Force-Frequency Responses and other contractile phenomena

Question 1

What is Rest-Decay?

Answer 1

Rest-dependent decline in contraction amplitude, seen in the first beat after a rest.

Question 2

Cause of Rest-Decay

Answer 2

• Time-Dependent
• During rest, a finite amount of Ca leaks from the SR (Ca leakage)
• Random flickering of RyR
• Ca then extruded by NCX
• Amount of rest-decay is proportional to the duration of the rest

Question 3

RyR leakage

Answer 3

• Channels can always open randomly

- Po is simply higher if activator (ligand, voltage) is present

Question 4

NCX in Rest-Decay
Cooling Experiment
- 1st contracture
- 2nd contracture

Answer 4

• CM supercoole, RyR undergo conformational change and lock open

1st
- CM experiences contracture for as long as cell is cooled

2nd
- Repeat contracture not as large because NCX has extruded some of the Ca

Question 5

Cooling Experiment

- Na/Ca free medium

Answer 5

• NCX inhibited in Na/Ca free solution
• 2nd contracture will be the same size as the first
• No Ca extruded

Question 6

Relaxation

• Major Contributors
• Minor Contributors

Answer 6

SERCA = ~65-70%
NCX = ~25% 

Minor

• Mitochondrial uptake
• SL CaATPase*

*Thought to affect long-term [Ca] but negligible importance beat-to-beat

Question 7

Ryanodine in Rest-Decay

Answer 7

• Ry causes RyR to stay open longer in a sub-conductance state
• Make SR ‘leaky’
• Speeds up Rest-Decay

Question 8

Caffeine in Rest-Decay

Answer 8

• Locks RyR in fully open configuration

- SR leaks all its Ca

Question 9

SR-dependence of Twitch in different species

Answer 9

Depends how extensively Ca is stored in the SR

• If a lot (rat), Ca transient depends on CICR having high gain
  (amplified EC-coupling effect)
• If very little (frog), LTCC and NCX provide most of Ca transient

Question 10

Problem with rat/mouse model and what is better for SR-depenedence

Answer 10

• Mouse/rat are often used

- Rabbit/guinea pig have more similar amount of SR-depedence

Question 11

Rest Potentiation

Answer 11

• Post-rest beat is actually larger in rats and mice
• Higher [Na] causes NCX to be more likely to function in reverse, bringing in Ca during rest
• If membrane potential more +ve than reversal , NCX will reverse to influx Ca (and depolarise the cell)

Question 12

Force-Frequency Relationship in humans/similar models

Answer 12

• Progressive (climbing) increase in force with increased frequency of stimulation

Question 13

Factors affecting +ve F-f

Answer 13

• Transient increase in I(Ca) as new level is established
• Higher [Ca]diastole
• Higher [Ca]SR
• Increased [Na] (up to new steady state)

Question 14

Decrease in force with lower f

Answer 14

• First beat at each lower f is actually large
  (longer time for SR to leak Ca)
• Subsequent contractions are smaller

Question 15

F-fR variation in species, why

*(Shattock and Bers. Am J P 1989)

Answer 15

• Rabbit, guinea pig and human have +ve F-f
• Rat has flat/negative F-f
  (I(Ca) rapidly inactivated, so less Ca-loading into SR)*

Question 16

F-fR in HF

Answer 16

• Flat or negative F-fR
• Reduced SERCA current
• Less Ca in SR if uptake time is reduced

Question 17

Multiple caffeine exposure

Bassani, Bassani and Bers. Am J P 1993

Answer 17

• Thapsigargin inhibits SERCA (with 90s application)
• NCX stopped
  (Ca/Na-free solution)
• Caffeine opens RyR, causes contracture
• Repeat caffeine gives smaller contracture
• Difference in contracture amplitude is result of the SR Ca release

Question 18

How much Ca is left with continued, non-replenished twitch?

Answer 18

• 50% on first
• 15% by 15th
• Empty after 100 twitches