CVS S4 - Cellular and Molecular events + ANS innervation in the CVS Flashcards
How is the resting potential of cardiac cells set up? What is the resting membrane potential of cardiomyocytes?
NOT Na+/K+ ATPase Resting permeability to K+ results in K+ efflux from the cell, causing depolarisation Small ‘leakage’ of Ca2+ and Na+ across the membrane means that resting potential is slightly higher than Ek -90mV
What does this picture show?
A sino-atrial node action potential
What does this picture show?
An action potential in the cardiac ventricle
Summarise the generation of the cardiac action potential
Initial depolarisation occurs to threshold
Main depolarisation due to opening of voltage gated Na+ channels - influx of Na+
Initial repolarisation due to opening of voltage gated K+ channels - efflux of K+
Plateu due to opening of voltage gated Ca2+ channels - influx of Ca2+ into cytoplasm (this balances K+ efflux)
Reuptake of Ca2+ into cellular stores or ejection from the cell
K+ efflux then repolarises the cell
How long is a cardiac action potential?
Why is it longer than normal?
280ms
Due to influx of Ca2+ into the cytoplasm
Why is there influx of Ca2+ into a cell during a cardiac action potential?
Ca2+ in the cytoplasm initiates contraction (i.e. the heartbeat)
For all cells but pacemeaker cells in the heart, how does the initial depolarisation to threshold come about?
Spread of electrical excitation from adjacent cells through ion movement through gap junctions
Summarise how the action potential is generated in a pacemeaker cell in the heart
During diastole the cells depolarise steadily of their own accord due to influx of Na+
This is referred to as the ‘funny current’ (If)
Once past threshold, voltage gated Ca2+ channels open and the cell will depolarise
The depolarisation stimulates voltage gated K+ channels to open, causing repolarisation (Ca2+ channels will close as the K+ channels open)
What channels are responsible for the funny current?
How are they activated?
HCN Channels (Hyperpolarisation-activated, Cyclic Nucleotie-gated)
Will activate when membrane potential is more negative than -50mV
How long does an SA node action potential last?
What heart rate would they set if they were not affected by other factors?
100ms
100bpm
Where are cardiac pacemaker cells in the heart found?
What rates do they all set?
SA node (primary) - 100bpm (not considering ANS innervation)
AV node - 40-60bpm
Bundle of His, Left and right bundle branches and purkinje fibres - 30-40bpm
What would happen if the SA node didn’t fire action potentials?
What would happen if both the SA and AV nodes didn’t fire APs?
SA node only:
- AVN takes over as primary pacemaker at 40-60bpm
SA and AV nodes:
- Bundle of His and downstream fibres take over as primary pacemaker at 30-40bpm
What are the major histological features of cardiac cells?
Striated
Branching
Centrally positioned nuclei
Intercalated disks between cells
Adherens and gap type junctions
T tubules inline with Z-disk
Describe in detail how cardiac cytosolic Ca2+ concentration is raised by an action potential
What percentages of Ca2+ influx into the cytoplasm come from which sources?
Depolarisation opens L-type Ca2+ channels in the T-tubules
Localised Ca2+ entry into cell cytoplasm (10-25% of overall)
Ca2+ binds to ryanodine receptors on the SR
Opens Calcium Induced Calcium Release (CICR) channels on the SR resulting in influx of Ca2+ into the cytoplasm (90-75% of overall)
How does Ca2+ influx into the cytoplasm of striated muscle initaite contraction?
Same as skeletal muscle
Ca2+ binds to troponin (TnC subunit)
Conformational change shifts tropomyosin to reveal myosin binding site on the actin filament
Contraction can begin (Sliding filament - REVISE IT)
How does relaxation of cardiac muscle occur?
Ca2+ is returned to resting levels
Msst is pumped back into SR by SERCA, which is stimulated by raised Ca2+ levels in cytoplasm
Some exits across cell membrane via:
- Sarcolemmal Ca2+ ATPase
- Na+/Ca2+ Exchanger
Describe the main mechanim for regulating smooth muscle contraction
How are these processes inhibited?
Why is this process necessary?
Ca2+ entry into the smooth muscle cells of the tunica media promotes constriction of the vessel
Ca2+ in cytoplasm binds to calmodulin (CaM) and activates myosin light chain kinase (MLCK)
MLCK will phosphorylate the myosin head and permit interaction with actin (contraction)
MLCK can be inhibited by PKA, inhibiting contraction
myosin light chain phosphatase (MLCP) will dephosporylate the myosin head, blocking it from binding to actin
Necessary as smooth muscle doesn’t contain Troponin complexes to block actin myosin interactions
What are the two major divisions of the ANS?
Describe the anatomical similarities of both divisions
Sympathetic and parasympathetic nervous systems
Both are made up of a series of 2 neurones, pre and post ganglionic
Pre ganglionic cell bodies in the CNS
Post ganglionic cell bodies in the ganglions of the PNS
The ANS exerts action on what types of effectors?
