Test 1: lecture 10-13 Flashcards
flight or fight is —
sympathetic
rest and digest is —
parasympathetic
sympathetic has — preganglionic nerves and — post ganglionic nerves
short
long
sympathetic= flight or fight
parasympathetic has — preganglionic nerves and — post ganglionic nerves
long
short
parasympathetic= rest and digest
— come from cranial and sacral
parasympathic
(rest and digest)
— comes from thorasic and lumbar
sympathetic = flight and fight
— is dilated pupil
mydriasis
happens with SYM
— is constrict pupils
miosis
adrenergic can also be called
SYMP
epi
adrenaline
norepinephrine
neoadrenaline
catecholamine
cholinergic responses are also called
PARA
acetylcholine (ACh)
what type of nerves release ACh
all PARA
all somatic
all preganglionic SYMP
only SYMP to sweat glands
what type of sympathetic neuron releases ACh
all preganglinic neurons
but only post ganglionic are the nerves to sweat glands
all other symp release NE after post ganglion
what kind of neurotransmitter does PARA release
ACh at pre and post
unlike symp which release ACh at pre and NE at post, exception is sweat glands where ACh released at both
epinephrine is the same as —
adrenaline
catecholamines
— is the starting chemical for catecholamines
L-tyrosine
how to get from L-tyrosine to epi
what is the rate timing step in the synthesis of epi?
tyrosine hydroxylase
enzyme that takes L-tyrosine and turns it into dopa
— acts as negative feed back inhibitor of the enzyme tyrosine hydroxylase
norepinephrine (NE)
tyrosine hydroxylase and DOPA decarboxylase are both found in the cytoplasm
dopamine gets into vesicle by VMAT(vesicular monoamine transporter)
dopamine β hydroxylase is found inside the vesicle
where does dopamine turn into NE in neuron
dopamine gets into vesicle by VMAT(vesicular monoamine transporter)
then interacts with dopamine β hydroxylase to form NE
EPI is made in — cells in the adrenal medulla
chromaffin cells
how does EPI form in adrenal gland
inside chromaffin cell
Tyrosine( tyrosine hydroxylase)→DOPA
DOPA(DOPA decarboxylase)→ Dopamine
dopamine moves through VMAT into vesicle
dopamine (dopamineβ hydroxylase) → NE
NE leaks out of vesicle
NE (PNMT) →epi
epi moves through VMAT back into vesicle
vesicle released= will be full of EPI and small amounts of NE
PNMT
Phenylethanolamine-N-methyl transferase
NE(PNMT) → EPI
happens in cytoplasm of chromaffin cells of the adrenal medulla
chromaffin cell vesicles contain
80% epi and 20% NE
(some of the NE do not move back out of vesicle and get released at the same time)
NE and EPI released by acetylcholine (ACh)-mediated —
Ca2+-dependent exocytosis
from chromaffin cells in the adrenal medulla
where is PNMT found
found in chromaffin cells of the adrenal medulla
not found in nerve terminals- nerves can’t make EPI, only get to NE stage
No active reuptake of — into adrenal gland …. unlike in — reuptake in neurons
EPI
NE
why does the adrenal gland act as a modified sympathetic ganglion
preganglionic releases ACh
but chromaffin cell releases NE and EPI directly into blood supply
no post ganglion
Stimulation of preganglionic fibers release ACh directly onto chromaffin cells which then release — directly into the blood stream
EPI/NE
what happens to NE released into post synaptic cleft
can bind to postsynaptic receptor on other nerve
can bind to ⍺2 presynaptic autoreceptor: cause negative feedback
can be pulled through plasma membrane transporters back into synapse
from there NE can either move through VMAT back into vesicles or it can be broken down by MAO (monoamine oxidase)
any left over NE in the terminal will get eaten by COMT
NE in the cytoplasm of 1st nerve can
move through VMAT back into vesicle
can be broken down by MAO (monoamine oxidase)
— is a receptor on the presynaptic membrane side that pulls NE back into cytoplasm of 1st nerve
plasma membrane transporter
two ways catecholamines are metabolized
MAO (monoamine oxidase)
* degrades cytoplasmic NE
* MAO found in outer member of mitochondria
COMT (Catechol-o-methyl transferase)
* found in synaptic cleft and liver
* will break catecholamines (EPI, NE) into metabolites that are then excreted in the urine
how does Gprotein cycle work
how to measure drug affinity
saturation binding isotherm
Kd= concentration of drug that fills 50% of the receptors
lower the Kd= higher affinity
The lower the Kd the — the ligand affinity
higher
Described by the agonists intrinsic activity (IA) which is the maximal amount of system stimulation achievable in the presence of saturating concentrations of the agonist
efficacy
Described by the EC50: the concentration of drug that results in 50% of its maximal stimulation
potency
which one is more potent?
