Regulation of Cardiac Output

Question 1

What is cardiac output?

Answer 1

The amount of blood that the heart pumps through the circulatory system every minute

Question 2

What equation gives cardiac output?

Answer 2

CO = HR x SV

Question 3

True or false:
Cardiac output always remains the same

Answer 3

False
It varies - it changes in response to the body’s demand for oxygen

Question 4

Give an example of a physiological process in which cardiac output increases

Answer 4

Exercise

Question 5

What is the average value of cardiac output at rest compared to exercise?

Answer 5

Rest = 4.9 litres per minute
Exercise = up to 25 litres per minute (40 in athletes)

Question 6

Why does cardiac output vary with exercise?

Answer 6

The demand for oxygen in the muscle and heart increases significantly with exercise

Question 7

How does parasympathetic stimulation cause the heart to slow?

Answer 7

Vagal nerves to the heart increase the resting potential and decreases the rate of diastolic depolarisation

Question 8

How does sympathetic stimulation increase heart rate?

Answer 8

Through the release of hormones (catecholamines - epinephrine and norepinephrine) which accelerate the heart rate

Question 9

True or false - sympathetic stimulation also affects stroke volume

Answer 9

True - it increases the force of contraction thus increasing stroke volume

Question 10

What 2 things influence stroke volume?

Answer 10

Sympathetic innervation and length-tension relationship of muscle fibres

Question 11

What is stroke volume?

Answer 11

The volume of blood pumped by the heart per contraction

Question 12

What 3 things determine the value of stroke volume?

Answer 12

Heart contractility
Preload
Afterload

Question 13

What is preload?

Answer 13

The volume of blood in the heart at the end of diastole (end diastolic volume)

Question 14

What is afterload?

Answer 14

The amount of pressure the heart requires to open the aortic valve

Question 15

What is ejection fraction?

Answer 15

Fraction of blood in the left ventricle that is pumped out in each beat

Question 16

Give the equation for ejection fraction

Answer 16

EF = (SV/EDV) x 100

Question 17

What are the units for ejection fraction?

Answer 17

%

Question 18

What does the Frank-Starling Relationship show?

Answer 18

The more the cardiac muscle is stretched, the greater the force the muscle exerts on contraction

Question 19

What happens to the following with an increased EDV?:
Myocardium
Sarcomere length
Force of contraction

Answer 19

Myocardium becomes more stretch
Sarcomere length increases
Force of contraction increases

Question 20

Increased stretch is caused by increased venous return which can be caused by what?

Answer 20

Increased skeletal muscle activity
Adrenergic effects of blood vessels (increased venous tone)
Respiratory pump (Increased depth and frequency of breathing)

Question 21

How does a beta-1-adrenergic receptor agonist such as isoprenaline cause protein phosphorylation?

Answer 21

The beta-1-AR activates Gs, which increases cAMP via adenylate cyclase, which activates PKA which leads to protein phosphorylation

Question 22

What are the meanings of the following words?:
- Inotropic
- Luisitropic
- Chronotropic

Answer 22

Inotropic - force of contraction
Luisitropic - rate of relaxation
Chronotropic - rate of contraction

Question 23

What effect does isoprenaline (beta-1-agonist) have on the following:
- Calcium transients
- Twitches

Answer 23

Causes:
Bigger calcium transients
Bigger and faster twitches

Question 24

Name some targets of PKA in cardiomyocytes?

Answer 24

Phospholamban
RyR
L-type Calcium Channel
Iks
Troponin I
Phospholemman

Question 25

What is protein phosphorylation?

Answer 25

Reversible, post-translational attachment of phosphate groups to specific amino acids (Serine, Threonine, Tyrosine) within proteins

Question 26

What is the common side chain in Serine, Threonine and Tyrosine?

Answer 26

Hydroxyl group

Question 27

What adds phosphate groups to substrate proteins and what removes phosphate groups to substrate proteins during protein phosphorylation?

Answer 27

Added by protein kinases Removed by protein phosphatases

Question 28

True or false: At physiological pH the phosphate groups are negatively charged

Answer 28

True

Question 29

What are the two main types of protein kinase?

Answer 29

Serine/threonine kinases (e.g. PKA, PKC) Tyrosine kinases (e.g. GFRs, EGF-R, PDGF-R)

Question 30

What group of protein kinases acutely controls cardiac output?

Answer 30

Serine/threonine kinases

Question 31

What are the major phosphates in the heart regulating cardiac output?

Answer 31

PP1 PP2A

Question 32

What does PP1 do?

