Session 4 Flashcards
What sets the resting membrane potential in cells?
Permeability of a cell to K+
K+ cells move out of the cell down their concentration gradient
Is there more Na+ within a resting cell or outside?
Outside
What are the rough concentrations of K+ intracellularly and extracellularly?
140 mM - IN
4 mM - OUT
Is a relatively small or big movement of ions responsible for the negative resting membrane potential?
Small
What is the rough value for Ek?
What is the rough resting membrane potential of a cardiac myocyte?
Why are the two values not the same?
- 95 mV
- 90 to -85 mV
There is very small permeability to other ion species such as Na+ at rest
An action potential in a cardiac myocyte triggers…
An increase in cytosolic Ca2+ allowing actin and myosin interaction, generation of tension and contraction
What is the rough resting membrane potential of a ventricular myocyte?
-90 mV
What happens first as a result of depolarisation in a ventricular myocyte?
Voltage gated Na+ channels open and then inactivate
What is the most positive membrane potential that a ventricular myocyte reaches during an action potential?
~+30 mV
What happens after the opening of voltage gated Na+ channels in a ventricular myocyte action potential leading to a plateau phase in the action potential curve?
What causes the plateau?
There is a transient outward K+ current
Opening of voltage gated Ca2+ channels (and some K+ channels)
There is a balance between ECa and Ek as there is the movement of both ions
What happens after the plateau phase during the action potential of a ventricular myocyte?
Ca2+ channels inactivate
V-gated K+ channels open
After the membrane potential returns to normal resting levels in a ventricular myocyte there is a longer period where…
The cell is not excitable
RMP is due to ______________ ____ channels
Background K+
The upstroke of a cardiac action potential is due to the…
Opening of voltage gated Na+ channels (which then inactivate)
There is initial repolarisation in a cardiac action potential due to…
Transient outward K+ channels
The plateau phase of a cardiac action potential is due to…
Opening of voltage gated Ca2+ channels balanced with K+ efflux
Repolarisation in a cardiac action potential is due to…
Efflux of K+ through voltage gated K+ channels
Which type of Ca2+ channels open during the plateau phase of a radial action potential?
Voltage gated L type calcium channels
What is meant by the pacemaker action potential?
Refers to the action potential in cells of the pacemaker (SA node)
The SA node contain specialised myocytes, how do they differ from typical myocytes? (2)
They don’t contain much contractile machinery
They spontaneously depolarise
Describe the resting membrane potential of a pacemaker cell
Spontaneously depolarise so not as negative as usual
~-60mV
What is the pacemaker potential?
The initial slope to threshold in pacemaker cells as a result of the funny current resulting in an influx of Na+
The pacemaker potential involves which channels?
HCN channels are activated by…
HCN channels
Hyperpolarisation- the more negative the more it activates
HCN channels can also be described as…
‘Slow’ sodium channels
What is the upstroke in a pacemaker action potential due to?
Opening of voltage gated L-type Ca2+ channels
Which type of calcium channels are opened during the SA node action potential?
L-type calcium channels
What is the repolarisation of an SA node action potential a result of?
Closure of calcium channels and opening of voltage gated K+ channels
Which cells in the heart are fastest to depolarise? What is the consequence of this?
Cells in the SA node
These cells set the rhythm and act as the pacemaker
Triggering of action potentials results in contraction.
If action potentials fire too slowly…
If action potentials fail…
If action potentials fire too quickly….
If electrical activity becomes random…
Bradycardia
Asystole
Tachycardia
Fibrillation
Plasma K+ concentration must be controlled within a tight range. What is this range?
3.5-5.5 mM/L
Which organ in the body is most affected by too high/low potassium levels?
Heart
What plasma K+ levels can be described as…
I) Hypokalaemia
II) Hyperkalaemia
I) < 3.5 mM/L
II) > 5.5 mM/L
Why are cardiac myocytes particularly sensitive to changes in [K+]?
They have a very negative resting membrane potential close to Ek
What effect does hyperkalaemia have on action potentials of cardiac myocytes?
Hyperkalaemia depolarises the myocytes and slows down the upstroke of the action potential
What causes the depolarisation of myocytes seen in hyperkalaemia?
Ek becomes less negative, so more easily depolarised
What causes the slowing in the uptake of the action potential seen in hyperkalaemia?
Inactivation of voltage gated Na+ channels due to membrane depolarisation
What is a serious risk associated with hyperkalaemia? What initially happens to the excitability of a cardiac myocyte during hyperkalaemia?
Heart can stop - asystole
Initially there is an increase in excitability
Give the reference ranges for mild, moderate and severe hyperkalaemia
Mild 5.5 - 5.9
Moderate 6.0 - 6.4
Severe > 6.5
What is the treatment for hyperkalaemia?
Calcium gluconate
Insulin + glucose
How does calcium gluconate work in the treatment for hyperkalaemia?
How does insulin + glucose work in the treatment for hyperkalaemia?
Makes the heart less excitable
Promotes K+ into cells
What effect does hypokalaemia have on the action potential in cardiac myocytes?
