Theme 3: Lecture 18 - The molecular and ionic basis of cardiovascular control Flashcards
What is the H band
The part with only thick filaments and no overlapping thin filaments
What is the A band
All the thick filaments, it will have some overlapping thin filaments
What is the I band
The area that has thin filaments only
What is the M line
Where the thick filament cell bodies are
What is the Z line
What holds 2 sarcomeres together
How does the Frank Starling law affect force of contraction of cardiac muscle
- Increased contractility
- Longer and stronger
- “More crossbridges means more of everything”
- Intrinsic regulation
How does sympathetic activity affect the force of contraction of cardiac muscle
- Faster and stronger
- NOT longer duration
- “Extant crossbridges work harder and faster”
- Extrinsic regulation
How does an increased end diastole volume lead to an increased force of comtraction
- When the sarcomeres are fully stretched there is an increased overlap of thick and thin filaments
- More overlap leads to more force generators
- Which leads to a stronger contraction
What is heart rate mostly determined by
The slope of the pacemaker potential
How does sympathetic stimulation lead to a faster heart rate
- Noradrenaline leads to an increased of If (Net inward current). This increases slope of pacemaker potential via Beta 1 receptor
- Noradrenaline leads to an increase in ICa which leads to an increased force of contraction
- Noradrenaline leads to an increase in IK. IK = delayed rectifier which shortens AP duration allowing a faster HR
Describe the funny current (If)
- Net current is inward
- Conducts both Na in and K out
- “non-specific monovalent cation channel”
- The reversal potential of If is -10 mV
- It is NOT a sodium channel
- HCN Channel opens when membrane gets more negative
- Controls slope of pacemaker potential
- Na/Ca exchange also helps with PP
How does parasympathetic stimulation lead to a slower heart rate
- Acetylcholine leads to a increase in K current IK(Ach) which hyperpolarizes membrane
- decreases slope pacemaker potential
Describe an acetyl choline K channel
- G protein (Gi coupled)
- Muscarinic
How does atropine increase heart rate
It blocks vagal slowing of the heart rate
Name 3 different types of K channels in cardiomyocytes
- Delayed rectifiers
- Inward rectifiers
- ACh sensitive K channels
When are inward rectifier K channels open
When the voltage goes below -60mV and stay open until the next depolarisation
When are the delayed rectifier K channels open
In repolarisation and after hyperpolarisation
The refractory period
When there is so much positive current leaving the cell, it is impossible to depolarise it again
Why is the voltage in after hyperpolarisation more negative than at rest
-Both the delayed rectifiers & inward rectifiers are open during early AHP
-The inward rectifiers open when the membrane is more negative than -60 mV
The delayed rectifiers are still open during the AHP -b/c they are slow to close
-At rest the delayed rectifiers are closed
-During AHP: the ↑ K+ permeability and ↓ Na+ permeability means the membrane potential moves very close to EK
What is the effective refractory period
When it becomes nearly impossible to start a new action potential
How long does the effective refractory period last in cardiomyocytes
The whole duration of the AP
Why does the effective refractory period last for the the duration of the AP in cardiomyocytes
- Protects the heart from unwanted extra action potentials between SA node initiated heart beats
- Extra APs could start arrhythmias
Describe T tubules
- Membrane currents can be near contractile machinery
- Contiguous with extracellular fluid
- Adjacent to SR
- T tubule depolarises leads to
- Terminal Cisterna detects it leads to
- Terminal cisterna sends it throughout SR
What are T tubules
Invaginations of plasma membrane into myocyte
What are Terminal Cisternae
Enlarged area of the SR
Describe terminal cristernae
- Continuous with SR
- Specialised for storing and releasing calcium
What is a triad in a myocyte
1 T tubule surrounded by terminal cisternae
What is excitation-contraction coupling
the link (molecular process) between the depolarisation of the membrane (with a tiny influx of calcium) and the consequent huge cytosolic calcium that then leads to contraction
What is excitation in muscle contraction
when a neuron stimulates a muscle cell
What leads to contraction
Diffusion of free Ca2+ into the cytoplasm is how a voltage change (AP) leads to contraction
Where does most of the calcium come from during contraction
The sarcoplasmic reticulum
How is calcium released into the cytosol in skeletal muscle
- membrane depolarises which leads to
- membrane calcium channels undergo a conformational change which leads to
- calcium-release-channels in SR (RyR) undergo a conformational change that opens them which leads to
- calcium flows from SR to cytosol
What is the Ryanodine receptor (RyR)
- In SR membrane
- Channel that releases Ca2+
