Length dependent modulation of electrical activity

Question 1

Describe what increased stretch does to activity?

Answer 1

Increased Diastolic Filling leads to an increased rate of beating (chronotropy) due to PACEMAKER region

Question 2

What are the two main mechanisms?

Answer 2

1) Alteration in intracellular Ca2+ cycling (indirect)

2) Stretch-Activated Channels (SACs) (direct)

Question 3

Describe process of alteration of intracellular Ca cycling

Answer 3

• Stretch leads to an increased TnC affinity for Ca2+ so the Ca2+ transient decreases.
• Leads to less inward NaCa exchange
• Reduced Action Potential Duration

Question 4

Describe the channels responsible for stretch activated openings

Answer 4

2) Stretch-Activated Channels (SACs) (direct)
- Channels which only open in response to stretch
o E.g. non-selective cationic SACs (Na, K, Cl)
- Channels whose function is modulated by stretch
o E.g. L-type calcium channel

Question 5

Evidence of what does ventricular stretch do to the APD and what evidence is there?

Answer 5

Franz et al., 1989
Canine ventricular myocytes used, increased ventricular volume resulted in a decrease action potential amplitude. A decrease in APD20 and an increase in APD90.
The peak depolarisation is hyperpolarised by stretch, this was only seen in the LV due to the technique used with a balloon solely in this ventricle. I would expect to see a similar relationship with the balloon in the RV too.

Question 6

What does stretch in SAN do?

Answer 6

Stretching the SAN increases the heart rate and identified SACs as critical in affecting pacemaker rate.

Question 7

What evidence is there for the role of SAC in SAN node?

Answer 7

Cooper et al., 2000
Rabbit SAN cells were used for perforated patch-clamp recordings and carbon fibres longitudinally stretched the cells.
A stretch-induced increase in spontaneous beating rate and a reduction in both MDP and MSP.
SAC reversal potential between 0 and −20 mV, typical for cation nonselective SACs.
Shows the positive chronotropic response of the heart to stretch.
However, because the stretch-induced whole cell current was obtained as a difference current, we cannot exclude that this net current is made up of more than one underlying current component. A specific blocker of cationic SAC, would improve the idea of this being one non-selective cationic channel.

Question 8

what properties of SAC allow increased chronotropy?

Answer 8

Cooper & Kohl, 2006
Guinea pig SAN cells, injected GsMTx-4 caused full and reversible inhibition of the stretch-induced increase in heart rate.
SACs with Erev>Em will increase the slope of the pacemaker potential – which will translate into increased rate of beating

Question 9

What other channels are affected by stretch?

Answer 9

Potassium Current
Chloride Current
L-type calcium current

Question 10

Give the evidence for the potassium current in stretch dependence?

Answer 10

Kim, 1992
Patch clamp in rat atrial cells assessed effect of stretch by using the negative pressure technique.
Negative pressure in the pipette rapidly caused opening of the K + channel, and return to atmospheric pressure resulted in closure of the channel.
Reversal potential changed when bath concentration of K was changed and the outward current was abolished by replacing K with another cation.

Question 11

Give the evidence for the chloride current in stretch dependence?

Answer 11

Hagiwara et al., 1992
Sino-atrial cells studied SAC anionic currents using the whole-cell patch clamp technique.
Application of positive pressure through the patch clamp electrode, the cell was inflated and the membrane conductance was increased.
The reversal potential was in keeping with a chloride channel at around -49mV and was shifted by change in intracellular Cl- concentration.
Cl deficient solution reduced the amplitude of the current and conductance was reduced by the Cl- channel blockers DNDS.

Question 12

Give the evidence for L type modulation in stretch on electrical activity

Answer 12

ICa,L increases with pressure inflation and osmotic swelling in sino-atrial node cells
Matsuda et al., 1996
Using whole-cell voltage-clamp method, mechanical stimuli enhanced the L-type Ca2+ current (ICa,L) in rabbit cardiac sino-atrial cells by osmotic cell swelling and by positive pressure.
The current-voltage relationship was unaffected however the open probability appears to increase which leads to the increase in current through the channel.
The increase was abolished by nifedipine indicating the specificity of the L-type current.