CVS 9 - Electrical + Molecular Mechanisms

Question 1

What is the primary factor in setting up the RMP in cardiac myocytes?
Why does the RMP not = Ek?

Answer 1

• Their permeability to K+ ions at rest
• K+ moves out of the cell, down the concentration gradient, making inside negative.
• RMP = -85/90 mV, but Ek = -95mV. Small permeability to positive ions are rest, making RMP slightly more positive than Ek.

Question 2

How does excitation in cardiac myocytes result in contraction?

Answer 2

• Action potentials fired by cardiac myocytes triggers an increase in IC Ca2+
• A rise in Ca2+ allows actin and myosin to interact generating contraction.

Question 3

Describe the phases of a ventricular myocytes AP and the ion channels responsible for each phase.

Answer 3

1) Upstroke - opening of VG Na+ channels
2) Early initial repolarisation - Transient outward K+
3) Plateau - Opening of LTCC’s
4) Repolarisation - Ca2+ channels inactivate, VG K+ channels open

• Then back to RMP - K+ efflux dominant.

Question 4

Describe the phases of a SAN action potential and the ion channels responsible for each phase.

Answer 4

1) Pacemaker potential - due to If (funny current), primarily an influx of Na+
2) Upstroke - AP caused by opening of VG Ca2+ channels
3) Repolarisation - Opening of VG K+ channels

• No RMP, pacemaker potential starts again after repolarisation.

Question 5

What is funny current carried by?

When is it activated?

Answer 5

• Activated by hyperpolarisation (-50mV and more negative)
• Carried by HCN-gated channels, allows influx of Na+ ions
• Also involves turning off of K+ current + L/T-type Ca2+ channels

Question 6

Why is the SAN the primary pacemaker in the heart?
What are the consequences of AP’s firing too slowly, AP’s failing, AP’s firing too quickly or electrical activity becoming random?

Answer 6

• It depolarises the fastest/has the highest intrinsic firing rate.
• Too slowly = bradycardia
• Too fast = tachycardia
• Failing = Asystole
• Random = Fibrillation

Question 7

What is the normal plasma K+ concentration?

Why are cardiac myocytes so sensitive to changes in K+?

Answer 7

• 3.5-5.5 mmol/L

- K+ permeability dominates the resting membrane potential.

Question 8

What are the effects of hyperkalaemia on the ventricular myocyte AP?
What are the risks associated with hyperkalaemia?
How is it treated?

Answer 8

• Raised plasma K+ = Ek gets more negative (more K+ outside cell so gradient is decreases). This DP’s myocytes, slowing down the upstroke AP (myocytes already dp’d so more Na+ channels in inactive state) as well as speeding up repolarisation.
• Heart may stop (asystole)
• Calcium gluconate, insulin + glucose.

Question 9

What is the effect of hypokalaemia on the ventricular myocyte AP?
What are the potential consequences of this?

Answer 9

• Lengthens the AP by delaying repolarisation

- Can lead to EAD’s, which can result in oscillations in mV and ventricular fibrillation.

Question 10

Describe the process of excitation-contraction coupling in ventricular myocytes.

Answer 10

• Depolarisation open LTCC’s in T-tubules
• Localised Ca2+ entry from T-Tubules opens CICR channels in SR (LTCC’s and T-tubules in close association allowing for this)
• 25% Ca2+ enters across sarcolemma, 75% from SR.

Question 11

How does Ca2+ entry into ventricular myocytes lead to contraction?
How do cardiac myocytes relax after contraction?

Answer 11

• Ca2+ binds to troponin C - same sliding filament theory as skeletal muscle.
• IC Ca2+ levels must return to resting levels, most is pumped by into SR via SERCA, the rest exits across cell membrane via Ca2+ ATPase and NCX.

Question 12

Describe the excitation-contraction mechanism of smooth muscle located within the tunica media or blood vessels.

Answer 12

1) DP of vascular SM opens VG Ca2+ channels
2) Ca2+ binds to calmodulin
3) CaM activates MLCK, which PP’s myosin light chain
4) This activates myosin head, allowing binding to actin and contraction to occur. Phosphate removed from light chain for relaxation by MLCP.

Alternatively …

1) SM activated by NA binding to a1-adr’s
2) IP3 receptor activated, Ca2+ released from SR, which then binds to CaM (same mechanism from here).
3) DAG from Gq can inhibit MLCP so that contraction is maintained.

Question 13

Can MLCK be phosphorylated itself?

Answer 13

• Yes, by PKA which will inhibit the actions of MLCK, thus inhibiting contraction.