Smooth muscle
Viscera
Secretory glands
Describe the anatomical features of the ANS specific to the sympathetic nervous system
Nerve fibres have cell bodies from T1 - T12 and L1 - L2 (throracolumbar outflow)
Short preganglionic fibres and long post ganglionic fibres
Pre and post ganglionic neurones might synapse in 3 different locations:
- Same level of origin (paravertebral origin)
- Different level to origin (paravertebral origin)
- Not in the paravertebral chain
What neurotransmitters are involved in the Sympathetic nervous system?
Where exactly are these transmitters found?
What receptor types do they bind to in the ANS?
Pre-ganglionic neurones:
- Acetylcholine (Cholinergic)
- Binds to nicotinic Ach receptors (ion channels) on the post-ganglionc neurone
Post-ganglionic:
- Noradrenaline (Noradrenergic)
- Alpha (1&2) and Beta (1&2) adrenoceptors (GPCRs) expressed by the effector
- Exceptions are perspiration and ejaculation pathways, these are cholinergic
Describe the anatomical features of the ANS specific to the para-sympathetic nervous system
Fibres originalte from cranial nerves (3, 7, 9 and 10) and S2 - S4 (Craniosacral outflow)
Long preganglionic fibres and short postganglionic fibres
Tend to synapse close to the target structures
What neurotransmitters are involved in the parasympathetic nervous system?
What receptors might they bind to?
Only Acetylcholine
Post-ganglionic neurones express nicotinic Ach receptors (ion channels)
Effectors express muscarinic (M1, M2 and M3) Ach receptors (GPCRs)
Where can you find chromaffin cells and what is their action?
How do they interact with the sympatheic nervous system?
Specialised cells of the adrenal medulla that release adrenaline into the bloodstream
Inervated by pre-ganglionic neurones, so act like specialised postganglionic neurones (with effector capabilities)
When a tissue has both parasympathetic and sympathetic innervation how are the effects of the two related?
Tend to be opposing (eg. Relaxation and contraction)
Under what general conditions do parasympathetic and sympathetic innervation predominate?
Parasympathetic dominant under basal conditions
Sympathetic activity increased when under stress
Give the effects of the sympathetic innervation of the:
- Heart
- Airways
- Pupil
- Sweat glands
And include the receptor expressed for sympathetic innervation by each of these effectors
Heart:
- Increase rate/force of contraction (Beta 1)
Airways:
- Relaxation (Beta 2)
Pupil:
- Dilation (Alpha 1)
Sweat glands:
- Localised secretion (Alpha 1)
- Generalised secretion (M3)
Give the effects of the parasympathetic innervation of the:
- Heart
- Airways
- Pupil
- Sweat glands
And include the receptor for parasympathetic innervation expressed by each of these effectors
Heart:
- Decrease rate (M2)
Airways:
- Contract (M3)
Pupil:
- Contract (M3)
Sweat glands:
- No effect
What effect does the increased output of the ANS to the vasculature have on vascular tone?
How does it exert this effect?
Vasoconstriction
Sympathetic innervation of the smmoth muscle in the walls of arteries, arterioles and veins
Increased sympathetic activity causes constriction via Alpha 1 receptors
Liver + Coronary and skeletal muscle vessels have Beta 2 receptors also, these cause vasodilation
How are variations in vasomotor tone brought about by the sympathetic nervous system?
Sympathetic output to the vasculature is constant, holding vessels in vasomotor tone (a resting level of constriction)
A decrease in sympathetic output resuts in vasodilation
An increase results in vasoconstriction
Activation of B2 receptors in causes vasodilation
What is the major mechanism by which vasomotor tone is reduced?
Why is an important counterbalance to sympathetic activity?
Vasomotor tone is reduced by the action of local vasodilatory metabolites, which act as sympathetic antagonists, reducing sympathetic output to the smooth muscle of the vascular system
The interplay between the action of vasodilatory sympathetic antagonists and sympahetic vasoconstriction is the principal means of controlling flow around the cardiovascular system
Describe how vasomotor tone normally varies in the skin
Why does vascular tone of the skin need to be changed?
At rest, vasomotor tone is high
Arterioles, pre-capillary sphincters and arterio-venous anastomoses are generally shut down
Variations in sympathetic outflow then produce large changes in tone
This is neccessary for vascular thermoregulation
What is the baseline vasomotor tone in skeletal muscle?
When does this change and how?
Baseline tone is high at rest
In exersize vasomotor tone is reduced (vasodilation) by local vasodilatory metabolites to increase blood flow
How does vasomotor tone in the skin and skeletal muscle affect the CVS?
A mechanism for controlling total peripheral resistance
How is vasomotor tone regulated in the gut?
High tone at rest
When a meal is consumed local vasodilators antagonise sympathetic activity, reducing vasomotor tone
How is the vasculature of the brain affected by sympathetic innervation?
Virtually unaffected
How is sympathetic output to the vasculature controlled?
Controlled by the ‘vasomotor’ centres of the medulla oblongata in the brainstem
How does activating Alpha 1 receptors in the vasculature cause vasoconstriction?
