What are the two main divisions of the autonomic nervous system?
Parasympathetic and sympathetic
What portions of the spinal cord supply parasympathetic nerves?
Cranial and sacral
What portion of the spinal cord supply sympathetics?
Thoracic and lumbar (1st thracic to 2nd or 3rd lumbar)
Which cranial nerves are parasympathetic?
3, 7, 9, 10
What do the sacral parasympathetic nerves supply?
bladder, rectum, sex organs
Describe the length of presynaptic and postsynaptic parasympathetic neurons.
Long presynaptic and short post-synaptic (ganglion is close to the target organ)
Describe the length of pre-synaptic and post-synaptic sympathetic neurons.
Short pre-synaptic to paravertebral and prevertebral ganglia
The parasympathetic nervous system is organized __________ with very little ____________.
Discretely with very little cross-talk. Response will typically be one-to-one
What is the transmitter at the parasympathetic ganglion?
Ach
What is the transmitter at parasympathetic neuroeffector junctions?
Ach
We can think of parasympathetic as largely ____________ while the sympathetic system is ____________________________.
Parasympathetic = cholinergic Sympathetic = adrenergic
Where do sympathetic axons emerge and where do they synapse?
The emerge from anterior roots and synapse in paravertebral or prevertebral ganglia
Where is the paravertebral ganglion?
Where is prevertebral?
Para- chains beside the vertebral column
Pre- in the abdomen and pelvis (celiac, superior mesenteric, etc)
What system (parasympathetic or sympathetic) controls the adrenal medulla? What nerve specifically?
Sympathetic- greater splanchnic nerve where it makes NE which can be converted to epi.
80% epi, 20% NE
Proximity of sympathetic ganglia to the spinal cord permits ________ and a ________ organization of the system.
This allows a _____________ response as opposed to the ________ response of parasympathetics.
Proximity permits branching and a diffuse organization of the systems.
This allows a generalized response as opposed to the specific response of parasympathetics
What is the transmitter at sympathetic ganglion?
Neuroeffector junction>
Ach at the ganglion and NE at the neuroeffector junction most of the time but for sweat glands- Ach
Pharmacological effects can have direct actions and indirect actions via change in reflex. Using an alpha1 sympathetic blocker, describe the direct and indirect effects.
a1 blocker would DIRECTLY cause vasodilation–> reduced PVR–> reduced BP
INDIRECTLY- the lower BP would trigger the vagal reflex to increase sympathetic tone (HR, contractility) .
What is the only source for naturally produced epinephrine?
Adrenal medulla
Describe the pre and post-ganglionic neurons of the somatic nervous system.
The somatic nervous system acts on muscles DIRECTLY via long myelinated cranial and spinal nerves.
There are no pre or post ganglionic neurons because there are no ganglions outside the CNS
What neurotransmitter is at the neuromuscular junction of somatic neurons?
Ach
The vagal reflex is (parasympathetic/sympathetic) and is a ________ and __________ receptor to provide information about what three things?
Vagus is parasympathetic and is a mechano and chemoreceptor.
It gives info on BP, CO2 and gut distension
What is an example of sympathetic reflex?
The dorsal horn provides info about temperature, tissue injury, pain
Acetylcholine is synthesized from ______ and ______ by _____________.
choline and acetyl CoA by choline acetyltransferase (CAT)
Where is acetylcholine synthesized?
In the cytoplasm of the presynaptic terminal and then is stored in vesicles
What initiates the release of Ach from storage vesicles?
Depolarization of the nerve terminal which causes an influx of calcium through voltage-gated channels.
After Ach is released into the synaptic terminal, how is it removed?
acetylcholinesterase enzyme at the cholinergic synapses
What cholinesterase degrades Ach in the plasma and liver?
Plasma- butyrocholinesterase
Liver- pseudocholinesterase
How long does it take to hydrolyze Ach at the neuromuscular junction?
less than a millisecond
What toxin blocks the exocytosis of Ach? What does this cause?
Botulinum toxin blocks Ach exocytosis causing flaccid paralysis?
What does botulinum toxin A do?
It blocks the release of Ach from the presynaptic terminal causing flaccid paralysis
What does alpha-latrotoxin do?
Where does it come from?
Causes massive release of Ach vesicles from the presynaptic terminal.
