PNS General + Cholinergic Flashcards
Characteristics of the Autonomic Nervous
System
Largely involuntary
Innervates everything except skeletal muscle
Controls visceral functions necessary for life: Cardiac output Blood flow to organs Metabolism Gastrointestinal motility Urogenital functions Body temperature Sweating Endocrine gland secretions
Parasympathetic
Preganglionic neurons arise in CNS, send axons out through the spinal cord from the cranial and sacral spinal nerves
Axons synapse in peripheral ganglia; most ganglia are close to or within the walls of the innervated organs but some ganglia are located outside the organs innervated
Postganglionic neurons arise within ganglia, send axons out to synapse at
end organs
Discrete output
LONG Pre-ganglionic
SHORT post-ganglionic
Sympathetic
Preganglionic neurons arise in CNS, send axons out through the spinal cord from the thoracic and lumbar spinal nerves
Axons synapse in 3 prevertebral ganglia (celiac, superior mesenteric, and
inferior mesenteric) or in 22 pairs of paravertebral ganglia located along the
spinal cord
Postganglionic neurons arise within ganglia, send axons out to synapse at
end organs
Distributed output
SHORT Pre-ganglionic
LONG post-ganglionic
Organs w/dual innervation
Eye Heart Bronchial tree Gastrointestinal tract Salivary glands Urinary bladder Sex organs
Organs with ONLY sympathetic innervation
Blood vessels
Spleen
Piloerector muscles
Sweat glands
Flight or fight response
Sympathetic Response:
- dilate pupil (mydriasis)
- decrease saliva
- increase HR
- dilates bronchi
- inhibits peristalsis and secretion
- increase glycogenolysis in liver (we need glucose)
- secrete epi and NE
- inhibit bladder contraction
- vasodilation to skeletal muscles
- vasoconstriction elsewhere
Rest and Digest Response
Parasympathetic Response:
- Pupil constriction (miosis)
- Slow HR
- Increase saliva
- Increase peristalsis and secretion
- Release of bile
- Contracts bladder
Cholinergic NT System
Cholinergic: neurons that release ACh:
- All motor neurons to skeletal muscle (somatic nerves)
- All preganglionic ANS neurons; first synapse in ANS is always
cholinergic - All postganglionic parasympathetic neurons
- Some postganglionic sympathetic neurons
Most sweat glands
Some blood vessels in skeletal muscle
Adrenergic NT System
Adrenergic: neurons that release catecholamines: NE, Epi, DA
- Most postganglionic sympathetic neurons release NE
- Adrenal medulla (a modified sympathetic ganglion) releases E and
NE - Some postganglionic neurons release DA
-especially in venous system
-renal SMC (dilation to increase RBF)
2 Ways to get a cholinergic post-ganglionic sympathetic neuron (remember most post sympa are noradrenergic)
- Target-dependent noradrenergic/cholinergic switch
- Target-independent cholinergic differentiation
- started that way
*Slide 21
Describe the 1st synapse in all of the autonomic NS
All preganglionic ANS neurons; first synapse in ANS is always
cholinergic!!!
