Cardiac Contraction Flashcards
What ion is responsible for cardiac contraction?
Rise in [Ca2+]ᵢ is central to contraction
Summarise how cardiac contractions occur
0) Na+ channels open allowing Na+ to enter and
depolarise cell
2) Plateau phase due to Ca2+ influx and CICR
- force of contraction is proportional to [Ca2+]ᵢ
3) Ca2+ channels close and K+ channels fully open
causing K+ to leave and repolarise cell causing muscle
relaxation
4) Stable Na+/K+ ATPase - 3 Na+ out for every 2 K+ in
Approximately what is the Diastolic [Ca2+]ᵢ ?
0.1 µM
What is the normal and maximum systole [Ca2+]ᵢ ?
Can rise to 1.0 µM to a maximum of 10.0 µM
How long does an action potential last?
200 - 500 ms
What causes cardiac myocyte contraction?
Electrical excitability contracts cardiac myocytes
Explain how [Ca2+]ᵢ affects cardiac contraction?
Contraction is determined by increases in [Ca2+]ᵢ
Higher increases in [Ca2+]ᵢ . increases contraction force
What are T tubules?
invaginations of the sarcolemma that penetrate into the centre of myocytes
What is the sarcoplasmic reticulum?
A membrane bound structure which stores Ca2+ in muscle cells, similar to ER
What is a Ryanodine Receptor?
Intracellular Ca2+ channel
Explain how cardiac contraction occurs in myocytes on a molecular basis
- Action potential (Na+ ions) depolarise T tubules,
activating VGCCs causing Ca2+ influx - Ca2+ binds to RyR on SR
- Release of Ca2+ from SR causing CICR
- Ca2+ binds to troponin, displacing the troponin-
tropomyosin complex to activate the actin active site - Myosin thick filament head binds to actin active site
- Myosin head ATPase activity releases energy
(ATP -> ADP) allowing filaments to bind
Why does an increase in [Ca2+]ᵢ cause more contractility?
Rises in [Ca2+]ᵢ causes more actin-myosin interactions as more actin active sites are exposed so more cross-bridges can form = more contractility
What is the role of troponin?
Troponin regulates tropomyosin conformation
Describe the structure of troponin
Troponin composed of 3 regulatory subunits
- TnT : troponin T binds to tropomyosin
- TnI : troponin I binds to actin filaments
- TnC : Troponin C binds to Ca2+
What affect does [Ca2+]ᵢ have on Troponin?
Binding of Ca2+ to TnC causes conformational changes in tropomyosin, exposing actin binding sites
What are the specialised roles of TnI and TnT?
TnI and TnT are important blood plasma markers for cardiac cell death (e.g. following MI)
What does a decrease in [Ca2+]ᵢ cause?
Muscle relaxation
Explain how cardiac muscle relaxation occurs?
- Action potential repolarisation (K+ influx) repolarises T
tubules causing closure of VGCCs and Ca2+ influx - No Ca2+ influx so no CICR
- Extrusion of Ca2+ from cell
- 30% by Na+/Ca2+ exchanger
- 70% by SR uptake via SR membrane Ca2+ ATPase - Uptake of Ca2+ in mitochondria via importer
How does Starling’s Law affect contractility?
Increased Pressure / Volume causes increased SV and intrinsic stretch. Even at the same pressure / Volume, contractility can increase (inotropic effect)
Extrinsic effect due to rise in [Ca2+]ᵢ
Clinically what are most drugs related to contractility used for?
In the clinic, drugs mostly needed to increase contractility of heart, mostly to correct acute / chronic heart failure
How do drugs increase [Ca2+]ᵢ ?
- Increase VGCC activity (sympathetic mimetic)
2. Reduce Ca2+ extrusion (Cardiac glycosides)
How does the sympathetic nervous system affect contractility?
ꞵ₁ adrenoceptors increase contractility and are found on contractile cells of the heart (atrial / ventricular cells)
Outline the effects of the sympathetic nervous system on contractility
- Noradrenaline binds to ꞵ₁ adrenoceptors stimulating Gs
sub unit - Activates adenyl cyclase which activates cAMP
- cAMP phosphorylates PKA, phosphorylating VGCCs,
increasing Ca2+ channel activity - Ca2+ influx causes CICR
- Myosin-actin interactions increase contractility
What are the effects of increased PKA?
- Increased Ca2+ channel activity - higher [Ca2+]ᵢ = more
contractions - Increased K+ channels open -> faster repolarisation so
shorter action potentials and faster HR - Increased SR Ca2+ ATPase - Ca2+ uptake into SR
storage for faster relaxation - Overall stronger and faster contractions but diastolic
time for filling with blood and coronary perfusion
remains same
What is the effect of cardiac glycosides?
Posiitive inotropic action of heart
Explain how Digoxin increases contractility
Digoxin reduces Ca2+ extrusion
What is Digoxin used for?
Chronic heart failure
-> reduced use now due to side effects
Outline the mechanism of action of Digoxin
- Digoxin inhibits Na+/K+ ATP pump
- Build up of [Na+]ᵢ
- Less Ca2+ extrusion by Na+/Ca2+ Exchanger
- More Ca2+ uptake into stores - greater CICR
Give examples of inotropic agents
Digoxin Dobutamine Dopamine Glucagon Amrinone
When are Dopamine and Dopabutamine used?
ꞵ₁ adrenoceptors stimulants used in acute heart failure
What is the effect of Glucagon on the heart?
Glucagon acts as a GPCR stimulating the Gs pathway
increasing cAMP & PKA activity
Used for patients with acute heart failure taking ꞵ blockers
What is the role of Amrinone on the heart?
Amrinone is a Heart specific Type III phosphodiesterase inhibitor (PED 3)
PDE reduces cAMP levels and PKA activity by converting cAMP to AMP, reducing contractility
What is the effect of PDE inhibition?
PDE inhibition leads to a build up of cAMP activating PKA to phosphorylate VGCCs and increasing Ca2+ influx.
Only used in severe cases
e.g. patients on heart transplant waiting list
