Mechanism if heart regulation

Question 1

What is a high heart rate predictive of

Answer 1

A high heart rate is predictive of a cardiovascular disease related mortality and morbidity. - due to inc likelihood of developing atherosclerosis

• high heart rate: increased demands of the the coronary vessels and a reduced coronary perfusion time

Question 2

What does the SAN do?

Answer 2

The pacemaker potentials generated by the SAN provide a stimulus for myogenic activity.
Directly proportional relationship between pacemaker potential frequency and heart rate
The SAN area is innervated by the vagus nerves.

Answer 3

The heart rate is dependent on the ability and frequency of depolarisations caused by the SAN.

The outflux of k+ ions from a previous action potential results in the repolarisation of the membrane.
At -60mv, the HCN cells generate a funny current- this results in the diastolic depolarisation of the cell - this is what initiates the pacemaker activity of the cell.
Hyperpolarising activated Na+ channels open which result in the slow depolarisation of the cell, this slow depolarisation ensures that the ventricles are empty. At -40mv, the ca2+ channels open, result in the rapid depolarisation of the cell. The K+ channels open, that result in repolarisation of the membrane.

Diastolic depolarisation:
1. linear phase: If current which is generated by the hyperpolarising HCN channels activated <-45mv

2. exponential phase: Na/Ca exchanger, results in a net increase of charge in the membrane

Question 4

Does the calcium clock drive the voltage clock?

Answer 4

• In the diastolic depolarisation- in the Exponential phase - highest levels of calcium compared to any other phases in the pacemaker potential.
• If we block the RYR - stops local calcium release and reduce pacemaker potential frequency
• If we block SERCAI: slows down and stops pacemaker potential activity.
• If we block the NCX using lithium triode - RYR still releases calcium but you dont get a pacemaker potential being generated

Block L-type VGCC- reduced fillonjg of the SR and pacemaker potential failure.

Ca2+ is released from the sarcoplasmic reticulum via the RYR receptors. Calcium can be recycled back into the cell by the Calcium ATPase pump- SERCAII.
Ca feeds into the Na/Ca exhanger, reusulting in the depolarisation of the membrane. The calcium removed is replaced by L-VGCC and T-VGCC.

Question 5

What determines the speed of the calcium clock

Answer 5

-The rate at which the RYR releases calcium
-SERCAI recycling activity.

What determines RYR activity:

• Consecutive PKA activation- SAN consecitively express adenyl cyclase– cAMP mediated PKA phosphorylation of the RYR
• The overall frequency of pacemaker potentials: increased frequency means that more calcium comes from the L-VGCC and the T-VGCC. So more is taken up by SERCAII and released from the RYR.

Question 6

Evidence that IF is important for producing resting heart rate

Answer 6

In HCN4 KO mice- heart rate reduced by half in 4 days- bradycardia
it shows that the HCN4 gene is crucial for encoding the HCN channels that produce If channels- needed for the pacemaker potentials.

Question 7

What does isoprenaline do

Answer 7

• increases heart rate and contractility by binding to the b1 adrenergic receptors.
• These increase adenylyl cyclase, which results in the increase of cAMP.
• Increased cAMP mediated PKA phosphorylation of RYR— RYR are open for longer periods—-inc release of calcium— more released to the NCX exchanger
• Inc adenyl cyclase—– increased If funny current— diastolic depolarisation

Question 8

What happens upon blocking the If current

Answer 8

Ivabradine is used to block the If current
this prevents the linear phase of diastolic depolarisation.
It does not block the NCX, the Calcium channels or the K+ channel
- slows down pacemaker potentials