The postganglionic receptor is always a Nicotinic ACh receptor
Biosynthesis of ACh
Slide 23
*In the pre-ganglionic neuron
Choline + acetyl co-A =ACh
enzyme: ChAT: choline-acetyl transferase
*ACh transported into vesicle via VAT (driven by H+ grandient)
(slide 24)
Metabolism of ACh
Slide 23
ACh –> acetate + choline
- Occurs in the synapse
- Enzyme: AChE: Acetylcholine esterase
- choline taken back up via Na+ dependent transporter (Slide 24)
Catecholamine biosynthesis
Slide 25
Tyrosine + TH (Tyrosine Hydroxlase) –> DOPA
DOPA + AAAD (Aromatic amino decarboxylase) –> dopamine
Dopamine + DBH (Dopamine B Hydroxylase) –> NE
NE + PNMT (phenylethanolamine N-methyl transferase) –> Epi
Enzymes used in catecholamine metabolism
Phase I: MAO, ALDH
Phase II: COMT
Vanillylmandelic Acid (VMA)
Product of NE/Epi metabolism
Urine Marker for NE/EPi
Used to dx pheochromocytoma (a lot of VMA)
Adrenergic Synapse
Slide 28
- VMAT: vesicle monamine transporter
◦ transports DA into vesicle
◦ There are 2 VMATs
‣ VMAT2 most common - In contrast to ACh, NE is re-taken back
into the cell via NET
◦ There’s also a SERT and DET (for serotonin and DA)
◦ Important targets for certain drugs
like anti-depressants, psychoactives
◦ Cocaine blocks NET, SERT, DET
Receptors of the PNS (peripheral)
2 cholinergic receptors
3 adrenergic receptors
Receptors of the PNS:
Two types of cholinergic receptors
- Muscarinic receptors
G protein-coupled
Respond to the plant alkaloid muscarine
Five subtypes (M1-M5)
**In PNS M1-M3 are the most important, with M2 and M3 doing 90%
- Nicotinic receptors
Ligand-gated ion channels
• Basically Na+/K+ pentameric channels
Respond to the plant alkaloid nicotine
Two subtypes
• Nm-skeletal muscle
• Nn-neuronal (on post-ganglionic)
Receptors of the PNS:
Three types of adrenergic receptors respond to catecholamines
* all G protein-coupled*
- Two types of receptors respond to NE and E
alpha receptors, two subtypes (a1, a2); each subtype has three subtypes (a1A, a1B,
a1D and a2A, a2B, a2C)
B receptor, three subtypes (B1-B3)
- One type of receptor responds to DA
Five subtypes (D1-D5)
PNS cholinergic receptor: M2
Tissue: Heart and Axon terminals (autoreceptors)
Response: ↓ Heart rate, conduction velocity,
contractility
Mechanism: ↓ AC → ↓ cAMP; ↑ K+ channel
efflux, ↓ Ca++ channel influx
PNS cholinergic receptor: M1
Tissue: Autonomic ganglia
Response: Depolarizes postsynaptic
neurons (slow EPSP)
Mechanism: ↑ PLC → ↑ IP3, DAG, Ca++
(Gq)
PNS cholinergic receptor: M3
1. Tissue: Smooth muscle (eye,bronchioles, GI tract, urogenital system) Response: Contraction Mechanism: ↑ PLC → ↑ IP3, DAG, Ca++ (Gq)
- Tissue: Secretory glands
Response: ↑ Secretion
Mechanism: ↑ PLC → ↑ IP3, DAG, Ca++
(Gq)
3. Tissue: Vascular endothelium Response: Dilates blood vessels -this is from local ACh b/c remember that PNS doesn't innervate vasculature Mechanism: Ca++/CaM activates eNOS → ↑ NO → ↑ cGMP → relaxation
PNS cholinergic receptor: Nm
Tissue: Neuromuscular junction
Response: Skeletal muscle contraction
Mechanism: Opens Na+/K+ channels →
depolarization
PNS cholinergic receptor: Nn
- Tissue: Autonomic ganglia
Response: Depolarizes postsynaptic neurons - Tissue: Adrenal medulla
Response: Depolarizes medullary cells →
secretion of catecholamines
For both: Mechanism: Opens Na+/K+ channels →depolarization
PNS adrenergic receptor: a1
Mechanism: ↑ PLC → ↑ IP3, DAG, Ca++
- Tissue: Smooth muscle (eye, vascular,
urogenital, hair follicles)
Response: Contracts smooth muscle (Increase BP, or keep it up enough to perfuse) - Tissue: Liver
Response: ↑ Glycogenolysis, gluconeogenesis
PNS adrenergic receptor: a2
Mechanism:
↓ AC → ↓ cAMP; ↑ K+ channel efflux (via Gβγ); ↓ L- and N type
Ca++ channel influx; ↑
PLC → ↑ IP3, DAG, Ca++
- Tissue: Axon terminals (autoreceptors)
Response: ↓ NE release - Tissue: Pancreatic b cells