It comes from a black widow spider
What would you expect from a specific inhibitor of pseudocholinesterase?
- No effect on neuroeffector junctions because plasma Ach has no effect
- Longer half life for exogenously given choline esters (succinyl choline muscle relaxer)
What drug blocks the nicotinic effects of Ach?
Curare
What drug blocks the muscarinic effects of Ach?
Atropine
What does curare do?
blocks the effects of nicotinic receptors
What does atropine do?
blocks muscarinic receptors
Where are nicotinic receptors found?
- skeletal muscles
- neurons (autonomic ganglia)
- chromaffin cells in adrenal medulla
What type of receptor is a nicotinic receptor?
Ligand-gated ion channel with 5 subunits (2 of which are alpha)
What is required to open a nicotinic receptor?
What happens when the channel opens?
The binding of 2 Ach molecules will open the channel causing increased permeability of Na and Ca depolarizing and exciting the muscle (contraction), neuron (firing) or chromaffin cell (secretion of NE)
What determines the isoform of the nicotinic receptor?
What are two important isoforms to be aware of?
The subunits determine the isoforms
Ng is a ganglionic nicotinic receptor
Nm is a muscular nicotinic receptor
What type of receptor is a muscarinic cholinergic receptor?
What are the different types of M receptor?
G-protein coupled receptors
M1,3,5 are Gq so they increase Ca
M2,4 are Gi/o so they decrease Ca and increase K
What type of G protein do M135 act through?
M24?
135- Gq activating PLC, IP3 DAG and increasing Ca
24- Gi/o activate K channels and inactivate Ca
What type of muscarinic receptor is present on the heart? What would be the effect of activation?
M2 would increase K hyperpolarizing the heart. This would decrease HR and contractility
Where can muscarinic receptors be found?
- Heart (M2)
- Smooth muscle
- Autonomic ganglia (but nicotinic overrides)
- glands
What is the function of an M2 autoreceptor at the pre-synaptic terminal?
Ach that is released will bind to the M2 receptor which will increase K and decrease Ca effectively dampening further release of Ach
What neurotransmitter do peripheral sympathetic neurons synthesize? What does the adrenal medulla synthesize?
What compound are they synthesized from?
Peripheral sympathetic- NE
Adrenal- epi and NE
NE and epi come from tyrosine
What is the rate limiting step in adrenergic transmitter synthesis?
Tyrosine to L-DOPA catalyzed by tyrosine hydroxylase
What are the five steps of NE/epi synthesis?
- Tyrosine
- DOPA
- Dopamine
- NE
- epi
What enzyme converts DOPA to dopamine?
Where does this step occur?
DOPA decarboxylase in the cytosol
What enzyme converts dopamine to NE? Where does this step occur?
Dopamine is transported into a vesicle where dopamine B-hydroxylase converts it to NE
Where is NE converted to epinephrine? What enzyme catalyzes this?
In the adrenal medulla, PNMT converts NE to epi
phenyl ethanolamine N-methyltransferase
What are the adrenergic vesicle contents?
- NE
- DBH (enzyme for dopamine–>NE)
- chromagranins
- ATP
How is NE inactivated?
- Mostly reuptake into the presynaptic terminal by a specific transporter
- some NE can diffuse from site of action
What two enzymes are able to inactivate catecholamines?
MAO- monoamine oxidase
COMT- catechol-O-methyl transferase
Inhibition of MAO and COMT does what for the acute action of NE released by nerve stimulation?
Nothing really- the enzymes do no prolong action of NE even though they are technically able to inactivate the enzymes
Where is MAO found?
it is a mitochondrial enzyme that metabolizes catecholamines in the nerve terminal
Where is COMT found?
It is found circulating and is widely distributed. It is important for metabolizing circulating catecholamines like epi
MAO inhibitors would increase levels of what catecholamine?
What is this used to treat?
Increases dopamine which can help treat parkinson’s migrane prophylaxis and decrease anxiety
What metabolite is formed by the actions of MAO and COMT?
Why is this important?
VMA (vanillylmandelic acid). It is important because it can be measured in urine to diagnose pheochromocytoma.
What is pheochromocytoma?
Adrenal gland tumor that has excessive secretion of catecholamines like NE and epi
Why are MAOI and COMT different in size of effect from an Achesterase inhibitor?