- Triggered by intracellular Ca2+ increase
- Positive feedback loop
What is SERCA
- In SR membrane
- Pumps Ca2+ Back into SR
- Requires ATP
What is calcium induced calcium release
Is how EC coupling works in cardiomyocytes
Describe calcium induced calcium release in cardiomyocytes
- Initially Calcium enters the cell from the outside
- This calcium is detected by calcium release channels on the SR (intracellular)
- The calcium release channels (RyR) open, allowing calcium to flood from the SR to the cytosol
- Positive feedback loop
- After a time delay, the calcium release channels close
- SERCA pumps the calcium back into the SR
What is calcium overload
- Excessive intracellular calcium
- Also possibly excessive calcium in the SR
What can calcium overload cause
Ectopic beats and arrhythmias
Why can calcium overload cause ectopic beats and arrhythmias
Calcium may spill out of SR into cytosol at inappropriate times in the cardiac cycle
What is calcium overload made worse by
Fast rates and sympathetic drive
Give an example of a calcium channel blocker that works on the heart
Amlodipine
What do calcium channel blockers acting on the vessels do
Vasodilate, opposite hypertension
What do calcium channel blockers acting on the heart do
- anti-anginal & antiarrhythmic agents
- Reduce nodal rates and conduction through AV node
- But makes HEART FAILURE worse
Name 2 non-dihydropyridine calcium channel blockers
Verapamil and diltiazem
Describe verapamil
- Not a DHP
- Blocks Ca2+ channels
- Used as antiarrhythmic
- Blocks heart channels more than vessel channels
- Affects nodal cells
- Slows nodal rate
- Protects ventricles from rapid atrial rhythms
- Slows conduction through AV node
Describe diltiazem
- Not a DHP
- Blocks Ca2+ channels
- Used as antianginal
- Also antiarrhythmic
- Blocks both heart and vessel channels (halfway)
- Slows nodal rate
- Vasodilates coronary arteries
- Prevents angina by reducing workload while increasing perfusion
Inotropic meaning
An inotrope is an agent that alters the force or energy of muscular contraction
What are cardiac glycosides
Cardiac glycosides are a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by acting on the cellular sodium-potassium ATPase pump.
Describe digoxin
- Positive inotropic agent
- Increases stroke volume
- Increases contractility
- Also called a “cardiac glycoside”
How does digoxin work
- Works by (slightly) inhibiting Na/K pump on membrane
- This leads to increased calcium in cytosol
- Also stimulates vagus
- Slows heart rate, increases AV delay
What is digoxin used to treat
- Atrial fibrillation
- Use in heart failure now controversial
What does the endothelium detect
- Stretch
- Plasma factors
What does the endothelium produce
NO
Describe smooth muscle cell contraction
- Vascular Smooth Muscle Cell contraction initiated by MLCK
- In smooth muscle, myosin must be phosphorylated to contract (Instead of control by troponin & tropomyosin)
- MLCK phosphorylates myosin (at its light chain)
- MLCK is activated by Calcium-calmodulin
What is MLCK activated by
Calcium-calmodulin
How does relaxation of vascular smooth muscle occur
- Relaxation occurs by dephosphorylating myosin
- Done by a phosphatase activated by NO induced cascade
Name 3 biomarkers for CVD
- Troponin
- Creatine Kinase
- C reactive protein
Troponin as a biomarker for CVD
- Released from cardiomyocytes during necrosis
- Elevated during AMI, HF and many others
- Not elevated during unstable angina
Creatine kinase as a biomarker for CVD
Released from myocytes during necrosis
C reactive protein as a biomarker for CDV
- Increases in response to inflammation
- Acute phase protein
- Risk of cardiovascular disease & future events
What does beta 2 stimulation do in peripheral skeletal muscles
Phosphorylates K channels which leads to vascular smooth muscle contraction (Myosin is dephosphorylated)
What does alpha 1 stimulation do in core organs and GI tract
Phosphorylates MLCK which leads to smooth muscle contraction (Myosin is phosphorylated)
Describe what NO does
- NO is made inside Endothelial cells —> vasodilatation
- Relaxes Vascular Smooth Muscle Cells (VSMC)
- As dissolved molecule, NO travels through VSMC membrane
- Inside VSMC, it activates an enzymatic cascade
- Cascade ends by dephosphorylating myosin which relaxes muscle
Describe what nitrates glyceride trinitrate does
- Prodrug: in body it degrades to produce NO
- Leads rapidly to vasodilatation
How should glyceride trinitrate be administered
- Continuous administration leads to tolerance
- Therefore pulsed use works best
What is the side effect of ACE inhibitors involving bradykinin
- ACE Inhibitors prevent degradation of bradykinin
- Which causes dry cough associated with ACE inhibitors
Describe bradykinin
- Peptide hormone
- “Loosens” capillaries and blood vessels
- Constricts bronchi and GI tract smooth muscle
- Dilates arterioles (endothelium-dependent, stimulates NO production in endothelium)
- Increases capillary permeability (E.g. Increases saliva production)