Response: ↓ Insulin release - Tissue: Vascular smooth muscle
Response: Contracts smooth muscle (Increase BP, or keep it up enough to perfuse) - Tissue: Platelets
Response: Aggregation
PNS adrenergic receptor: B1
Mechanism:
↑ AC → ↑ cAMP → ↑ PKA →↑ L-type Ca++ channel influx
- Tissue: Heart
Response: ↑ Heart rate, conduction velocity, contractility - Tissue: Kidney (juxtaglomerular cells)
Response: ↑ Renin release
PNS adrenergic receptor: B2
Mechanism:
↑ AC → ↑ cAMP;
in smooth muscle, inhibits MLCK → ↓ myosin-PO4 → relaxation
- Tissue: Smooth muscle (eye, bronchioles,
GI, urogenital, vascular)
Response: Relaxes smooth muscle - Tissue: Heart
Response: ↑ Heart rate, contractility - Tissue: Liver and skeletal muscle
Response: ↑Glycogenolysis, gluconeogenesis (liver) - Tissue: Pancreatic b cells
Response: ↑ Insulin release
PNS adrenergic receptor: B3
Tissue: Lipocytes
Response: activates lipolysis
PNS adrenergic receptor: D1
Tissue: Vascular smooth muscle, especially
renal vasculature
Response: Dilates blood vessels, increasing RBF thus increasing GFR
Mechanism:
↑ AC → ↑ cAMP
PNS adrenergic receptor: D2
Tissue: Axon terminals (autoreceptors) and
Cholinergic neurons in the gut
Response:
↓ DA release
↓ GI motility
Mechanism:
↑ AC → ↑ cAMP;
↑ K+ efflux; ↓Ca++ influx
Eye Pupil Diameter
Slide 33
1. Iris circular muscle M3 activation → muscle contraction → miosis β2 activation → muscle relaxation → mydriasis (slight effect) -eases the way for a1
- Iris radial muscle
α1 activation → muscle contraction →mydriasis
Eye Lens Shape (Slide 34)
- Ciliary smooth muscle:
M3 activation → muscle
contraction → relaxes
ligament → accommodation for
near vision (rest and read)
β2 activation → muscle
relaxation → stretches
ligament (slight effect)
-flat lens for distance sight
Eye secretion
- Lacrimal glands
M3 (ACh) activation → lacrimation
Lung (Slide 35)
- Bronchial Smooth Muscle
- Bronchial Glands
1. Bronchial smooth muscle M3 activation → muscle contraction → bronchoconstriction β2 activation → muscle relaxation → bronchodilation
2. Bronchial glands M3 activation → mucous secretion β2 activation → watery secretion via CFTR activation
CV: Heart
Vagal Tone: M2 activation → bradycardia (SA node), ↓ AV node conductivity, ↓ atrial contractility *only in atria *overall relaxing effect
β1 and β2 activation → tachycardia (SA node), ↑ AV node automaticity and conductivity, ↑ His-Purkinje automaticity and
conductivity, ↑ ventricular automaticity and contractility
CV: Vascular System
M3 activation (endothelial cells) → relaxation → ↓ blood pressure
α1 and α2 activation (smooth muscle cells) → constriction → ↑
blood pressure
β2 activation (liver and skeletal muscle) → relaxation → ↓ TPR →
↑ blood flow to these tissues
D1 activation → dilation of renal arteries and arterioles → ↑ renal
blood flow
Muscarinic NT on the heart (See slide 38 now)
Overall ACh relaxes the heart
- Decreased cAMP results in less current through If (I funny)
- decreases rate of depolarization
- leads to slowed HR
• ACh binds to M2R and then Beta gamma subunits act upon Ik to activate it and more K+ leaves the cell and causes hyperpolarization–>relaxing effect
Decreased PKA–>decreased
Phosphorylation of L-Ca2+ channels–> decreased contractility–>conduction–>Heart rate
Beta activation of the heart (See Slide 39 now)
Excitatory:
Gprotein
Increases cAMP activates PK
PK phosphorylates L-type Ca2+ channel
Increases HR, conduction velocity, force of contraction
Explain the innervation of the vascular system
- Innervated by the SYMPATHETIC NS
- Not innervated by parasymp.
- Although no neurons, ACh still has influence
- Because there is ChAT activity on vasculature allowing for local production of ACh
- May perhaps be stretch activated
Describe the control of the vascular smooth muscle cells at rest and during flight.