Lengthens the action potential by delaying repolarisation
Why is repolarisation delayed in hypokalaemia?
Some K+ channels are less active when there is low potassium levels
What is the possible consequence of the longer action potentials as a result of hypokalaemia?
Early after depolarisations —> Oscillations in membrane potential —-> VENTRICULAR FIBRILLATION
Describe excitation-contraction coupling
Depolarisation opens L-type Ca2+ channels in T-tubule system
Localised Ca2+ entry opens CICR channels in the SR
Both channels are closely linked
How much calcium enters a cardiac myocyte during an action potential…
I) Across the sarcolemma (L-type Ca2+ channels)
II) From the SR (CICR channels)
As percentages
25%
75%
By which mechanism do cardiac myocytes contract? Describe the mechanism
Sliding filament mechanism
Ca2+ binds to troponin C, causing a conformational change shifting tropomyosin to reveal myosin binding site on actin filament
What happens to the calcium levels in cardiac myocytes during relaxation? Which channels are involved in achieving this?
They return to resting levels
Most is pumped back to the SR via the SERCA
Some exits across the sarcolemma via Ca2+ ATPase and NCX
How is the tone of blood vessels controlled?
By contraction and relaxation of vascular smooth muscle cells in the tunica media of blood vessels
Tunica media is present in which blood vessels?
Arteries
Arterioles
Veins
How does excitation-contraction coupling work in smooth muscle?
Activation of myosin light chain allows interaction with actin. Calcium binds to calmodulin. Ca/Calmodulin complex binds to MLCK and activates it. MLCK phosphorylates the myosin light chain to enable actin-myosin interactions.
The _________________ of the __________ __________ _________ allows actin/myosin interactions in smooth muscle
Phosphorylation
Myosin light chain
Which enzyme is responsible for the activation/phosphorylation of the regulatory myosin light chain?
MLCK - myosin light chain kinase
What activates MLCK?
The binding of the calcium/calmodulin complex
What happens in smooth muscle as Ca2+ levels begin to decline?
Relaxation - MLC phosphatase de phosphorylates the myosin light chain
MLCK itself can be phosphorylated by…
What effect does this have?
Protein kinase A (PKA)
Inhibits MLCK and prevents contraction
What are the 2 divisions of the autonomic nervous system? In which conditions is each division more dominant?
Sympathetic
Parasympathetic
Fight or flight - STRESS
Rest or digest - BASAL conditions
Give an example of 2 physiological functions regulated by the ANS
Blood pressure
Heart rate
What is the sympathetic effect on the pupil of the eye? What is the parasympathetic effect on the pupil of the eye?
Which receptor is responsible for each effect?
Dilation - a1
Contraction - m3
What is the sympathetic effect on the airways of the lungs? What is the parasympathetic effect on the airways of the lungs?
Which receptor is responsible for each effect?
Relaxation - B2
Contraction - m3
What is the sympathetic effect on the heart? What is the parasympathetic effect on the heart?
Which receptor is responsible for each effect?
Increased heart rate, Increased force of contraction - B1
Decreased heart rate - m2
What is the sympathetic effect on sweat glands? What is the parasympathetic effect on sweat glands?
Which receptor is responsible for each effect?
Localised secretion - circulating adrenaline at a1 receptors
Generalised secretion - acetylcholine at m3 receptors
NO EFFECT FROM PARASYMPATHETIC
Can sympathetic activity to the heart be increased without increasing activity to the GI tract?
Yes, sympathetic drive to different tissues is independently regulated in
Name three things the ANS is responsible for controlling in the CVS
Heart rate
Force of contraction of the heart
Peripheral resistance of blood vessels
Does the ANS initiate the electrical activity in the heart?
No
Pacemaker cells spontaneously depolarise
Will a denervated heart still beat?
Yes, but at a faster rate
Why does the heart beat at a faster rate when denervated?
Under normal conditions, the heart is largely under parasympathetic control
Which nerve fibres provide the parasympathetic input to the heart?
Preganglionic fibres from the 10th cranial nerve - vagus nerve
The vagus nerve is the ______th _________ nerve
10th cranial nerve
Parasympathetic preganglionic fibres from the vagus nerve synapse with…
Postganglionic cells on epicardium surface or at the SA and AV node
Where do parasympathetic fibres synapse when providing input to the heart?
At the epicardial surface
At the SA/AV node
Postganglionic parasympathetic fibres release ______ acting on which receptors in the heart?
What effect will this have on the heart?
ACh
M2-muscarinic receptors
Decreased heart rate by decreasing AV node conduction velocity
Which sympathetic nerve fibres provide input to the heart?
These nerve fibres innervate… (3)
These nerve fibres release which neurotransmitter?
Postganglionic fibres from the sympathetic trunk
SA node, AV node, myocardium
Noradrenaline
Sympathetic nerve fibres in the heart release ________ acting on which receptors?
What effect will this have on the heart?
Noradrenaline
Mainly B1 (some B2,B3)
Increased heart rate
Increased force of contraction
What effect does sympathetic or parasympathetic activity have on the pacemaker potential of an SA node action potential?
