S4) Cellular & Molecular Events in the CVS

Question 1

In four steps, describe how the resting membrane potential of cardiac cells is generated

Answer 1

⇒ Cardiac myocytes are permeable to K⁺ at rest

⇒ K⁺ move out of the cell (down concentration gradient)

⇒ Inside becomes more negative relative to the outside

⇒ As charge builds up an electrical gradient is established

Question 2

In three steps, briefly explain how excitation leads to action

Answer 2

⇒ Cardiac myocytes are electrically active & fire action potentials

⇒ Action potential triggers increase in [Ca²⁺]_i

⇒ Actin and myosin interact, triggering the contraction mechanism

Question 3

State the RMP for the following:

• Axon
• Skeletal muscle
• SAN
• Cardiac ventricle

Answer 3

Question 4

Describe the 4 different stages of the ventricular (cardiac) action potential

Answer 4

• Depolarisation – Na⁺ influx
• Initial repolarisation – K⁺ efflux
• Plateau – Ca²⁺ influx
• Proper repolarisation – K⁺ efflux

Question 5

Describe the 3 different stages in the SAN action potential

Answer 5

Question 6

Describe the mechanisms behind the slow depolarising pacemaker potential

Answer 6

• Turning on of slow Na⁺ conductance (If – funny current)
• Activated at membrane potentials more negative than - 50mV
• HCN (Hyperpolarisation-activated Cyclic Nucleotide-gated) channels are activated which allow influx of Na⁺ for depolarisation

Question 7

Describe how the action potential waveform varies throughout the heart

Answer 7

• SAN is fastest to depolarise, it is the pacemaker and sets rhythm
• Other parts of the conducting system also have automaticity, but it’s slower

Question 8

Describe the action potential diagrams for different parts of the heart:

• SAN
• Purkinje fibres
• Atrial muscle
• Ventricular muscle
• AVN

Answer 8

Question 9

Explain four problems that could occur during the process of excitation leading to contraction

Answer 9

• Action potentials fire too slowly → bradycardia
• Action potentials fail → asystole
• Action potentials fire too quickly → tachycardia
• Electrical activity becomes random → fibrillation

Question 10

What is the normal range of plasma [K⁺]?

Answer 10

3.5 – 5.5 mmol L^-1

Question 11

If [K⁺] is too high or low it can cause problems, particularly for the heart.

In terms of plasma [K⁺] levels, define hyperkalaemia and hypokalaemia

Answer 11

• Hyperkalaemia – plasma [K⁺] is too high > 5.5 mmol.L^-1
• Hypokalaemia – plasma [K⁺] is too low < 3.5 mmol.L^-1

Question 12

In 5 steps, describe the effects of hyperkalaemia

Answer 12

⇒ E_K becomes less negative (smaller concentration gradient)

⇒ Membrane potential becomes less negative and depolarises

⇒ Early depolarisation causes Na channels to open then inactivate (less steep uptake slope)

⇒ HCN channels are activated by hyperpolarisation (remain inactive)

⇒ Depolarisation is slow and over a long duration

Question 13

What are the risks associated with hyperkalaemia?

Answer 13

• Pacemaker potential decreases, heart rate decreases/stops (asystole)
• May initially get an increase in excitability but then conductance may cease

Question 14

Risks associated with hyperkalaemia depend on the extent and how quickly it develops.

Describe the severity of hyperkalaemia

Answer 14

• Mild: 5.5 – 5.9 mmol/L
• Moderate: 6.0 – 6.4 mmol/L
• Severe: > 6.5 mmol/L

Question 15

How can hyperkalaemia be treated?

Answer 15

• Calcium gluconate
• Insulin + glucose

Ineffective if the heart already stopped

Question 16

In 4 steps, describe the effects of hypokalaemia

Answer 16

⇒ E_K becomes more negative (greater concentration gradient)

⇒ Membrane potential becomes more negative

⇒ Action potential is prolonged as plateau phase is longer (Ca²⁺ channels remain open)

⇒ Repolarisation is delayed & slower

Question 17

What are the risks associated with hypokalaemia?

Answer 17

• Longer action potentials lead to early after depolarisations (EADs)
• Prolonged plateau phase provides greater opportunity to stimulate more action potentials and cause more contractions

⇒ Leads to oscillations in membrane potential which result in ventricular fibrillation

Question 18

In two steps, describe excitation-contraction coupling

Answer 18

⇒ Depolarisation opens L-type Ca²⁺ channels in the T-tubule system

⇒ Localised Ca²⁺ entry opens closely-linked CICR channels in the SR

25% enters across sarcolemma, 75% released from SR

Question 19

How does relaxation occur in cardiac myocytes?

Answer 19

[Ca²⁺]_i must return to resting levels:

• SERCA is stimulated and pumps calcium back into SR
• PMCA & NCX remove calcium across the cell membrane

Question 20

What controls the tone of blood vessels?

Answer 20

Tone of blood vessels is controlled by contraction & relaxation of vascular smooth muscle cells:

• Located in tunica media
• Present in arteries, arterioles and veins

Question 21

In 5 steps, describe the cellular mechanism leading to the contraction of blood vessels

Answer 21

⇒ Ca²⁺ binds to calmodulin

⇒ Ca²⁺- calmodulin complex is formed

⇒ Myosin Light Chain Kinase is activated

⇒ MLCK phosphorylates myosin so it interacts with actin

⇒ Contraction mechanism is triggered

Question 22

In 5 steps, describe the cellular mechanism leading to the relaxation of blood vessels

Answer 22

⇒ Ca²⁺ levels decline

⇒ Myosin light chain phosphatase dephosphorylates myosin

⇒ PKA phosphorylates MLCK & inhibits its action

⇒ Myosin light chain is not phosphorylated

⇒ Contraction is inhibited