Session 5 Flashcards
What physiological functions does the autonomic nervous system regulate?
- Heart rate
- Blood pressure
- Body temperature
- Response to exercise and stress
What does the autonomic nervous system exert control over in the body?
- Vascular smooth muscle
- Visceral smooth muscle
- Rate of heart contraction
- Force of heart contraction
- Exocrine secretion
What are the two divisions of the autonomic nervous system and how are they defined?
- Parasympathetic (craniosacral)
- Sympathetic (thoracolumbar)
What is the ‘third’ division of the autonomic nervous system and how is it controlled?
ENTERIC SYSTEM
- Neurones surrounding GI tract
- Controlled via sympathetic and parasympathetic fibres
How are sympathetic pre and post ganglionic fibres arranged?
- Pre ganglionic neurone is short and has the cell body in the CNS.
- Synapse at a ganglion.
- Post ganglionic neurone is very long and originates from sympathetic trunk to the target tissue
How are parasympathetic pre and post ganglionic fibres arranged?
- Pre ganglionic neurones long.
- Synapse at a ganglion.
- Post ganglionic neurones are very short, often in the tissue that is being innervated.
When is sympathetic activity dominant?
Under stress (eg. fight or flight response)
When is parasympathetic activity dominant?
Under basal/resting conditions
What happens when both parasympathetic and sympathetic divisions innervate a tissue?
They have opposite effects and work together to maintain a balance most of the time.
What are some examples of ANS control and how are they controlled under parasympathetic and sympathetic innervation? *
- Eye - contraction and dilation
- Airways - contraction and relaxation
- Heart - increased force of contraction and rate, and reduced rate ONLY
- Sweat glands
What receptors are in the parasympathetic system and what neurotransmitter do they use?
- Muscarinic (M1, M2, M3)
- Acetylcholine
What receptors are in the sympathetic system and what neurotransmitters do they use?
- Alpha-1, Alpha-2, Beta-1, Beta-2
- Noradrenaline + circulating adrenaline
What does it mean if the sympathetic activity to the tissues is independently regulated?
Activity can be increased to one system (eg. heart) without affecting the other (eg. GI)
What does the ANS control in the cardiovascular system?
- Heart rate
- Force of contraction
- Peripheral resistance of blood vessels
What does the ANS N O T control?
- Does not initiate electrical activity in the heart
What influence is the heart under?
Vagus nerve (parasympathetic dominant)
What happens when the heart is denervated?
Will still beat but at a faster rate (about 100bpm)
What is the parasympathetic input to the heart?
VAGUS NERVE
Where do the preganglionic fibres synapse?
On epicardial surface/within the walls of the heart at AVN or SAN.
Why can the parasympathetic system not change the force of contraction?
There is not much innervation of the myocardium (heart muscle)
What receptors does the acetylcholine released by the postganglionic fibres in the PNS act on and what are the effects?
M2 receptors (Gi)
- Negative chronotropy
- Reduced AVN conduction velocity
What is the sympathetic input to the heart?
Post ganglionic fibres from the sympathetic trunk.
What do the postganglionic fibres innervate and what transmitter do they release?
- SAN, AVN and myocardium
- Release noradrenaline
What receptors does noradrenaline mainly act on, and what is the effect?
- Beta-1 adrenoceptors (main in heart)
Effects: - Positive chronotropy
- Negative inotropy (contraction)
What other receptors are present in the heart aside from beta-1?
Beta-2 and beta-3.
Look at the diagram showing ANS input to heart!*
OK :)
How do the SAN cells initiate an action potential?
- Steadily depolarise toward threshold (pacemaker potential)
- Slow Na+ conductance is turned on (funny current, slow inward movement of Na+)
- Opening of Ca2+ channels
What is the action potential firing in SAN responsible for?
Setting rhythm of heart
How are action potentials in SAN initiated?*
- HCN channels open, allowing Na+ in and slow depolarisation
- Opening of fast Ca2+ channels (upstroke of AP)
- Closing of Ca2+ channels and opening of K+ channels to allow repolarisation (efflux of K+)
What effect does sympathetic activity have on the pacemaker potential?
