Autonomic Cardiac Control Flashcards
How do pacemaker cells spontaneously depolarise?
Pacemaker cells spontaneously depolarise due to the pacemaker (funny) current
Why is it called the ‘funny’ current?
Because, very unusually, this channel is activated to open by hyperpolarisation
What is the function of the ‘funny’ channel?
It mainly allows Na+ into the cell (also by some K+)
Known as inward (If) current
What causes depolarisation in the pacemaker cells?
Hyperpolarisation activates funny (If) current.
Na+ moves into the cell causing depolarisation
What is the predominant ion involved in pacemaker potential?
Na+ ions
What are the two currents involved in pacemaker potential?
Funny (If) current Inward rectifier (Ik)
At what voltage to T type Ca2+ channels open?
-55mV
What happens to the cell when the T type Ca2+ channels open?
Influx of Ca2+, increases depolarisation
How long are T type Ca2+ channels open?
T type channels are transient (they open and close very quickly)
When do L type Ca2+ channels open?
At threshold potential
Why, when L type Ca2+ channels open, is there such a large influx of Ca2+?
Far more L type channels than T type channels
How does membrane depolarisation in a pacemaker cell differ from the depolarisation of a normal cell?
Pacemaker - influx of Ca2+
Normal - influx of Na+
What initiates the repolarisation of the pacemaker cells?
Opening of K+ channels
What causes the hyperpolarisation phase of the pacemaker potential?
Efflux of K+, and inactivation of Ca2+ channels
How does the SNS affect the heart?
Releases noradrenaline onto SA node, AV node, atria and ventricles
Enhances HR and contractility
How does the PNS affect the heart?
Releases acetylcholine onto SA and AV nodes, and ventricles
Decreased HR, AV conduction and contractility
Why is reduced AV node conduction velocity preferable?
Less likely to develop life threatening arrythmias
How did Dale and Loewi confirm the existence of acetylcholine?
Dissected frog hearts, placed in separate organ baths in Ringer’s solution:
Heart 1: vagus nerve attached
Heart 2: no vagus nerve
Heart 1: Electrically stimulation of the vagus nerve decreased HR
Heart 2: Loewi took some of the solution bathing the first heart and applied it to the second heart - showed decreased HR
Conclusion: a soluble chemical released by the vagus nerve was controlling the heart rate
When the SNS stimulates the heart, how long does it take to reach 90% of max heart rate?
13s (+/-5s)
When the PNS stimulates the heart, how long does it take for maximum reduction in heart rate to occur?
3s (+/-1s)
When the PNS stimulates the heart, how long does it take for the heart rate to begin to change?
~200ms
When PNS stimulation stops, how long does it take for heart rate to recover to baseline?
~900ms
Why is the rate of change in heart rate so different between the PNS and SNS stimulation?
PNS - ACh 2nd messenger route
SNS - NA 2nd messenger route-slower
Describe the PNS 2nd messenger route
Acetylcholine released into synapse and binds to postsynaptic muscarinic cholinergic receptors (GPCRs)
G-proteins diffuse across membrane, and stimulate K+ channel to open, causing efflux of potassium.
G-protein also stimulates closure of the T-type Ca2+ channel.
This prevents pacemaker potential, reducing heart rate. Also, K+ efflux causes increased hyperpolarisation, meaning it is harder for the cell to depolarise.
ACh is rapidly hydrolysed by acetylcholinesterase.
How does ACh binding to the muscarinic cholinergic receptor effect the T-type and L-type channels, and the ‘funny’ current?
Closes the channels and prevents the current.
Describe the SNS 2nd messenger route
Noradrenaline (or adrenaline) binds to β1 adrenergic receptor (GPCR), located in the SA node.
G-protein diffuses across the membrane, activating adenylate cyclase. ATP is converted to cAMP.
cAMP activates Protein Kinase, which phosphorylates the funny channel and the Ca2+ channel.
Why does it take longer to for heart rate to return to baseline with SNS stimulation, compared to PNS stimulation?
There are more steps involved in NA stimulation than ACh stimulation.
Also, ACh is hydrolysed quickly, whereas NA metabolism and reuptake is slower.
What is the importance of response time to ANS stimulation?
Vagal stimulation will alter SAN firing rate within 1 cardiac cycle. Switch off is also quick
So, beat to beat changes in heart rate are modulated by PNS
What modulates beat to beat changes in heart rate?
PNS stimulation
What causes rapid increase in heart rate in response to exercise or stress?
Parasympathetic withdrawal
How are sympathovagal interactions balanced?
Inhibitory parasympathetic influence
Excitatory sympathetic influence
Tonic input from both limbs
At rest, which division of the ANS is dominant in humans?
PNS
Define reciprocal control of the ANS
Increase in one division of the ANS, decrease in the other.
Give examples of non-reciprocal activation of the ANS
Independent activation
Co-activation
Cardiac responses to vagal stimulation enhanced if concurrent sympathetic activation
How does diving reflex exhibit co-activation of the SNS and PNS?