(slide 43)
- Rest: only NE
- alpha-1 Receptors for NE control
- vasoconstriction of vascular SMCs
- this is balanced with vasodilation from ACh MR action on endothelial cells - Flight: Epi
-B2 receptors in liver and skeletal muscle cause relaxation
-↓ TPR →
↑ blood flow to these tissues
Intestine
- M3 activation → contraction of circular and longitudinal muscles in intestinal walls →
↑ motility - α1 and β2 activation → muscle relaxation→ ↓ motility
In GI smooth muscle, hyperpolarization and relaxation is caused by
activation of calcium-dependent K+ efflux channels
Gastrointestinal Sphincters
M3 activation → relaxation
α1 activation → contraction
GI secretions
- M3 activation → ↑ acid secretion from parietal cells, ↑ secretions from gastric and intestinal glands, gall bladder contraction
β2 activation → ↓ gastric acid secretion, relaxes gall bladder, ↑amylase secretion (want more free glucose)
Where are these receptors located in the GI tract?
- M3
- a1, B2
(Slide 45)
- • M3 (ACh) receptors of the PNS are in the glands
of the mucosa and submucosa, and in the circular
and longitudinal muscle
◦ promotes peristalsis - SNS receptors (adrenergic)
are in the circular and
longitudinal muscle
Kidney and bladder
Slide 47
D1 activation → vasodilation → ↑ blood flow, GFR
β1 activation → stimulates renin release from kidney
M3 activation → contraction of bladder detrusor, relaxation of trigone and sphincter → promotes urination
β2 activation → relaxes detrusor → urinary retention
α1 activation → constricts trigone and sphincter → urinary retention
Penis
**Rare example of SNS and PSNS working together to stimulate!
M3 activation → relaxation of vessels → erection
α1 activation → contraction of seminal vesicles, prostatic capsule, vas deferens → ejaculation
Uterus
- Nonpregnant: β2 activation → relaxes uterus
- Pregnant
***Rare example of SNS and PSNS working together to stimulate!
M3 activation → contracts uterus
α1 activation → contracts uterus
β2 activation → relaxes uterus
Secretion
- M3 activation → stimulates watery secretions from salivary, nasopharyngeal, pulmonary, gastrointestinal, and eccrine sweat glands
- α1 activation → stimulates secretion from apocrine sweat glands found in axillary and pubic regions; produces viscous salivary
secretions
Metabolism
α2 activation → ↓ insulin release from pancreatic b cells
β2 activation → promotes glycogenolysis and gluconeogenesis in
liver, glycogenolysis and K+ uptake in skeletal muscle, ↑ insulin release from pancreatic β cells
-Want glucose available and insulin so skeletal muscles can take glu in
β3 activation → stimulates lipolysis in adipocytes
Predominant tone of the body?
Mainly run on ACh except vasculature. Overall body is under the control of the PSNS
Predominant tone of:
Arterioles and Veins
Sympathetic (adrenergic)
Predominant tone of:
Sweat glands
Sympathetic (cholinergic)
Predominant tone of:
Heart
Parasympathetic (cholinergic
Predominant tone of:
Iris
Parasympathetic (cholinergic
Predominant tone of:
Ciliary Muscle
Parasympathetic (cholinergic
Predominant tone of:
GI Tract
Parasympathetic (cholinergic
Predominant tone of:
Urinary Bladder
Parasympathetic (cholinergic
Predominant tone of:
Salivary glands
Parasympathetic (cholinergic
Summary of SNS
Prepares for strenuous activity, mobilizes energy stores (fight or flight)
Widespread output
↑ Pupil diameter, ↑ respiration, ↑ heart rate, ↑ blood pressure, ↓
GI motility and secretions, ↓ urination, ↑ sweating
Summary of PSNS
Accumulation and conservation of energy (rest and digest)
Discrete output
Maintenance functions during periods of minimal activity
↓ Pupil diameter, accommodation for near vision, ↑ lacrimation, ↓
respiration, ↓ heart rate, ↓ blood pressure, ↑ GI motility and secretions, ↑ urination
Cholinergic Drug classes
Cholinomimetic drugs: drugs that mimic ACh activity
Cholinolytic drugs: drugs that inhibit ACh activity
Cholinomimetic drugs: drugs that mimic ACh activity
Muscarinic agonists: M receptor agonists
Nicotinic agonists: N receptor agonists
Drugs that slow the inactivation of ACh by blocking AChE
Cholinolytic drugs: drugs that inhibit ACh activity
Muscarinic antagonists: M receptor antagonists
Nicotinic antagonists: N receptor antagonists
Drugs that speed the inactivation of ACh by activating AChE
Common precautions for Cholinergic agonists . Why would cholinimimetics make things worse for these patients?