Answer 32

Dephosphorylates phospholamban and ryanodine receptor

Question 33

What does PP2A do?

Answer 33

Dephosphorylates LTCC, ryanodine receptor and troponin I

Question 34

What determines protein kinase substrate specificity?

Answer 34

Whether or not a serine, threonine or tyrosine residue becomes phosphorylated

Question 35

What determines whether or not a serine, threonine or tyrosine residue becomes phosphorylated?

Answer 35

The surrounding amino acid sequence

Question 36

Describe the structure of PKA

Answer 36

Tetramer consisting of 2 catalytic and 2 regulatory sub-units

Question 37

True or false: The catalytic subunits of PKA bind cAMP

Answer 37

False The regulatory subunits bind cAMP which causes release of the catalytic subunits

Question 38

Apart from cAMP, what else do the regulatory subunits of PKA bind to?

Answer 38

A-kinase anchoring proteins (AKAP)

Question 39

What is the function of AKAPs?

Answer 39

Responsible for compartmentalisation of PKA and other signalling enzymes within particular cellular microdomains Facilitate spatiotemporal regulation of cell signalling in response to cAMP generation

Question 40

What processes to cardiac AKAPs regulate?

Answer 40

Calcium influx Release from and reuptake of calcium into SR Myocyte repolarisation

Question 41

What is the function of the ryanodine receptor?

Answer 41

Calcium channels responsible for calcium reduced calcium release from SR

Question 42

What things influence the opening of ryanodine receptors?

Answer 42

Free cytosolic calcium and luminal calcium

Question 43

How does free systolic calcium open ryanodine receptors?

Answer 43

Calcium binds to cytosolic region causes channel opening and calcium release from SR

Question 44

How does luminal calcium open ryanodine receptors

Answer 44

Calcium binding to RyR on luminal side of SR enhances channel opening

Question 45

True or false: Ryanodine receptors are located very close to T-type calcium channels?

Answer 45

False Ryanodine receptors are located very close to LTCC

Question 46

Where are ryanodine receptors located?

Answer 46

In the SR membrane

Question 47

What is the region between the LTCC and RyR called?

Answer 47

Dyadic cleft

Question 48

In what ways may RyRs be regulated?

Answer 48

pH Caffeine Nitric oxide Other proteins Kinases

Question 49

How does acidosis regulate the RyRs?

Answer 49

Reduces channel opening

Question 50

How does caffeine regulate the RyRs?

Answer 50

Increases calcium sensitivity and increases channel opening

Question 51

Which isoform of RyR is found in the heart?

Answer 51

RyR2

Question 52

How many transmembrane domains do RyRs have?

Answer 52

6 transmembrane domains with hydrophobic loop buried within the membrane

Question 53

How does mAKAP regulate RyR activity?

Answer 53

mAKAP brings PKA into close proximity with RyR2 mAKAP recruits several other signalling molecules to RyR2

Question 54

What causes resetting of the RyR system?

Answer 54

PP2A bound to mAKAP dephosphorylating RyR and pDE4D3

Question 55

PDE4 expression is increased/reduced in heart failure? What does this lead to?

Answer 55

Reduced Leads to RyR hyperphosphorylation and excessive Ca-release from SR via leaky RyR

Question 56

What phase of the action potential is the voltage-gated calcium channel responsible for?

Answer 56

The plateau phase

Question 57

Where is the LTCC located?

Answer 57

Sarcolemma

Question 58

Function of LTCC

Answer 58

Entry of triggering calcium into myoocyte

Question 59

What regulates LTCC?

Answer 59

Channel opening occurs following membrane depolarisation which is facilitated by entry of Na into cell Rad phosphorylation by PKA

Question 60

How does beta adrenergic stimulation cause an increase in LTCC activity?

Answer 60

Through increasing amount of time the calcium channel spends in the open state

Question 61

Adrenergic regulation of LTCC activity: Increases/decreases the amount of calcium induced calcium release?

Answer 61

Increases

Question 62

What is rad?

Answer 62

A small Ras-lilke G protein which is a known inhibitor of voltage-gated calcium channels

Question 63

The interaction between Rad and what is essential for PKA regulation of Cav1.2 activity?

Answer 63

Interaction between rad and beta-2B is essential for PKA regulation of Cav1.2 activity

Question 64

Function of SERCA2A

Answer 64

Removal of calcium at the beat by pumping calcium from cytosol back into lumen of SR

Question 65

What regulates SERCA2A?

Answer 65

Nitric oxide

Question 66

How does phospholamban inhibit SERCA activity?

Answer 66

It reduces its affinity for Ca