- Increases the slope and speeds up the action potential
- Mediated by B1 receptors
- Increased cAMP
What effect does parasympathetic activity have on the pacemaker potential?
- Decreases the slope and therefore slows down the action potential
- Beta-gamma subunit directly increases potassium conductance
- Decreased cAMP
- Mediated by M2 receptors
How does adrenaline increase the force of contraction?
- Acts on B1 receptors, increases cAMP and activates PKA
- PKA phosphorylates Ca2+ channels and increases Ca2+ entry
- Increased uptake of Ca2+ in SR
- Increased force
What kind of innervation do most vessels receive, and what are exceptions?
Sympathetic innervation (exception is erectile tissue - parasympathetic)
What receptors do most arteries and veins have?
Alpha-1
What additional receptors to a1 do coronary and skeletal muscle vessels have?
B2 receptors
What is the vasomotor tone?
A basal level of activity that permits both vasodilatation and vasoconstriction.
How does the sympathetic output initiate vasodilation and why?
- Less NAd, less sympathetic output
- Reduces blood pressure
- Allows more blood flow to tissue
How does the sympathetic output initiate vasoconstriction?
- Increased sympathetic output
- Restricts blood flow to tissue
- Increases blood pressure
Which blood vessels have B2 AND a1 adrenoceptors?
Vascular smooth muscle of the vessels in skeletal muscle, liver and myocardium.
What is the effect of noradrenaline on a1 receptors?
- Causes vasoconstriction
- Controls arterial blood pressure
What is the effect of circulating adrenaline on B2 receptors?
Relaxation of vascular smooth muscle.
What is the affinity of adrenaline and how does it change?
- Circulating adrenaline has a higher affinity for B2 receptors than for a1
- If at higher concentrations than physiological, adrenaline will also activate a1 receptors which can cause vasoconstriction.
How does activating B2 adrenoceptors affect vascular smooth muscle?
VASODILATION (Gs)
- Affected by circulating adrenaline
- Increased cAMP
- Activated PKA
- Open K+ channels and inhibited MLCK (can’t phosphorylate)
- Relaxation of smooth muscle
How does activating a1 receptors affect vascular smooth muscle?
VASOCONSTRICTION (Gq)
- Stimulates IP3 production
- Increased intracellular calcium from stores and influx of extracellular Ca2+
= Contraction
- DAG activates PKC which inhibits MLCP and promotes the active conformation
Look at the excitation contraction coupling diagram!*
Ok :D
What is the role of local metabolites and how are they important?
- Ensure adequate perfusion of skeletal + coronary muscle
- Local increases have strong vasodilator effect
- More metabolites produced by active tissue (eg. K+, H+, more CO2)
How are the changes in the state of the cardiovascular system communicated to the brain?
Afferent nerves
- Baroreceptors (aortic arch/carotid sinus) - high pressure
- Atrial receptors - low pressure
What is the effect of the changes that are being communicated?*
Altered activity of efferent nerves.
Where are baroreceptors located and what are they?*
- Nerve endings sensitive to STRETCH (stretched by increased arterial pressure).
How does the information from the carotid sinus travel to control centre?
Glossopharyngeal nerve.
How does the information from the aortic arch travel to control centre?
Vagus nerve.
Describe the baroreceptor reflex. *
- Increase in MABP
- Stretch detected by baroreceptors, which send the information to the coordinating centre in the medulla (oblongata)
- Increased parasympathetic and reduced sympathetic activity
- Reduced heart rate and vasodilation occur to reduce BP.
Why is the baroreceptor reflex important?
Compensates for short term changes in BP
What is the issue with the baroreceptor reflex?
Baroreceptors can reset to higher levels with persistent increases in BP
What are sympathomimetics?
Agonist drugs that mimic the action of the sympathetic nervous system.
What are cardiovascular uses of sympathomimetics?
