Lecture 7: Physiology 2

Question 1

In some pathological conditions the SR may leak Ca into the cytosol during diastole, what will this do to the membrane potential and why?

Answer 1

Localised depolarisation that may trigger arrhythmic activity

Question 2

How does cardiac muscle vary from SM when it comes to generation of force? and why must force be varied?

Answer 2

Force must be varied because:
CO=Venous return

• All muscle fibres are activated, we cannot use recruitment of additional fibres like SM
  = Modulation

Question 3

How is CO changed?

Answer 3

HR
SV

But increase rate = less time for ejection

Question 4

What is the force of contraction modulated by?

Answer 4

• Myocyte stretch (Frank starling)
• Rate of automacity (i.e HR)
• Neurotransmitters affect Rate and Ca handling
• Inotropic drugs

Question 5

Describe the two types of contractions the CM undergoes during systole

Answer 5

• Isometric force (increase pressure, no volume change)

- And rapid shortening (ejection)

Question 6

What are the two main ways myocytes change force?

Answer 6

• Altering Ca transient (amplitude and duration)

- Altering myofilament Ca sensitivity

Question 7

Describe the frank starling concept;

Answer 7

Mechanosensitive regulation of contraction

• Increased EDV increases SV by stretch induced increased in contractility

Excessive stretch results in less actin myosin overlap and decreased force produced (and same with too little)

Question 8

What is the biphasic response of myocytes to stretch?

Answer 8

Rapid response
- Due to myofilament properties

Slow force response (SFR)
- SFR to stretch is due to increased Ca influx

Question 9

What changes myofilament sensitivity to stretch?

Answer 9

• Acidosis = Dec
• Catecholamines = Dec
• Inorganic PO4 = Dec
• Sarcomere = Inc
• ATP = Inc
• Caffeine = Inc

Different troponin C sites have different affinity for Ca

Question 10

Can we change myofilament sensitivity to Ca in failing hearts?

Check the understanding on this

Answer 10

In failing hearts, contraction and relaxation are much the same problem thus cant change Ca sensitivity

Question 11

How does HR regulate force?

Answer 11

Force frequency response

Question 12

How does the force frequency response change in heart failure?

Answer 12

In heart failure Ca stores compromised thus FF is compromised

Question 13

Describe how HR increases inotropy

Answer 13

• Less time for Ca extrusion
• Decrease in the average membrane potential which decreases overall Ca efflux via NCX
• Overall effect is to load the SR with Ca and for the amplitude of the Ca transient to increase…

Overloads NCX therefore increased SERCA and Ca store.

Question 14

What is the impact of parasymp on heart:

Answer 14

(Vagal) decreases SA node discharge and rate and hence force

Question 15

What is the impact of symp nerves;

Answer 15

• Increases SA node discharge rate
• Increases Ca influx via Ca channels
• Increase SR pump rate
• Decrease sensitivity of troponin for Ca

Question 16

Where are beta adrenergic nerves found in the heart and describe their intracellular signalling mechanisms

Answer 16

• Beta Adrenergic nerve endings found throughout the heart

- B-agonists act via adenlyl cyclase, increase cAMP. This activated cAMP dependant PKA which phosphyrlases key proteins

Question 17

What are the key proteins phosphorylased by PKA?

Answer 17

• Tnl ( decrease Ca affinity of TnC)
• SL Ca channels
• Phospholambam (Inc SR Ca pump)
• SR Ca release channels (RyR gating)

Inotropy, lusitropy (rate relaxation), and chrotropy

Question 18

How is force modulated by drugs?

Answer 18

Digoxin, i.e cardiotonic steroids, increase [Na]i by inhibiting Na pumps , hence reducing Ca extrusion by NCX

Sympathomimetics acrting via B-1 receptors

Bipyridines act via phosphodiesterase (inhibits breakdown of cAMP) (limited use)

Question 19

How do current therapies target decreasing filling pressures?

Answer 19

• NO donors relax vasculature
• Diuretics
• ACE inhibitors