Molecular and ionic basis of CVD

Question 1

Intrinsic regulation of the force of contraction of cardiac muscle.

Answer 1

Frank-Starling relationship.

The more the cardiac cells are stretched, the greater force of contraction produced.

Increased overlap of thin + thick filaments= greater force generated.

Question 2

Extrinsic regulation of the force of contraction of cardiac muscle.

Answer 2

Controlled by sympathetic regulation- release of noradrenaline.

Increased sympathetic stimulation increases Ca2+ conductance= stronger cardiac muscle contraction.

Question 3

Vagal control of heart rate

Answer 3

Tonic parasympathetic stimulation keeps the HR around 60 bpm.

Neurotransmitter: acetylcholine.

ACh acts on ACh-activated K+ channels.

This system increase K+ conductance which hyperpolarizes the cells and makes the pacemaker potential slope less steep.

Question 4

What determines heart rate

Answer 4

Pacemaker potential.

The steeper the slope, the quicker the HR.

Question 5

Sympathetic control of HR

Answer 5

Noradrenaline increases Na conductance via the funny current.

Conductance of Ca2+ and K+ also increased.

Question 6

NADR and the funny current

Answer 6

Sympathetic control of HR- leads to a faster HR, via Beta-1 receptors.

Increases net inward current in funny current- Na+.

Question 7

NADR and K+ in pacemaker cells

Answer 7

Increases conductance in delayed rectifier K+ channels.

This shortens AP duration as repolarisation occurs at a quicker heart rate.

Question 8

Funny current

Answer 8

A non-specific monovalent cation channel present in nodal cells.

Net current of Na+ inwards with small amount of K+ outwards.

The HCN channel opens when membrane becomes more negative.

This current increases with sympathetic stimulation.

Question 9

ACh-activated K+ channels

Answer 9

A muscarinic G-protein coupled channel.

Contains receptor for ACh

K+ conductance increases with vagal stimulation- decreases pacemaker potential slope by hyperpolarising membrane.

Question 10

Inward rectifying K+ channels

Answer 10

G-protein coupled channels- activated by ACh

ACh binds to M2 receptors- interacting with Gi protein to decrease cAMP.

K+ flow out of cell and hyperpolarise it- slowing down action potential generation.

They open when neural Vm is below -60 mV.

Question 11

M2 muscarinic receptor

Answer 11

Activated by ACh– slows down HR.

1. ACh binds to M2 receptor.
2. Interacts with Gi protein- causes G-alpha to dissociate from beta-gamma complex.
3. This decreases cAMP produced= increased chronotropy and dromotropy.

Question 12

Atropine

Answer 12

A drug that blocks M2 receptors- increases HR, dilates pupils, reduces saliva and other exocrine secretions.

Question 13

After hyperpolarization

Answer 13

Occurs when Vm is below resting potential in neurones.

The delayed-rectifier K+ channels are slow to close which makes membrane more negative.

The inward rectifier are open at the start of AHp but close when Vm is below -70mV.

When potential returns to rest, delayed rectifiers close.

Question 14

Effective refractory period

Answer 14

The period where it is nearly impossible to start a new AP.
- Lasts for the duration of an AP in cardiomyocytes.

Protects the heart from unwanted extra APs between SAn initiated heart beats- extra APs= arrhythmias.

Question 15

T-tubules

Answer 15

Invaginations in myocyte plasma membrane- adjacent to the SR.

Contiguous with extracellular fluid.

Connected to terminal cisternae which detects when the T-tubules depolarises

Question 16

Terminal cisternae

Answer 16

Enlarged area of SR connected to the T-tubules.

Detects depolarisation from T-tubules.

Question 17

Excitation coupling

Answer 17

The link between the molecular process of depolarisation of the membrane and the consequent huge influx of cytosolic Ca2+- leading to depolarisation.

Question 18

Dihydropyridine receptor calcium channel

Answer 18

L-type Ca2+ channels

Channel that allows influx of Ca2+ from extracellular environment to intracellular environment.

In skeletal muscle cells.

Ca2+ influx through L-type channels trigger conformational change in RyR channels in terminal cisterna- opening them.

Influx of Ca2+ from SR to sarcolemma.

Question 19

Excitation-contraction coupling in cardiac myocytes

Answer 19

There are L-type Ca2+ channels in the T-tubule envaginations.

When the cell is depolarised, L-type channel opens and allows Ca2+ into cardiomyocyte.

Depolarisation of L-type channels directly touch ryanodine receptors in SR membrane and transmit signals to cause conformational change- triggering further release of Ca2+.

Question 20

SERCA

Answer 20

Smooth endoplasmic reticulum calcium ATPase

Pumps Ca2+ back into the SR, using ATP.

Question 21

Calcium induced calcium release

Answer 21

Calcium is detected by Ryanodine channels.

This opens the RyR channels and causes influx of Ca2+ into the cytosol from the SR.

Positive feedback loop.

Question 22

Calcium overload

Answer 22

Occurs when there is too excessive intracellular calcium.

Due to excessive release of Ca2+ from SR.

Risk: ectopic heartbeats and arrythmias

Exacerbated by fast HR and sympathetic drive

Question 23

Diltiazem

Answer 23

A non DHP Ca2+ blocker for heart and blood vessels.

Used as antianginal and antiarrhythmic.

Vasodilates coronary arteries.

Slows SAN rate.

Question 24

Verapamil

Answer 24

A non DHP Ca2+ blocker

Anti antiarrhythmic agent.

Affects nodal cells and slows conduction through AVN.

Question 25

Digoxin

Answer 25

Positive inotropic agent- cardiac glycoside.

Inhibits Na+/K+ pump.

Increases Ca2+ in cytosol:
Increases SV and heart contractility.

Slows HR by stimulating vagus nerve.

Was used for HR.

Question 26

Myosin Light Chain kinase

Answer 26

Myosin is phosphorylated by MLCK in order to allow it to contract in cardiac muscle cells.

(troponin and tropomyosin control phosphorylation in skeletal muscle)

Calcium-calmodulin activates MLCK.

NO-activated phosphatase dephosphorylates myosin= relaxation.

Question 27

GTN

Answer 27

Glyceryl trinitrate- a nitrate drug

Prodrug- taken in an inactive form and degrades into NO.

Causes vasodilation rapidly but has short term effects.

Continuous administration can cause tolerance.

Question 28

Bradykinin

Answer 28

Peptide hormone:
Loosens capillaries and BVs

Constricts bronchi and GI SMs.

Vasodilator:
Stimulates NO production.

Increases capillary permeability.

Question 29

Troponin as a biomarker

Answer 29

Tn is released by cardiomyocytes during necrosis.

Therefore elevated during:
Heart failure
Acute myocardial infarction

Not elevated during unstable angina.

Question 30

Creatine kinase as a biomarker

Answer 30

CK/CPK is released from myocytes during necrosis

Question 31

C reactive protein (CRP)

Answer 31

Increases in response to inflammation.

An acute phase protein that predicts risk of cardiovascular disease.

Made in the liver