Activation of the trigeminal nerve which causes bradycardia (activating PNS)
Vasoconstriction of arterioles, to reduce loss of body heat and reduce in oxygen demand, preserving oxygen for brain and vital organs (SNS)
How are cardiac responses to vagal stimulation affected if there is also concurrent sympathetic activation?
Much greater response.
Give an example of how cardiac responses to vagal stimulation is enhanced if there is concurrent sympathetic activation
Performing exercise (e.g. biceps contraction) whilst stimulating the diving reflex.
Bradycardia induced by diving reflex is much greater.
Describe the features of the parasympathetic pathways
Preganglionic parasympathetic fibres
- Originate in the medulla oblongata of the brainstem
- Exit with the cranial nerves (vagus: Xth)
- Cardiac branches diverge within thorax
- Project to ganglionic plexuses located in epicardial fat pads on dorsal atrial surfaces
- Dense baskets of varicosities
- Synapse with postganglionic efferent nerves close to heart.
- Sinoatrial node
- Atrioventricular node
- Ventricles (Lewis et al. 2001)
- Muscarinic Cholinergic receptors
Describe the features of the sympathetic pathways
Preganglionic sympathetic fibres
- Originate in the medulla of the brainstem
- Exit in spinal nerves and travel from the spinal cord (T1-T4/5) to the ganglia
- Synapse with postganglionic efferent nerves
- Cell bodies originate in prevertebral and paraveterbral sympathetic ganglia - Descend as bilateral branches to the cardiac plexus
- Innervate
- Heart (SAN, AVN, atria and ventricles)
- Blood vessels - Beta adrenergic receptors (a and β subtypes)
What techniques can be used to find the location of the somata of the vagal neurones within the brainstem?
Electrophysiology
Tracing
Describe the process of electrophysiology to find the cell bodies of the vagal neurones
Place rat in a stereotaxic frame, securing the head in a specific orientation
Expose the skull. Use identifiers on the skull to get level of head correct
Remove part of the skull to expose the correct section of the brain.
Using atlas of the rat brain, identify the region of the brain needed.
Place a stimulating electrode or fine pipette containing excitatory amino acid, to activate the region of the brain access, and observe what happens.
Describe the process of tracing to find the cell bodies of the vagal neurones
Inject tracer into the epicardial fat pads.
Trace will flow up the nerve to the brain, and can be observed with immunofluorescence or infrared.
Where do most of the nerves involved in reducing heart rate originate?
Nucleus ambiguus
How does stimulation of the nucleus ambiguus affect heart rate?
Decreases heart rate
Other than the nucleus ambiguus, where are some of the cardiac vagal motor neurones traced to?
Dorsal motor nucleus of the vagus
How many projection are there from the nucleus ambiguus compared with the projections of the dorsal motor nucleus of the vagus?
Same number of projections from each
How do the axons from the nucleus ambiguus amplify cardiac response compared to the DMV axons?
NA axons diverge 3x more than the DMV axons, which amplifies response
What type of fibres are the axons that project from the nucleus ambiguus?
B-type fibre
What type of fibres are the axons that project from dorsal motor nucleus of the vagus?
C-type fibre
What type of responses do axons from the nucleus ambiguus transmit?
Fast responses - reflex responses
What type of responses do axons from the DMV transmit?
Slow responses - tonic control
The axons from which nucleus (nucleus ambiguus or dorsal motor nucleus of the vagus) have a faster transmission and why?
The nucleus ambiguus as it’s axons are myelinated, compared to the DMV axons which are unmyelinated
Do parasympathetic cardiac neurons posses pacemaker activity?
No, they require an input be to activated
What activates the parasympathetic cardiac neurons?
Three major synaptic inputs; glutamatergic, cholinergic and GABAergic neurotransmission to the CVNs
What are the two major synaptic inputs that stimulate the parasympathetic cardiac neurons?
Glutamatergic and cholinergic neurotransmission
What is the major synaptic input that inhibits parasympathetic cardiac neurons?
GABAergic neurotransmission
What effect on the heart will result from stimulation of the parasympathetic cardiac neurons?
Decreased heart rate
Where does the glutamatergic input to the cardiac vagal motor neurons originate?
Nucleus tractus solitarius
What are the properties of the nucleus tractus solitarius?
Primary site of afferent termination (e.g. arterial baroreceptors)
NTS neurones project to the nucleus ambiguus
Stimulation of the nucleus tractus solitarius activates which receptor-mediated currents?
Excitatory NMDA and non-NMDA receptor-mediated postsynaptic currents in vagal cardiac neurons in the NA
Describe the pathway of the baroreflex-evoked response to increase in blood pressure
Increased blood pressure causes increased firing of the baroreceptors.
Baroreceptor transmit signal along nerve to the nucleus tractus solitarius.
NTS relays signal along interneuron to excite the cardiac vagal motor neurons. This results in decreased heart rate.
What is the result of the stimulation of baroreceptors by increased blood pressure?