Achesterase inhibitors prolong Ach in the synaptic cleft because that is the main way Ach is removed.
MAO and COMT have minimal response because MOST NE leaves the cleft via reuptake.
A NE reuptake inhibitor would have a larger effect than MAOI or COMTI
All adrenergic receptors are what type? What four are we concerned with?
They are all GPCR a1 is Gq (increases Ca) a2 is Gi/o (increases K, decreases Ca) b1 is Gs (increases AC/cAMP) b2 is Gs (increases AC/cAMP)
Where are a1 receptors located?
When activated, what do they cause?
Vasculature- contract
Glands- secrete
Liver- glycogenolysis
Smooth muscle- contract
Where are a2 receptors located?
What do they cause when activated?
Neuronal synapses (presynaptic)- inhibition (feedback from NE) Pancreatic islets- inhibition of secretion
Where are b1 receptors found?
What do they cause when activated?
Heart- ionotropic/chronotropic increase
Where are b2 receptors found?
What do they cause when activated?
Smooth muscle- relax
Liver- glycogenolysis
Skeletal muscle- relax
Where are b3 receptors found?
What do they cause when activated?
Adipose- lipolysis
Epinephrine is an agonist at which receptors?
a1,a2,b1,b2
Norepinephrine is an agonist at which receptors?
a1,a2,b1
it is a poor b2 agonist!
What drug inhibits tyrosine hydroxylase? What is the result?
Metyrosine- no DOPA is made which is the rate-limiting step in NE synthesis
Usually used to treat hypertension (decreasing a1,b1)
What does reserpine do?
Inhibits VMAT (which is how dopamine gets in the vesicle to make NE)
What does guanethidine bretylium do?
inhibits NE vesicle release
What is the action of cocaine and tricyclic antidepressents?
They block the reuptake of NE affecting the duration of the signal.
- prolonged excitation
- Desensitization
What is the function of tyramine and amphetamine?
They increase vesicular release of NE
What are the tell-tale signs of fight or flight?
Sympathetic response characterized by:
- dilated pupils
- increased HR/contractility
- decreased bowel movement
- dilated bronchioles
You want to dilate a patients pupils for exam. What type of drug should you use?
A1 agonist, but more commonly a muscarinic antagonist
What would be the ideal drug for relieving bronchoconstriction?
B2 specific agonist (don’t want B1 to be involved bc it will increase HR and contractility)
What is a major side effect of using an a1 blocker to treat hypertension/ high PVR?
The vessels will dilate, decrease BP, then reflex will increase HR to compensate –> tachycardia
What adrenergic receptor is on the ciliary muscle of the eye?
What does this do when stimulated?
It is b2 which when stimulated relaxes to allow to see far away
What are the two muscles that control the iris?
Which is adrenergic and which is cholinergic?
What are the results?
Radial muscle- a1- contractions (mydriasis-dilation of pupil)
Sphincter muscle- M2,M3- contraction (miosis-constriction of the pupil)
What are the adrenergic receptors on the heart?
What are the cholinergic receptors on the heart?
Adrenergic - B1»B2 (contract, increase HR increase conduction)
Cholinergic- M2»M3 (decrease HR, Contractility, conduction)
What areas of vasculature have a1 AND b2 receptors?
What is the overall result?
Coronary Skeletal Pulmonary Abdominal Renal Veins
Constriction slightly more than dilation
What artery has cholinergic receptors?
What is the result?
Salivary glands have M3-> dilation
What adrenergic receptors are on tracheal and bronchial smooth muscle?
What is the result?
What are the cholinergics? Result?
b2- relaxation
M2=M3 -> contraction
What adrenergics and cholinergics are on bronchial glands?
a1- decreased secretion
b2- increased secretion
M3,2- stimulation
What adrenergics control motility, sphincters and secretion of the stomach. What are the results?
Motility- all four–> decrease
Sphincters- a1–> contract
Secretion-a1–> inhibit
What adrenergics control renal secretion?
What is the result?
a1- decrease
b1- increase
What adrenergic act on the bladder?
B2- relax detruser
a1- contract sphincter
What adrenergic contracts a pregnant uterus?
What relaxes it?
a1- contracts
B2 relaxes