Sympathetic - Increases slope
Parasympathetic - Decreases slope
What type of GPCRs are the B1 receptors found in the heart?
What do these receptors do?
G-alphaS
Result in increased activity of adneylyl cyclase and increased production of cAMP
How does sympathetic activity increase the slope of the pacemaker potential?
Results in increased production of cAMP - cAMP is a cyclic nucleotide which stimulates the HCN channels to speed up the pacemaker potential and therefore the heart rate
What type of GPCRs are the M2 receptors found in the heart?
What do these receptors do?
G-alpha-i
Decreased activity of adenylyl cyclase and therefore cAMP?
How does increased parasympathetic activity decrease the slope of the pacemaker potential?
Less cAMP for HCN channels so slower pacemaker potentials and slower heart rate
How does noradrenaline increase the force of contraction in the heart? (3)
Noradrenaline —> B1 receptors —> cAMP —> PKA
PKA phosphorylates Ca2+ channels resulting in increased Ca2+ entry
Increased uptake of Ca2+ in SR at rest
Increased sensitivity of contractile machinery to Ca2+
Do most blood vessels receive sympathetic or parasympathetic innervation?
What is an exception to this?
Sympathetic
Erectile tissue
Most arteries and veins have which type of receptor?
a1-adrenoreceptors
Apart from a1-adrenoreceptors, vessels in which parts of the body may contain other receptors?
Which receptors are these?
Heart
Liver
Skeletal muscle
B2-adrenoreceptors
What feature of blood vessels allows them to dilate at all?
Vasomotor tone
What provides the vasomotor tone seen in blood vessels? (2)
Basal sympathetic output and the smooth muscle cells themselves
Some blood vessels have ______________________ as well as a1-adrenoreceptors
B2-adrenoreceptors
a1-adrenoreceptors typically use which neurotransmitter?
Noradrenaline
Which receptors does circulating adrenaline preferentially bind to?
B2-adrenoreceptors
Does circulating adrenaline activate a1-adrenoreceptors as well as B2-adrenoreceptors?
At higher concentrations
What effect does activating B2-adrenoreceptors and a1-adrenoreceptors have on vascular smooth muscle?
B2-receptors - vasodilation
a1-receptors - vasoconstriction
How does activation of B2-adrenoreceptors cause vasodilation?
Increased cAMP —> PKA —> Inhibits MLCK —> Relaxation of smooth muscle
How does activation of a1-adrenoreceptors cause vasoconstriction in vascular smooth muscle?
Stimulates IP3 production, increase in intracellular calcium from stores and extracellular influx —> Contraction of smooth muscle
Which tissues produce the most metabolites?
What effect can local increases in metabolites have on blood vessels?
Where in the body do metabolites play a more important role than B2-adrenoreceptors in vasodilation/adequate perfusion?
Active tissues
A strong vasodilator effect
In skeletal/coronary muscle
Changes in the state of the CVS are communicated to the brain via _______________ nerves
Afferent
Which receptors detect changes in the CVS on the high pressure side of the system?
Which receptors detect changes in the CVS on the low pressure side of the system?
They both alter the activity of __________ nerves
Baroreceptors
Atrial receptors
Efferent
What are baroreceptors? Where are they found? (2)
Nerve endings that are sensitive to stretch
Found in the carotid sinus and aortic arch
Baroreceptors are sensitive to _________
Stretch
What effect does increased arterial pressure have on baroreceptors?
Stretches the receptors resulting in increased firing
The baroreceptor reflex is important for maintaining blood pressure over…
Short term
Persistent increases in blood pressure have what effect on baroreceptors?
Can result in them ‘resetting’ to higher levels
What are sympathomimetics?
Drugs that promote stimulation of sympathetic nerves
Give 4 examples of sympathomimetics
Adrenaline in cardiac arrest
B1 agonist (Dobutamine) given in cardiogenic shock
Adrenaline in anaphylactic shock
B2 agonist (Salbutamol) given in asthma
Give an example of a…
B1 agonist
B2 agonist
Dobutamine
Salbutamol
Cardiogenic shock can be simplified as…
Pump failure
Give 2 examples a-adrenoreceptor antagonists
Prazosin - a1 antagonist
Anti-hypertensive agents - inhibit NA action on vascular smooth muscle a1 receptors causing vasodilation
Give an example of an a1 antagonist
Prazosin
Give 2 examples of B-adrenoreceptor antagonists
Propranolol
Atenolol
What is propranolol? What effects does it have in the body?
Non-selective B1/B2 antagonist
Slows heart rate, reduces force of contraction, causes bronchoconstriction
What is atenolol? What benefits does this have over propranolol?
Selective B1 antagonist
Less risk of bronchoconstriction
Give an example of a muscarinic agonist
Pilocarpine
What is pilocarpine commonly used in the treatment of? How does it work?
Glaucoma
Activates the constrictor pupillae muscle
Give an example of a muscarinic antagonist
Atropine
Tropicamide
What effects do atropine/tropicamide have on the body? In what way can they be used for examination purposes?
Increase heart rate
Cause bronchial dilation
To dilate the pupils for examination of the eye