Decreased heart rate
Describe respiratory sinus arrhythmia
Increased heart rate on inspiration
Decreased heart rate on expiration
What causes respiratory sinus arrhythmia?
Excitation of post-inspiratory neurones
How does Acetylcholine excite cardiac vagal motor neurons via three sites of action?
Activates a direct ligand-gated postsynaptic nicotinic receptor
Enhances postsynaptic non-NMDA currents
Facilitates transmitter release presynaptically
What is the role of cholinergic input to CVMNs in mediating respiratory sinus arrhythmia?
Excites cardiac vagal neurons during post-inspiration
Decreases HR
What is the effect of stimulation of post-inspiratory neurons on heart rate?
Decreases heart rate
What is the effect of activation of the inspiratory neurons on heart rate?
Inspiratory neurons inhibit parasympathetic activity, raising heart rate
How does GABAergic input to cardiac vagal neurons play a role in heart rate?
Tonically active GABAergic input to cardiac vagal neurons that plays an important role in the tonic and reflex control of heart rate
Inhibitory action on CVMN’s
What is the role of GABAergic in respiratory sinus arrhythmia?
Involved in generating respiratory sinus arrhythmia
- the inhibition of cardiac vagal neurons during inspiration
Where are the baroreceptors located?
Carotid sinuses: bifurcation of the internal and external carotid arteries
- glossopharyngeal (IX) nerve
Arch of the aorta
- vagus (X) nerve
What do baroreceptors respond to?
Amount and rate of stretch
Where are impulses from the baroreceptors taken to?
Impulses are taken to the Nucleus Tractus Solitarius (NTS) of the Medulla Oblongata
What is the difference in activity in the carotid sinus nerve in response to blood pressure?
At low blood pressure, low frequency of action potentials being produced.
As blood pressure increases, the frequency of the action potentials
What is the cardiovascular control centre?
Scattered group of neurones in the medulla oblongata situated close to the floor of the 4th ventricle, which is responsible for the regulation of the rate at which the heart beats
Where is the cardiovascular control centre located?
4th ventricle
What are two areas of the cardiovascular control centre that control blood pressure?
Pressor area
Depressor area
What is the function of the Pressor area?
Has tonic activity, so constantly producing and activating vasoconstriction of the arterioles and increase in heart rate
What is the function of the Depressor area?
Causes vasodilation and reduces heart rate
How does the Vasomotor centre reduce blood pressure?
- NTS neurons conveying baroreceptor signals then project to and excite neurons within the caudal ventrolateral medulla (CVLM)
- CVLM neurons project to and inhibit tonically active sympathoexcitatory neurons in the rostral VLM (RVLM)
- So, when the baroreceptors are activated (by an increased blood pressure), the NTS activates the CVLM, which in turn inhibits the RVLM
- Inhibits sympathetic activity - decrease in BP
- The NTS also sends excitatory fibres to the vagal nuclei (Nucleus ambiguus and dorsal motor nulceus of the vagus)
- Increases parasympathetic nervous system activity, aids decrease in sympathetic activity when BP is raised
- Also lowers HR
What is the response in the vasomotor centre to low BP?
Less inhibition of tonically active RVLM neurons
Causes an increase in sympathetic activity
Increased TPR, HR, contractility
What are three methods that SNS activity can be measured?
Microneurography
Plasma noradrenaline
Noradrenaline spillover
What are the problems with using plasma noradrenaline measurements as a measure of SNS activity?
Noradrenaline plasma clearance - data localised to where sample is taken from
What is the process of measuring noradrenaline spillover?
Regional, infuse radiolabelled NA, sample from centrally placed catheters
Invasive – but more accurate
What are the problems with measuring noradrenaline spillover?
Invasive
What are the problems with directly measuring parasympathetic activity?
Direct nerve recording
- Location of vagus nerve (In neck, next to carotid)
- Not readily accessible!
Plasma ACh hydrolysed too quickly
What is the problem with measuring plasma ACh?
Hydrolyses too quickly to be measured
What is the method used to measure the effect of the PNS on activity of the heart?
Monitor changes in heart rate in response to breathing (respiratory sinus arrhythmia)
What are the features of respiratory sinus arrhythmia?
Mediated through vagus nerve
Very rapid changes
Proportional to efferent vagal activity
Abolished (98%) by atropine
What is the evidence for respiratory sinus arrhythmia being mediated by the parasympathetic nervous system?
Abolished (98%) by atropine - blocks cholinergic receptors
In animal, cut vagus nerve - results in absence of respiratory sinus arrhythmia
Why is vagal tone measured?
Magnitude of Heart Rate Variability used as an indicator of health and disease status.
- High vagal tone - High aerobic fitness and health
- Low vagal tone - Adverse prognosis (post MI etc)
How does exercise training affect vagal tone?
Improves Heart Rate Variability measures of vagal tone in patients who suffer from MI or hypertension
How is vagal tone measured?
Assessed by the degree of respiratory induced fluctuations in heart rate
- heart rate variability (HRV)
