M&R Session 10: autonomic nervous system Flashcards by Charlotte Ralphs

ANS functions?

Controls all involuntary functions
Separate from voluntary (somatic) system
Entirely efferent, but regulated by afferent inputs

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Sympathetic division?

Fight or flight

Increase HR, force of contraction and blood pressure, pupils dilate, adrenaline release, sweating

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Parasympathetic division?

Regulates basal activities-“rest and digest”

Largely has effects opposing the sympathetic system

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Parasympathetic nerve characteristics

Originate in lateral horn of medulla and sacral region of spinal cord
Long myelinated pre-ganglionic neurones, short unmyelinated post-ganglionic neurones
Ganglia in tissues innervated by postsynaptic fibres

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Sympathetic nerve characteristics

Originate in lateral horn of the lumbar and thoracic spinal cord
Short myelinated pre-ganglionic neurones, long unmyelinated post-ganglionic neurones
Ganglia in the paravertebral chain close to the spinal cord

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Neurotransmitter and receptors for all pre-ganglionic neurones?

All are cholinergic (use ACh)

So cause activation of post-ganglionic nicotinic ACh receptors (ligand-gated ion channels)

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Neurotransmitter and receptors for parasympathetic post-ganglionic neurones?

Cholinergic: use ACh

Acts on muscarinic ACh receptors in the target tissue (GPCRs. 5 types)

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Neurotransmitter and receptors for sympathetic post-ganglionic neurones?

Most:
Noradrenergic: use noradrenaline which acts on alpha or beta adrenoceptors (9 types, further subdivided, GPCRs)

Some:
Cholinergic: use ACh to act on mAChR
e.g. sweat glands, hair follicles (piloerection)

Adrenal glands different-release adrenaline into blood rather than target tissue. The sympathetic postganglionic neurones here differentiate to form neurosecretory chromaffin cells

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Non-adrenergic, non-cholinergic transmitters?

May be co-released with either NA or ACh

Examples:
ATP
nitric oxide
5-hydroxytryptamine (serotonin)
neuropeptides such as VIP

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Parasympathetic release of ACh effect on heart + receptors

M2 muscarinic ACh receptors activated, causing:

bradycardia (act on SA node to decrease beats)
reduced conduction velocity (act on AV node to decrease conduction from atria to ventricles)

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Parasympathetic release of ACh effect on smooth muscle + receptors

M3 muscarinic ACh receptors
Lungs: bronchial and bronchiolar contraction
GI tract: increased intestinal mobility and secretion
GU tract: bladder contraction (detrusor) and relaxation (sphincter). Also penile erection but via NO: ACh causes NO release which causes the erection
Eye: ciliary muscle and iris sphincter contraction

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Parasympathetic release of ACh effect on glands and receptor

M1 and M3 muscarinic ACh receptors

Increased sweat/salivary/lacrimal secretions

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Sympathetic release of NA effect and receptor-heart

Positive chronotropy-tachycardia-from SA node
Positive inotropy-increase FoC-from ventricles
B1 receptors (B2)

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Sympathetic release of NA effect and receptor-smooth muscle

Arteriolar contraction/venous contraction-a1 adrenoceptors
Some arteriolar relaxation in exercising muscle to run fast-so b2 adrenoceptors here to relax
Bronchiolar/intestinal/uterine relaxation: b2 (b3) adrenoceptors
Bladder sphincter contraction-b3 adrenoceptors
Radial muscle contraction-a1 adrenoreceptors

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Sympathetic release of NA effect and receptor-kidney

Renin release

b1 and b2 adrenoreceptors

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Sympathetic release of NA effect and receptor-glandular

Increased viscous secretions

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Describe the afferent (sensory) inputs to the ANS

Sensory neurones monitor levels of CO2, O2, nutrients in blood, arterial pressure, and GI tract content
blood composition also sensed by the carotid body (chemoreceptors of carotid artery): send info to CNS via glossopharyngeal nerve
nucleus tractus solitarius: integrates all visceral afferent info
this also receives input from the area postrema (detects blood and CSF toxins)

What is dysautonomia?

Distinct malfunctions of the ANS

Catecholamine disorders?

Pheohromocytoma

Baroreflex failure

Central autonomic disorders?

Mutiple system atrophy:

Peripheral autonomic disorders?

Guillain-Barre syndrome

Familial dysautonomia

Orthostatic intolerance syndromes?