- Adrenaline to restore heart function in cardiac arrest by vasoconstriction
- Dobutamine B1 agonist - given in cardiogenic shock
- Adrenaline given for anaphylactic shock, allows more a1 to be activated to prevent blood pressure from falling and allows vasoconstiction.
- Redirects blood to vital organs
What are non-cardiovascular uses of sympathomimetics?
B2 agonist salbutamol - causes relaxation of bronchial smooth muscle
What are adrenoceptor antagonists?
Drugs that reduce the actions of adrenaline
What are alpha adrenoceptor antagonists?
eg. prazosin
- Inhibits noradrenaline acting on a1 receptors to cause vasodilation
What are beta adrenoceptor antagonists?
- Propranolol - nonselective B1/2, slows heart rate and reduces force of contraction
- Atenolol - cardioselective B1 antagonist
Why is atenolol better than propranolol?
- Propranolol not selective - can also cause bronchoconstriction by acting on bronchial smooth muscle
- Atenolol specific so reduces risk of bronchoconstriction and side effects
What are muscarinic agonists?
Pilocarpine
- Treating glaucoma
- Activates constrictor pupillae muscle
What are muscarinic antagonists?
Atropine
- Increases heart rate and bronchial dilation
- Dilation of pupils for eye examination
What is hypertension?*
A sustained increase in blood pressure (mmHg). Normal blood pressure is 90/60 mmHg - 120/80 mmHg
(anything above 140/90 mmHg is hypertension)
What is the difference between primary and secondary hypertension?
- Primary: from an unknown cause (95% cases)
- Secondary: hyperaldosteronism, Cushing’s syndrome, renal and renovascular disease (must treat the cause)
What are the effects of hypertension?
LARGE RISK FACTOR FOR PREMATURE DEATH
Can damage heart and vasculature as well as lead to heart failure, MI, strokes, renal failure and retinopathies
What can contribute to hypertension?*
- All vascular diseases
- e.g. aortic aneurysm, heart failure, MIs
What can hypertension increase?*
- Afterload higher as heart must pump under a higher pressure to pump blood across in systole
- Can lead to LV hypertrophy and increased O2 demand, which can lead to heart failure and ischaemia respectively
- Can cause arterial damage, which leads to atherosclerosis and weakened vessels
- Can contribute to retinopathies and strokes
What target organs can be damaged by cardiovascular disease?*
- Brain
- Heart
- Eyes
- Kidneys
- Arteries
What can reducing blood pressure do?
Reduce risks of coronary heart disease, stroke, heart failure and mortality in general
How is blood pressure regulated in the short term?
Baroreceptor reflex - adjusting the sympathetic and parasympathetic inputs to the heart to alter the cardiac output, as well as adjust sympathetic input to vessels to alter TPR
What is the baroreceptor reflex?*
Baroreceptors/nerve endings found in carotid sinus and aortic arch which are sensitive to stretch.
- Will be stretched with increased pressure
- Signal will be send to the coordinating centre in the medulla via the afferent pathways
Why can’t baroreceptors control blood pressure long-term?
The threshold for baroreceptor firing resets
How is long-term control of blood pressure mediated and what are the 4 pathways?
Neurohumoral responses controlling sodium balance
- Renin-angiotensin-aldosterone system
- Sympathetic nervous system
- Anti-diuretic hormone
- Atrial natriuretic peptide
Where is renin released from?*
Granular cells of the JUXTAGLOMERULAR APPARATUS in response to reduced perfusion pressure detected by baroreceptors (so low circulating volume)
What stimulates renin release?*
- Reduced NaCl in distal tubule
- Reduced perfusion pressure in kidney
- Sympathetic stimulation of JGA
What is the function of renin?*
- Stimulates cleavage of angiotensinogen to angiotensin I
- Angiotensin converting enzyme (ACE) then converts angiotensin I to the biologically active angiotensin II
What are the effects of angiotensin?
- Stimulating aldosterone release
- Stimulating Na+ absorption
- Vasoconstriction
What and where are the angiotensin receptors?*
AT1 and AT2 (main AT1) - GPCR
- In arterioles, kidney, SNS, adrenal cortex and hypothalamus
What is the function of aldosterone that is released from the adrenal cortex?