M3 agonism would exacerbate these conditions!
Acute cardiac failure; bradycardia -ACh slows HR Asthma -ACh causes vasoconstriction Hyperthyroidism -they increased sensitivity to catecholamines Peptic ulcer -ACh causes increased secretions Urinary tract obstruction Parkinsonism
Parkinsonism
-dysjunction between DA and ACh control in the basal ganglia
◦ decreased DA function
◦giving a cholinimimetic is like ACh running unrestrained and w/muscarinic receptor activation you can increase this
Sjogren’s Syndrome
Chronic dry mouth due to autoantibodies against salivary glands
Open vs Closed angle Glaucoma
- Open: Too much aqueous humor being produced
- Closed: Angle is small but production may be normal
Either condition , miosis (thus opening of the angle)
is beneficial
Three Classes of AChE Inhibitors
1. SImple Alcohols Quaternary amine -they're simple competitive inhibitors that drift in and out over time -Drug: edrophonium
- carbamic Acid Esters
- covalently bonds but the bond is hydrolyzed water over time
- Drugs: Neostigmine, Physostigmine - Organophosphates
- Covalently bonds and modifies AChE
Organophosphates (Slide 87)
“Irreversible” cholinesterase inhibitors covalently bind to AChE
R groups may be alkyl, alkoxy, aryloxy, amido, and others
X is the leaving group and can be halogen, cyano, thiocyanate, phenoxy, thiocholine, carboxylate, and others
Uses: glaucoma, insecticides, nerve gases
Mechanism/Effects of organophosphate
• permanent phosphorylation of the serine in AChE-only one drug can reverse this (pralidoxime)
• If not done within 24 hours (sooner the better) aging
will occur
◦ the R groups will form a covalent bond to other
parts of the enzyme’s active site and will no
longer be able to come back
◦ will need to make more enzyme (AChR) instead
◦ aging=irreversible inhibition
Name two drugs that are antidotes for organophosphate poisoning:
- Atropine-muscarinic antagonist
2. pralidoxime-reversal of the poison binding to the AChE
Ganglionic Antagonists
- 1st synapse thought the PNS (peripheral) is always a Nicotinic cholinergic synapse (nAChR)
- Ganglionic Antagonists block these 1st synapses
- They DO NOT block NMJ: cannot affect somatic movement
- Thus they can block all PSNS and SNS effects since they block the 1st synapse in PNS
Effect of ganglionic blockade: General (Slide 104)
- Anything controlled by SNS will act like what it is under PSNS
- Vice versa for things under control of PSNS
Effect of ganglionic blockade:
- arterioles
- veins
- Sweat Glands
***normally SNS
- Vasodilation, ↑ peripheral blood flow, hypotension
- Vasodilation, peripheral pooling of blood, ↓ venous return, ↓ cardiac output
- anhidrosis—need SNS stimulation to sweat
Effect of ganglionic blockade:
- Heart
- Iris
- Ciliary Muscle
- GI Tract
- Urinary Bladder
- Salivary Glands
***normally PSNS
- Tachycardia
- mydriasis
- cycloplegia b/c normally ACh from PSNS causes the ciliary muscle to contract allowing tendons to relax and lens to bulge; now they’re just tonically relaxed by SNS
- ↓ tone and motility, constipation, ↓ gastric secretions
- xerostomia
Effect of ganglionic blockade on HTN and HR
-Demonstrated w/a vasoconstrictor (slide 106)
- in HTN, normally baroreceptors will inhibit the SNS = HTN + brady
* vagal tone - However w/ganglionic blockade, you get HTN + unchanged HR or tachy: -because baroreceptors can no longer inhibit the SNS b/c they can’t communicate (no baroreceptor reflex)
