and STEMI - will be elevated

Question 3

How does action potential downstroke lead to relaxation?

LOOK AT DIAGRAM!

Answer 3

• 1. AP DOWNSTROKE repolarises the T-tubules to closes the VGCCs = ↓Ca2+ influx = No CICR occurs.
     
     2. Some Ca removed from cell using Na/Ca exchanger (NCX) on membrane. Most Ca taken up by SR via Ca-ATPase (SERCA). Small amount taken up by mitochondria.
     3. ↓[Ca2+] stops cross-bridge formation and causes less binding sites to be exposed = Relaxation.

Question 4

What’s the difference between Starling’s and Contractility (Inotropy), using the EDV-SV graph?

LOOK AT GRAPH!

Answer 4

Starling’s:
As EDV increases, so does the resting pressure/volume, which ↑Energy of contraction (due to stretching) - intrinsic

Contractility:
When at the same EDV and resting pressure/volume, ↑Contractility is due to ↑[Ca2+] - extrinsic

Question 5

What is the importance of sympathetic innervation on the heart?

What does the SNS act on to increase contractility?

Answer 5

• During certain periods, like exercise/haemorrhage, SV/CO has to be increased. To do this, we produce an Inotropic Effect - mainly though sympathetic stimulation. Can also be done by positive inotropes (drugs).
• Uses NA at β1-receptors

Question 6

How does stimulation of β1-adrenoreceptors increase contractility?

LOOK AT DIAGRAM!

Answer 6

1. NA binds to β1-adrenoreceptor = ↑cAMP
2. ↑cAMP = ↑PKA, which phosphorylates the RyR and VGCCs to activate them
3. ↑RyR and VGCC = ↑[Ca2+] = ↑Contractility

Question 7

How can stimulation of β1-adrenoreceptors cause relaxation?

LOOK AT DIAGRAM!

Answer 7

1. Stimulation of receptor = ↑cAMP = ↑PKA
2. ↑pKA phosphorylates K+ channels and SERCA on SR (Ca-ATPase) to activate them
3. Activation of K channels = K+ efflux = Hyperpolarisation = VGCCs switch off = ↓Ca influx. Activation of SERCA = ↑Ca2+ uptake into SR.
4. Both of these ↓[Ca2+] = Relaxation

Question 8

How does sympathetic stimulation affect cardiac action potentials?

How does sympathetic stimulation affect the amount of contraction and relaxation?

LOOK AT GRAPHS!

Answer 8

• ↑Depolarisation and Repolarisation.
  ↑HR and conduction
• ↑Force of contraction and relaxation, and ↑CICR available for the next contraction (more Ca stored)

However, it maintains the diastolic time - maintains coronary perfusion as it only occurs during diastole

Question 9

What are the 4 types of effects the sympathetic nervous system can have?

Answer 9

1. Positive Ionotropic effect - ↑Contractility:
   Due to ↑Ca2+ influx (VGCCs) and ↑CICR (RyR)
2. Positive Chronotropic effect - ↑HR:
   Due to ↑Funny channel frequency at SAN
3. Positive Dromotropic effect - ↑Conduction through heart at AVN and between myocytes
4. Positive Iusitropic effect - ↑rate of relaxation:
   Due to ↑K channels opening = Hyperpolarisaiton = ↓Ca influx, and due to ↑SERCA = ↑Ca uptake

Question 10

What are the clinical concerns with Negative Ionotropic agents?

Answer 10

Hyperkalaemia:
↑[K+] stops heart. It causes depolarisation, makes action potentials smaller as Na channels become inactivated quickly.

↑[H+] - low PH:
H+ competes with Ca2+ for TnC binding site = impaired contraction.

Hypoxia:
Local Acidosis impairs contraction due to competition with Ca2+. It also affects ion channels to cause depolarisation and smaller/shorter = poor contraction.