Postural orthostatic tachycardia syndrome (POTS)

Paroxysmal autonomic syncopes?

Neurocardiogenic syncope

List the basic steps in neurotransmission, indicating which are the most common sites of drug action (*)

Uptake of precursors
Synthesis of transmitter
Vesicular storage of transmitter
Degradation of transmitter *
Depolarisation by propagated action potential
Depolarisation-dependent influx of Ca2+
Exocytotic release of transmitter
Diffusion to post-synaptic membrane
Interaction with post-synaptic receptors*
Inactivation of transmitter*
Re-uptake of transmitter*
Interaction with pre-synaptic receptors*

Manipulating cholinergic function?

Interfere at nicotinic ganglia-there will not be discrimination between sympathetic and parasympathetic Interfere at muscarinic receptors: more selective, mainly parasympathetic effects

How is ACh synthesised?

acetyl CoA + choline --> acetylcholine + coenzyme A Via choline acetyltransferase

How is ACh degraded?

acetylcholine --> acetate + choline Via acetylcholinesterase

How can nAChRs be targeted?

Differ in structure at autonomic ganglia and the neuromuscular junction So some drugs select for autonomic ganglia action: e.g. tripemethaphan (blocks ganglia) used in hypertensive emergencies. But undesirable side effects

How can mAChRs be targeted?

5 subtypes (M1-M5), but only a few subtype-selective agonists/antagonists currently available Agonists: pilocarpine (glaucoma), bethanechol (stimulate bladder emptying) Antagonists: ipratropium and tiotropium (COPD), tolterodine, darifenacin and oxybutynin (overactive bladder)

How can AChE inhibitors be used therapeutically?

Enhance the actions of endogenous ACh by preventing breakdown E.g. pyridostigmine (myasthenia gravis) and donepezil (Alzheimer's disease)

Side effects of non-selective muscarinic ACh receptor agonists?

Heat: decrease HR and output Smooth muscle: increase bronchoconstriction and peristalsis Exocrine glands: increase sweating and salivation "Sludge syndrome"

Describe the synthesis of noradrenaline

1. Tyrosine to DOPA by tyrosine hydroxylase **DOPA a drug itself for Parkinson's treatment** 2. DOPA to dopamine by DOPA decarboxylase. Dopamine moved from cytosol into vesicles 3. Dopamine to noradrenaline by dopamine beta-hydroxylase

What happens after Ca2+-dependent exocytotic release of NA?

1. NA diffuses across synaptic cleft to interact with adrenoceptors in post-synaptic membrane to initiate signalling in effector 2. NA interacts with pre-synaptic adrenoceptors to regulate processes within the nerve terminal Only limited time for effects as rapidly removed by noradrenaline transporter proteins

Termination of noradrenergic transmission?

Uptake 1: re-uptake into pre-synaptic terminal by this Na+-dependent, high affinity transporter (most) Uptake 2: residual NA taken up by a combination of lower-affinity, non-neuronal mechanisms

Metabolism of NA?

Within the pre-synaptic terminal, NA not taken up into vesicles is metabolised by: - monoamine oxidase (MAO) - catechol-O-methyltransferase (COMT)

How can presynaptic GPCRs e.g. a2 adrenoceptor regulate neurotransmitter release?

Inhibit Ca2+-dependent exocytosis: | G protein betagamma subunits inhibit specific types of VOCCs thus reducing Ca2+ influx and neurotransmitter release

Indirectly-acting sympathomimetric agents?

E.g. tyramine, amphetamine, ephedrine Taken up into NA synaptic vesicles, NA leaks from vesicle, then leaks into synaptic cleft

Uptake 1 inhibitors?

E.g. tricylclic antidepressents, selective NA reuptake inhibitors Exert ajor effects in CNS. Unwanted peripheral side effects can be minimised by choice of drug and dose

Salbutamol in asthma effect?

It is a beta 2 adrenoceptor-selective agonist Relieves bronchoconstriction The selectivity minimises possible CVS side effects (positive inotropic and chronotropic)

Hypertension treatment?

Alpha 1 adrenoceptor-selective agonists e.g. doxazosin | Beta 1 adrenoceptor-selective antagonists, e.g. atenolol

Chronic heart failure treatment?

Beta blocker, ACE inhibitor and diuretic Beta 1 adrenoceptor selective antagonists e.g. bisoprolol, metoprolol Mixed alpha1/beta1/beta2 adrenoceptor antagonist-carvedilol. Very useful for chronic heart failure