What is the major NTM of the PSN?
Where is it found?
What does it activate?
found at all preganglionic autonomic fibers, all postganglionic parasympathetic fibers, and few postganglionic sympathetic fibers (sweat)
activates nicotinic and muscarinic receptors
What is the major NTM of the SNS?
Where is it found?
What is its classification?
at most postganglionic sympathetic fibers
Epinephrine is made where?
How is epinephrine released?
how is it classified?
Adrenal medulla and a few places in the brainstem
Depolarization of the preganglionic sympathetic neuron releases Ach and it binds to its receptor on the adrenal medulla which releases Epi (and NE)
What is the precursor to NE and Epi?
What does it do?
Dopamine (made in neurons)
Works on CNS and renal vascular smooth muscle
What are the cotransmitters we should know?
Describe the synthesis of Ach
choline transporter takes choline from EC space into neuron
choline acetyltransferase (ChAT) catalyzes the synthesis of Ach by combining the acetyl from Acetyl CoA with choline
Describe the release of Ach
when the AP reaches the axonal terminal of the preganglionic fiber, it depolarizes it causing increase of Ca
Increase in Ca causes vesicular membrane fusion with the cell membrane and Ach is released
SNARE complex allows the fusion between the membrane and the vesicle using VAMPs and SNAPs
Describe the binding of Ach to cholinergic receptors
- Ach diffuses across the synaptic cleft and binds to nicotinic Ach receptors of the neuronal sybtype which allows Na to enter the postganglinoic fiber or adrenal medulla
- Na entry causes depol. and AP of the postganglionic fiber or release of Epi and NE
- Can bind to muscarinic Ach receptors on organs and cause decrease HR, glandular secretion, Sm. M relaxation (PNS)
- Can activate nicotinic and muscarinic presynaptic membranes as well and modify it’s own release
Describe the termination of Ach signaling
acetylcholinesterase cleaves Ach into acetate and choline
Ach Receptor Type: M1
Location: CNS, ganglia
Structure: GPCR, Gq/11
Mechanism: Activation of phospholopase C, IP3, DAG
Ach Receptor Type: M2
Location: Heart, nerves, Sm. M
Structure: GPCR, Gi/o
Mechanism: inhibtion of adenylyl cyclase, decrease cAMP, activates K channels
Ach receptor: M3
Location: Glands, SM. M, endothelium
Structure: GPCR Gq/11
Mechanism: activation of PLC, IP3, DAG
(Same as M1 but diff. location)
Ach Receptor: M4
Structure: GPCR, Gi/o
Mechanism: inhibits AC, decrease cAMP, activates K channels
(Same as M2 but in different locations)
Ach Receptor: M5
Structure: GPCR, Gq/11
Mechanism: Activates PLC, IP3, DAG
(Same as M1, same as M3 minus location)
Ach Receptor: Nm
location: skeletal NMJ
structure: ligand gated ion channel
mechanism: Na, L depolarizing ion channel
same as Nn receptor type except located in postganglionic cell body, dendrites, and CNS
Describe the synthesis of catecholamines
Tyrosine goes into the nerve terminal and becomes DOPA which becomes DOPAMINE which becomes NE and then Epi
the final step occurs only in the adrenal medulla and in a few epinephrine containing neuronal pathways in the brainstem
Describe the storage of catecholamines
vesicular monoamine transporter (VMAT2) tranports DA into the vesicle during de novo synthesis
VMAT2 is relatively promiscuous and tranports DA, NE, and Epi and serotonin across the vesicle membrane
Inhibited by Reserpine, causes depletion of catecholamines from sympathetic nerve endings
Describe the release of catecholamines
occurs upon AP and influx of Ca
triggering event in the adrenal medulla: release of Ach by the preganglionic fibers and it’s interaction with nAchRs on chromaffin cells to produce a localized depolarization
Describe the binding of catecholamines to adrenergic receptors
catecholamines diffuse across the synaptic cleft and bind to adrenergic alpha and beta receptors
this activates stimulatory and inhibitory G proteins
effector organ responses include contraction, glycogenolysis, gluconeogenesis, relaxation, and increased force and rate of heart contraction
What is the major mechanism that terminate teh actions of catecholamines?
reuptake into the nerve terminals
NET and the DAT are primarily involved
after reuptake, catecholamines are stored in vesicles by VMAT
What is the secondary mechanism of signal termination of catecholamines?
dilution out of the junctional cleft and uptake at the extraneuronal sites by the transporters ENT, OCT1, and OCT2 and subsequent metabolic tranformation
- MAO: metabolizes catecholamines that have been released and undergone reuptake, located on the outer surface of mitochondria
- COMT: metabolism of endogenous circulating and adminstered catecholamines, largely cytoplasmic
What is the end result of a1-receptor activation?