- Acting on collecting duct cells to stimulate Na+ reabsorption and therefore water reabsorption
- Activates apical Na+ and K+ channels (ENaC, epithelial Na+ channel)
- Increases Na+ extrusion via Na/K ATPase
What is the other function of angiotensin converting enzyme?
Breaking down bradykinin, which is a vasodilator, into peptide fragments
What is an example of an ACE inhibitor?
Captopril, Lisinopril
Why do high levels of sympathetic stimulation reduce renal blood flow?
- Arterioles vasoconstrict so reduced delivery of blood
- Decrease of glomerular filtration rate so less Na+ removed
What are the other functions of the sympathetic nervous system in regulating BP?*
- ++ apical Na/H exchanger and basolateral Na/K ATPase in PCT
- Stimulating renin release which eventually causes increased Na+ reabsorption
What is the main function of antidiuretic hormone?
Formation of concentrated urine by retaining water to control plasma osmolarity (reabsorption in distal nephron via aquaporin 2)
- Stimulating Na+ reabsorption
- Vasoconstriction
What stimulates ADH release?
- Increase in plasma osmolarity
- Severe hypovolaemia
What is atrial natriuretic peptide and how is it released?
- A compound synthesised and stored in atrial myocytes - Released in response to stretch by recognition from low pressure volume sensors in atria
- Less ANP with reduced filling
What are the actions of ANP?
- Vasodilation of afferent arteriole
- Increased blood flow form vasodilation (+ GFR)
- Inhibition of Na+ reabsorption
- Natriuresis (loss of sodium into urine)
What are prostaglandins?
Physiologically active lipid compounds that have diverse hormone-like effects
What are the functions of prostaglandins?
- Clinically important vasodilators
- Enhance glomerular filtration and reduce Na+ reabsorption
- Act when AngII levels high to prevent vasoconstriction further
What is dopamine and how is it formed?
- Neurotransmitter
- Formed in the kidney from circulating L-DOPA
Where are dopamine receptors found?
Renal blood vessels and cells in the proximal convoluted tubule
How does dopamine act?
- Causes vasodilation so more renal blood flow
- Reduces reabsorption of NaCl by inhibiting NHX + Na/K ATPase
How does renovascular disease cause hypertension?
- Occlusion of renal artery and therefore less perfusion pressure
- Increased renin production
- Renin-angiotensin-aldosterone
- Vasoconstriction and Na+ retention
How does renal parenchymal disease cause hypertension?
- Loss of vasodilators
- Na+ and water retention = poor filtration
What are the adrenal causes of hypertension?
- Conn’s syndrome (aldosterone-secreting adenoma)
- Cushing’s syndrome (excess cortisol)
- Phaerochromocytoma (AG tumour), secretes Ad + NAd
How can the targets for treating hypertension be worked out?
BP = CO X TPR so BP = SV X HR X TPR
What are non-pharmacological approaches to treating hypertension?
- Diet and exercise
- Reduced sodium intake
- Reeduced alcohol
How do ACE inhibitors and AngII receptor antagonists work?
ACEi: Prevent AngII production so prevents vasoconstriction and NaCl + water retention
- Will also reduce bradykinin breakdown so more vasodilation
AngII receptor antagonists: prevent angiotensin II binding to receptor
What vasodilators are used to treat hypertension?
- L-type Ca2+ channel blockers (verapamil) - reduce Ca2+ entry so relax muscle
- Alpha 1 receptor blockers (doxazosin) - relaxation of vascular smooth muscle
What diuretics are used to treat hypertension and how do they work?
Thiazide diuretics that reduce volume
- Will inhibit Na/Cl co-transporter on apical membrane of distal tubule cells
When are beta-blockers used in treating hypertension?
Used when there are other indications along with hypertension, such as previous MI (reduce sympathetic output)
What are the targets of drugs?*
SLIDE 48
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