Session 4 Lectures Flashcards
What sets the resting membrane potential in cardiac myocytes?
Potassium permeability
What is the intra and extracellular concentration of potassium in a cardiac myocyte?
4mmol extracellular
140mmol intracellular
Does resting membrane potential reach potassium equilibrium in a cardiac myocyte? (Ek)
No not quite
Ek = around -95mv and RMP = -85mv
This is because there is small permeability to other ions at rest
What ion generates contraction?
Calcium ions
Need for actin and myosin interaction
What is another term for the cardiac action potential?
The ventricular action potential
These are action potentials generated in non-nodal cells eg purkinje fibres
In ventricular action potentials - what stage number is rest and which is the plateau phase?
Rest = stage 4
Plateau phase = stage 2
Upstroke (depolarisation) = stage 0
Start of repolarisation = stage 1
Plateau phase = stage 2
Repolarisation = stage 3
What happens to VG sodium channels after opening?
When can they re-open?
They inactivate
When at negative membrane potential they close again and can be reopened
How long does diastole last compared to systole?
Diastole is 2/3 of time
Systole is 1/3 of time
What are the x and y axis when labelling the ventricular action potential?
x axis = Time (ms)
y axis = Membrane potential (Mv)
In cardiac action potential what causes upstroke?
Opening of VG Na+ channels (fast acting) and influx of Na+
What causes the plateau phase?
Opening of VG Ca2+ channels (Ca2+ influx) and K+ channels also being open (K+ efflux)
They are balanced so plateau
Do cardiac myocytes have more than one type of K+ channel?
Yes
Don’t need to know them all yet
What is another term for the pacemaker action potential?
The SA node action potential
What is unusual about the pacemaker cells?
They never sit at rest and spontaneously depolarise
What is the difference between HCN channels and VG Na+ channels?
HCN channels = cause gradual depolarisation of pacemaker cells (in SA node)
They are slow opening Na+ channels
VG Na+ channels = generate action potential in cardiac cells (ventricular action potential)
They are fast opening Na+ channels
What is the pacemaker potential?
Gradual opening of HCN channels (funny current) and gradual influx of Na+
What is the membrane potential in the SA node?
What is the resting membrane potential?
Membrane potential around -60mV
There is no resting membrane potential - the cells are never at rest
What drives the action potential in the SA node?
Opening of L type VG calcium channels
What membrane potential do VG Na+ channels need to reach before opening/activated?
Membrane potentials that are more negative than -50m/v
What does HCN channels stand for?
Hyperpolarisation-activated, Cyclic Nucleotide-Gated channels
Are the cells in the AV node the name as the SA node?
Yes they also spontaneously depolarise and have no resting membrane potential
However the SA node depolarises quicker - this is why it sets the rhythm
What is bradycardia?
When action potentials fire too slowly (decreased heart rate)
What is asystole?
When action potentials fail to fire - no heart beat
What is tachycardia?
When action potentials fire too quickly (increased heart rate)
What happens if electrical activity becomes random?
You get fibrillation
What is the normal range for K+ plasma concentration?
3.5-5.5 mmol
What is hypokalaemia?
Low potassium plasma concentration (less than 3.5 mmol)
What is hyperkalaemia?
A high K+ plasma concentration
Over 5.5 mmol
What is the effect on membrane potential in hyperkalaemia?
The membrane potential becomes less negative - depolarises slightly
Why does hyperkalaemia slow the upstroke of the action potential?
(2 reasons)
- Increased extracellular K+ = membrane potential slightly depolarised (less negative)
You reduce the driving force for K+ efflux - Some of the VG Na+ channels are inactivated which also slows upstroke
What K+ plasma concentration is severe hyperkalaemia?
Over 6.5 mmol
Normal = 3.5-5.5mmol
What are two possible treatments for hyperkalaemia?
Calcium gluconate - this makes the heart less excitable
Give insulin and glucose - promotes K+ moving into cells
Explain why hypokalaemia leads to a lengthened action potential and delays in depolarisation
Hypokalaemia = decreased extracellular K+ levels
Means there is an increased concentration gradient
K+ slower to move back into the cell and repolarise
L-type Ca+ channels also work best at negative membrane potential so remain open for longer
What can a longer action potential lead to?
Early after depolarisations
This can lead to oscillations in membrane potential and ventricular fibrillation
In a cardiac myocyte, what % of calcium for contraction is received extracellularly?
25% across the plasma membrane
75% of the calcium comes from the sarcoplasmic reticulum (via CICR - ryanodine receptors)
What does Ca2+ bind to in order for contraction to occur?
It binds to troponin C
-Troponin complex sits on top of tropomyosin and winds around the actin filament
When calcium binds it causes a conformational change - tropomyosin is moved out the way to allow myosin to bind at the binding site on the actin filament
What does most the Ca2+ go during relaxation of cardiac myocytes?
Into the sacroplasmic reticulum via SERCA
In the vascular system where is the smooth muscle and which vessel has the most?
In the tunica media layer of blood vessels
Arterioles have the most
In vascular smooth muscular cells - what 2 ways can Ca2+ levels be increased?
