Regulation of Cardiac Output Flashcards
What is cardiac output?
The amount of blood that the heart pumps through the circulatory system every minute
What equation gives cardiac output?
CO = HR x SV
True or false:
Cardiac output always remains the same
False
It varies - it changes in response to the body’s demand for oxygen
Give an example of a physiological process in which cardiac output increases
Exercise
What is the average value of cardiac output at rest compared to exercise?
Rest = 4.9 litres per minute
Exercise = up to 25 litres per minute (40 in athletes)
Why does cardiac output vary with exercise?
The demand for oxygen in the muscle and heart increases significantly with exercise
How does parasympathetic stimulation cause the heart to slow?
Vagal nerves to the heart increase the resting potential and decreases the rate of diastolic depolarisation
How does sympathetic stimulation increase heart rate?
Through the release of hormones (catecholamines - epinephrine and norepinephrine) which accelerate the heart rate
True or false - sympathetic stimulation also affects stroke volume
True - it increases the force of contraction thus increasing stroke volume
What 2 things influence stroke volume?
Sympathetic innervation and length-tension relationship of muscle fibres
What is stroke volume?
The volume of blood pumped by the heart per contraction
What 3 things determine the value of stroke volume?
Heart contractility
Preload
Afterload
What is preload?
The volume of blood in the heart at the end of diastole (end diastolic volume)
What is afterload?
The amount of pressure the heart requires to open the aortic valve
What is ejection fraction?
Fraction of blood in the left ventricle that is pumped out in each beat
Give the equation for ejection fraction
EF = (SV/EDV) x 100
What are the units for ejection fraction?
%
What does the Frank-Starling Relationship show?
The more the cardiac muscle is stretched, the greater the force the muscle exerts on contraction
What happens to the following with an increased EDV?:
Myocardium
Sarcomere length
Force of contraction
Myocardium becomes more stretch
Sarcomere length increases
Force of contraction increases
Increased stretch is caused by increased venous return which can be caused by what?
Increased skeletal muscle activity
Adrenergic effects of blood vessels (increased venous tone)
Respiratory pump (Increased depth and frequency of breathing)
How does a beta-1-adrenergic receptor agonist such as isoprenaline cause protein phosphorylation?
The beta-1-AR activates Gs, which increases cAMP via adenylate cyclase, which activates PKA which leads to protein phosphorylation
What are the meanings of the following words?:
- Inotropic
- Luisitropic
- Chronotropic
Inotropic - force of contraction
Luisitropic - rate of relaxation
Chronotropic - rate of contraction
What effect does isoprenaline (beta-1-agonist) have on the following:
- Calcium transients
- Twitches
Causes:
Bigger calcium transients
Bigger and faster twitches
Name some targets of PKA in cardiomyocytes?
Phospholamban
RyR
L-type Calcium Channel
Iks
Troponin I
Phospholemman
What is protein phosphorylation?
Reversible, post-translational attachment of phosphate groups to specific amino acids (Serine, Threonine, Tyrosine) within proteins
What is the common side chain in Serine, Threonine and Tyrosine?
Hydroxyl group
What adds phosphate groups to substrate proteins and what removes phosphate groups to substrate proteins during protein phosphorylation?
Added by protein kinases
Removed by protein phosphatases
True or false:
At physiological pH the phosphate groups are negatively charged
True
What are the two main types of protein kinase?
Serine/threonine kinases (e.g. PKA, PKC)
Tyrosine kinases (e.g. GFRs, EGF-R, PDGF-R)
What group of protein kinases acutely controls cardiac output?
Serine/threonine kinases
What are the major phosphates in the heart regulating cardiac output?
PP1
PP2A
What does PP1 do?
Dephosphorylates phospholamban and ryanodine receptor
What does PP2A do?
Dephosphorylates LTCC, ryanodine receptor and troponin I
What determines protein kinase substrate specificity?
Whether or not a serine, threonine or tyrosine residue becomes phosphorylated
What determines whether or not a serine, threonine or tyrosine residue becomes phosphorylated?
The surrounding amino acid sequence
Describe the structure of PKA
Tetramer consisting of 2 catalytic and 2 regulatory sub-units
True or false:
The catalytic subunits of PKA bind cAMP
False
The regulatory subunits bind cAMP which causes release of the catalytic subunits
Apart from cAMP, what else do the regulatory subunits of PKA bind to?
A-kinase anchoring proteins (AKAP)
What is the function of AKAPs?
Responsible for compartmentalisation of PKA and other signalling enzymes within particular cellular microdomains
Facilitate spatiotemporal regulation of cell signalling in response to cAMP generation
What processes to cardiac AKAPs regulate?
Calcium influx
Release from and reuptake of calcium into SR
Myocyte repolarisation
What is the function of the ryanodine receptor?
Calcium channels responsible for calcium reduced calcium release from SR
What things influence the opening of ryanodine receptors?
Free cytosolic calcium and luminal calcium
How does free systolic calcium open ryanodine receptors?
Calcium binds to cytosolic region causes channel opening and calcium release from SR
How does luminal calcium open ryanodine receptors
Calcium binding to RyR on luminal side of SR enhances channel opening
True or false:
Ryanodine receptors are located very close to T-type calcium channels?
False
Ryanodine receptors are located very close to LTCC
Where are ryanodine receptors located?
In the SR membrane
What is the region between the LTCC and RyR called?
Dyadic cleft
In what ways may RyRs be regulated?
pH
Caffeine
Nitric oxide
Other proteins
Kinases
How does acidosis regulate the RyRs?
Reduces channel opening
How does caffeine regulate the RyRs?
Increases calcium sensitivity and increases channel opening
Which isoform of RyR is found in the heart?
RyR2
How many transmembrane domains do RyRs have?
6 transmembrane domains with hydrophobic loop buried within the membrane
How does mAKAP regulate RyR activity?
mAKAP brings PKA into close proximity with RyR2
mAKAP recruits several other signalling molecules to RyR2
What causes resetting of the RyR system?
PP2A bound to mAKAP dephosphorylating RyR and pDE4D3
PDE4 expression is increased/reduced in heart failure?
What does this lead to?
Reduced
Leads to RyR hyperphosphorylation and excessive Ca-release from SR via leaky RyR
What phase of the action potential is the voltage-gated calcium channel responsible for?
The plateau phase
Where is the LTCC located?
Sarcolemma
Function of LTCC
Entry of triggering calcium into myoocyte
What regulates LTCC?
Channel opening occurs following membrane depolarisation which is facilitated by entry of Na into cell
Rad phosphorylation by PKA
How does beta adrenergic stimulation cause an increase in LTCC activity?
Through increasing amount of time the calcium channel spends in the open state
Adrenergic regulation of LTCC activity:
Increases/decreases the amount of calcium induced calcium release?
Increases
What is rad?
A small Ras-lilke G protein which is a known inhibitor of voltage-gated calcium channels
The interaction between Rad and what is essential for PKA regulation of Cav1.2 activity?
Interaction between rad and beta-2B is essential for PKA regulation of Cav1.2 activity
Function of SERCA2A
Removal of calcium at the beat by pumping calcium from cytosol back into lumen of SR
What regulates SERCA2A?
Nitric oxide
How does phospholamban inhibit SERCA activity?
It reduces its affinity for Ca