Alpha 1 receptors are GPCRs
Activates Gq proteins which result in the increase of intracellular Ca2+ via effectors
This leads to contraction of the smooth muscle (vasoconstriction)
How does activating Beta 2 receptors in the vasculature result in vasodilation?
B2 receptors are GPCRs
Activates Gs proteins which stimulate adenylyl cyclase and increase cellular cAMP concentration
Opens a type of K+ channel
This results in relaxation of the smooth muscle (vasodilation)
Give some examples of local vasodilatory metabolites
K+
H+
Adenosine
Increasing PCO2
What are the three major actions of the ANS on the CVS?
Control of:
- Heart rate
- Force of contraction
- Peripheral resistance (Vasomotor tone)
Describe the parasympathetic innervation of the heart
Hint: Structure and function
Preganglionic fibres originate from the 10th cranila nerve (Vagus nerve)
Synapse with post-ganglionic cells on the epicardial surface or at the SAN or AVN
Postganglionic cells release Ach
Acts on M2 receptors to:
- Decrease heart rate (Negative chronotrophic effect)
- Decrease AV node conduction velocity
Describe the sympathetic innervation of the heart
Hint: Structure and function
POstganglionic fibres originate from the sympathetic trunk (throracolumbar outflow)
Innervate the SAN, AVN and myocardium
Noradrenergic
Acts of Beta 2 receptors to:
- Increase heart rate (positive chronotropic effect)
- Increases force of contraction (positive ionotropic effect)
Describe how the sympathetic nervous system affects the pacemaker potentials in the heart
Hint: Start your explanation at the level of receptors
B1 receptors fire leading to increase in cAMP (via Gs proteins stimulating adenylyl cyclase)
This increases the gradient of the funny current slope, hence increasing frequency of pacemaker potentials
Describe how the parasympathetic nervous system affects the pacemaker potentials in the heart
Hint: Start your explanation at the level of receptors
M2 receptor firing increases K+ conductance of the membrane (via Gi protein and K+ channels) and decrease cAMP
This decreases the gradient of the funny current slope hence decreasing the frequency of pacemaker potentials
How does Noradrenaline affect the force of contraction in the heart?
Na acting on B1 receptors in the myocardium causes and increase in cAMP (via Gs and adenylyl cyclase) which in turn causes:
- Phosphorylation of Ca2+ channels causes increased Ca2+ entry during APs
- Increased uptake of Ca2+ into the sarcoplasmic reticulum
- Increased sensitivity of contractile machinery to Ca2+
This leads to an increased force of contraction
How are changes in blood pressure communicated to the brain?
- Baroreceptors in the carotid sinus and aortic arch (high pressure side of the system)
- Atrial volume (baro)receptors (low pressure side of the system)
Afferent nerves from these receptors communicate information about blood pressure to the medulla oblongata in the brainstem
How do baroreceptors function?
These receptors are excited by stretching of the carotid sinus or aortic arch, as would occur when blood pressure raises
They then communicate this information to the medulla oblongata
Describe how mean arterial pressure might be lowered after a rise
Baroreceptors excited by the stretch of the carotid sinus and aortic arch
They fire APs to the medulla oblongata
Medulla oblongata then increases parasympathetic output to the CVS
This results in bradycardia and vasodilation that counteract the rise in mean arterial pressure
What classes of drugs acting on the CVS do we need to be aware of in Semester 2?
Sympathomimetics:
- Alpha adrenoceptor agonists
- Beta adrenoceptor agonists
Adrenoceptor antagonists
Cholinergics
- Muscarinic agonists
- Muscarinic antagonists
Give two sympathomimetic drugs and their uses on the CVS
Include which receptors these drugs act on, and their action at those receptors
Adrenaline (general adrenoceptor agonist):
- Administered to restore function in cardiac arrest
- Can also be administered in anaphylactic shock
Dobutamine (B1 agonist):
- Can be given in cardiogenic shock (pump failure)
Give an example of a use of a sypathomimetic drug outside the CVS
Include it’s receptor type and action at that receptor
Salbutamol (B2 agonist):
- Treatment of asthma (bronchodilation)
Give an example of an alpha adrenoceptor antagonist and its function
Prazosin
Inhibits NA action on vascular smooth muscle A1 receptors causing vasodilation (anti-hypertensive agent)
Give an 2 examples of a beta adrenoceptor antagonist and their function
Mention any important side effects
Propanolol:
- Non selective B1 and B2 antagonist
- Slows heart rate and reduces force of contraction
- Also causes bronchoconstriction (B2 antagonism of bronchial smooth muscle)
Atenolol:
- Selective B1 antagonist
- Slows heart rate and reduces force of contraction
- Less risk of bronchoconstriction
Give an example of a drug that is a muscarinic agonist and include its function
Pilocarpine:
- Used in the treatment of glaucoma (activates the constrictor pupillae muscle)
Give an example of a drug that is a muscarinic antagonist and include its function
Atropine:
- Increases heart rate
- Increases bronchial dilation
- Used to dilate the pupils to examine the eye
What factors determine the magnitude of vasodilatory effect caused by local vasodilatory metabolites?
Rate they’re produced
Rate at which the blood stream washes them away