- Depolarisation of VG Ca2+ channels
2. Noradrenaline or adrenaline activating alpha 1 q (GPCR) resulting in IP3 acting on IP3R and SR Ca2+ release
In vascular smooth muscle cells - what does Ca2+ bind to and what does this do?
It binds to calmodulin
Calmodulin activates MLCK (myosin light chain kinase) which phosphorylates the light chain on the myosin head - allowing myosin to bind with actin
What enzyme in smooth muscle cells inactivates the acting of myosin on actin (contraction)?
Myosin light chain phosphatase
Can myosin light chain kinase be phosphorylated itself? What happens when it is?
Yes it can
When this happens it inhibits its ability to phosphorylate the myosin light chain and inhibits contraction
What can phosphorylate myosin light chain kinase to inhibit contraction?
Protein kinase C
What is a nicotinic receptor?
A ligand gated ion channels
All pre-ganglionic receptors are nicotinic
Most post-ganglionic receptors of sympathetic nervous system are nicotinic
Give a location where Ach is used as a post-ganglionic neurotransmitter rather than NA (in sympathetic nervous system)
Sweat glands
What are the 2 divisions of the autonomic nervous system &a where do their pre-ganglionic roots emerge from?
- Sympathetic (sacral and cranial)
2. Parasympathetic (lumbar and thoracic)
For sympathetic and parasympathetic nervous system - which receptors affect pupil of eye and what do they do?
Sympathetic = a1 receptor
Dilates the pupil
Parasympathetic = m3 receptor
Constricts the pupil
For sympathetic and parasympathetic nervous system - which receptors affect lungs and what do they do?
Sympathetic = b2 receptor
Relaxes lungs
Parasympathetic = m3 receptor
Constracts lungs
For sympathetic and parasympathetic nervous system - which receptors affect heart and what do they do?
Sympathetic = b1
Increased rate and force of contraction
Parasympathetic = m2
Decreased rate and force of contraction
For sympathetic and parasympathetic nervous system - which receptors affect sweat glands and what do they do?
Sympathetic = a1
Localised secretion
Parasympathetic = m3
Generalised secretion
What happens if you denervate the heart?
It will continue beating - as the pacemaker cells spontaneously depolarise
The heart will beat more quickly as it is usually under vagal control (of parasympathetic nervous system)
What are the postganglionic receptors of parasympathetic nervous system and what do they do?
M2 receptors
Decreases heart rate and decreases speed of AV node conduction
Where are the main sites of parasympathetic innervation in the heart? (postganglionic cells?)
The SA and AV node
Where do the preganglionic fibres of parasympathetic nervous system in heart come from?
The 10th cranial nerve - the vagus nerve
Where are the majority of sympathetic postganglionic cells in the heart?
In the SA node, AV node or myocardium (muscular tissue of heart)
Where the CV control centre located?
Within the medulla oblongata of the brain stem
What are baroreceptors? Where are they located?
They measure the arterial blood pressure
In carotid sinus and arch of aorta
How does NA increase force of contraction?
NA acts on B1 receptors which cause an increase in cyclic AMP - activating PKA
This leads to phosphorylation of Ca2+ channels and increased entry of Ca2+ during plateau phase
There is an increased uptake of Ca2+ in SR and increased sensitivity of contractile machinery to Ca2+
What receptors do most arteries and veins have - are they innervated by sympathetic or parasympathetic nervous system?
Most have a1 receptors (some also have b2)
Most vessels therefore receive sympathetic innervation
What does the vasomotor tone allow?
Vasodilation of vasoconstriction depending on level of sympathetic output
Where might you find blood vessels with a1 and b1 receptors?
Liver
Skeletal muscle
Myocardium
At physiological concentration which receptor in vasculature will adrenaline prefer to bind to?
b2 - they are more sensitive to adrenaline than a1 which is in all vessels
What neurotransmitter binds to a1 receptors in vasculature?
Noradrenaline
At very high concentrations adrenaline will also bind here (but it prefers to bind to b1 receptors at physiological concentration)
Activating b1 receptors on smooth muscle vasculature causes what?
Vasodilation
B2 = Ga (s) GPCR
Causes increases in cAMP - activates PKA which opens potassium channels and inhibits MLCK needed for contraction (so relaxation occurs)
Activating a1 receptors on smooth muscle vasculature causes what?
Vasodilation A1 = Ga(q) GPCR Stimulates IP3 production Acts on IP3R on SR increase in Ca2+ release from stores = contraction of muscle
What causes the largest vasoconstriction effect of smooth muscle vasculature?
Increase in local metabolites eg K+, H+ and CO2
What type of nerves control input to medulla oblongata?
Afferent nerves
What do sympathimimetic drugs do?
Mimic the sympathetic nervous system e.g. alpha or beta adrenoreceptor agonist
Give a few examples of alpha and beta adrenoreceptor antagonist drugs
- Prazosin (for hypertension) - A1
- Propanolol (slows HR and force of contraction but also acts on bronchial smooth muscle to cause vasoconstriction) - non selective B1/2
- Atenolol (slows HR and force of contraction) - B1