(except in gut, where it relaxes)
Activation of A2 receptors results in what?
vascular smooth muscle contraction
decreased insulin secretion
decreased release of NE (presynaptic a2 receptors)
Activation of B1 receptors results in what?
increased force and rate of heart contraction and AV nodal conduction velocity
found in myocardium
Activation of B2 receptors causes what?
vascular, bronchial, GU, and GI smooth muscle relaxation
found in Sm. M and most other places
Activation of B3 receptors do what?
result in lipolysis
found on adipose
Dopamine activates D1 receptors in renal smooth muscle which leads to what?
natriuresis and diuresis via renal vascular smooth muscle
can increase HR and vascular vasoconstriction in high concentrations on a1 and B1 receptors
Alpha 1 receptors stimulate contraction of what?
all smooth muscle
vasoconstriction is due contraction of vascular smooth muscle
mydriasis is due to contraction of irisi radial muscle
uterine contraction during pregnancy
Beta 2 receptors stimulate relaxation of what?
All smooth muscle
relax tracheal and bronchial smooth muscle
relax uterine smooth muscle
relax intestinal smooth muscle
Muscarinic receptors stimulate contraction of all what?
Smooth muscle (different than a1 receptors)
miosis due to contraction of iris sphincter muscles
contraction of bladder detrusor muscle
contraction of intestinal SM. M
stimulate decrease in HR in SA node and contractility of heart muscle
vascular smooth muscle is only innervated by the sympathetic nervous system. Vascular relaxation happens how?
Ach and mAChR activate the release of Endothelium derived relaxing factor (Nitric Oxide)
Describe the release of EDRF (NO)
in response to an AP, Parasymp. neurons release Ach which reach mAchRs and activates them
NO is produced by endothelial cells and diffuses to the Sm. M around the vessel and causes relaxation
the primary controlled variable in cardiovascular function is what?
mean arterial pressure
Describe the baroreceptor reflex with the example of NE
NE produces direct effects on vascular and cardiac muscle
a slow infusion of NE increases PVR and increases MAP
in the absence of reflex control, this rise in NE will increase heart rate and contraction force
with intact reflex control, the negative feedback response to an increase in PSN discharge occurs at the SA node
this causes a marked increase in PVR and MAP and slowing of the heart rate
This bradycardia is the opposite of the drug’s effect (which we would expect, since it’s a negative feedback loop)
What medication can be used to treat stage fright?
(Nonselective beta receptor antagonist)
what medication treats respiratory distress due to narrowing of airways (asthma, bronchitis, etc)
B2 receptor agonist
too much can cause tachycardia
Overdosing on diphenhydramine can cause fever, fixed and dilated pupils, increased heart rate and delirium as well as cutaneous vasodilation.
What division of the ANS is overactive?
Which receptors are involved in the presenting sx?
Stimulating what receptor will fix this?
Inhibition of Muscarinic AchR (basically causing unopposed activation of the SNS by inhibiting the PNS)
mAchR agonist with an acetylcholinesterase inhibitor that cross the BBB (for the delerium)
How do you treat someone when you want to increase the heart’s force of contraction (inotropy) and decrease the heart rate (chronotropy)
How does it work?
Na/K ATPase (Digoxin)
Inhibiting Na/K keeps a bunch of Na in the cell which inactivates the Na/C Exchanger which leads to increased Ca in the cell which increases force of contraction without touching the rate
After treating someone with digoxin for a while, they may want to prescribe something to decrease both force of contraction and heart rate. How?
By targeting B1 receptors since they are the most specific for heart muscle
(muscarinic agonist would cause vague systemic PNS sx)
A child having an asthma attack shows airway constriction and increased pulse and HR. What divisions of the ANS are causing these issues?
What do you use to treat?
Pulse and HR is SNS
Airway restriction is PNS
B2 agonist and mAChR antagonist to relax Sm.M
too much B2 can act on B1 receptors on the heart and cause tachycardia
Giving alpha adrenergic receptor agonist causes increased mean blood pressure and decreased heart rate. Why?
How do we block the decrease in heart rate (not just speed up the heart)
baroreceptor mechanism says “oh the pressure is too high, we should calm things down and slow the HR” and so the HR slows down.
muscarinic Ach R antagonist
The key receptors on the heart responsible for increasing hr and contractility are what?
a muscarinic antagonist released on the effector cell in the lungs (end organ) causes what?
The SNS releases what compound at the synapse between the postganglionic cell and the target organ?
Which NTM is released from the presynaptic nerve to the post synaptic nerve in the SA node in the SNS?
NE (Epi if F.F)
Ach onto a nAchR
What NTM is always released between pre- and post-synaptic nerves?
Alpha 1 receptors
Beta 1 Receptors
Beta 2 Receptors
Contracts Smooth Muscle
increases HR and contractility of heart
Relaxes Smooth Muscle and Vasodilates (often talked about in terms of the lung)