what is the ranked order
A is more potent (takes less A to get to 50% activation)
rank order: A>B
EC50 of A= 0.01 nM
EC50 of B= 1 nM
smaller the EC50 the more potent the agonist
what is the intrinsic activity (IA) of each line and what does it mean
this is comparing potency and efficacy of different agonists
both A and B get to top= 100%= IA=1 full agonist (all the receptors are bound and working at full capacity)
C does not make it to the top, IA= 0.6= partial agonist
A and B are more efficacious than C (intrinsic activity is 1 for A+B, less then 1 for C)
A and B are also more potent then C (EC50 is smaller= more potent, takes less drug to get to 50% total)
A and B are more — than C
potent (EC50 smaller= increased binding)
efficacious (shorter= 0-1 → IA higher, agonist at max saturation has reached max stimulation)
rank order of catacholamines for ⍺ receptors
EPI ≥ NE > DA ⫸ ISO
rank order for β adrenergic receptors
what type of adrenergic receptors in the heart?
there are only β
increase HR, increased conduction velocity and decreased refractory period and increased contracility are all by β1 receptors
in skeletal muscle ⍺ receptors cause — and β receptors cause
contriction
β2: dilation
EPI has HIGHER affinity for — receptors than — receptors
β2
⍺
low dose epi will do what to vascular smooth muscle?
has lower Kd/ higher affinity for β2 receptors
will bind those first → relaxation
what happens with high dose EPI on vascular smooth muscle
1st fills β2 then will spill over to ⍺1
if there are more ⍺1 then will cause contraction
in the GI tract effect of ⍺ and β
same direction
both cause smooth muscle relaxation
in the heart effect of ⍺ and β
no ⍺
β only → increase HR, contractility and conduction velocity
in the blood vessel effect of ⍺ and β
⍺ and β opposite direction
⍺: constriction
β: dilation
in the urinary bladder (trigor and sphincter) effect of ⍺ and β
only ⍺ : contraction
no β
under basal conditions there is a continous release of NE onto vessels keeping them partillary contracted due to binding and activiation of — on the vascular smooth muscle cell
⍺1 receptors
for blood vessel:
Adding — causes vasodilation because there is already norepinephrine-mediated vasoconstrictive tone on vessels
α1 receptor antagonist
blood vessels always have small amount of NE causing slight contraction, if you decrease NE release or release ⍺1 antagonist, will cause vasodilation
GI tract is under — — tone which causes —. If you block this signal it will cause —
parasympathetic cholinergic
movement
constipation
cholinergic (receptor that responds to ACh- all PARA are under ACh control)
sweat glands are under SYM cholinergic control
all other SYM are controlled by NE/adrenergic receptors
arterioles is under — — tone which causes —. If you block this signal it will cause —
sympathetic adrenergic
vasoconstriction
vasodilation (increased flow) hypotension
heart is under — — tone which causes —. If you block this signal it will cause —
parasympathetic cholinergic
bradycardia
tachycardia
sweat glands are under — — tone which causes —. If you block this signal it will cause —
sympathetic cholinergic
hidrosis- sweating
anhidrosis- not sweating
if you give βblocker to healthy person what will happen to resting heart rate
nothing
NE binds to β1 adrenergic receptors to cause increased HR
if you block β1 receptor, HR will stay the same
heart controlled by PARA (Ach) → keeping HR down, under normal conditions very little SYM/NE tone on heart, therefore trying to block with B1 does not have a significant change
an antagonist needs an agonist present to block to change physiology
What would happen to resting heart rate if you gave a muscarinic ACh receptor blocker ?
ACh keeps heart in bradycardia
if you block ACh will cause tachycardia
heart controlled by PARA cholinergic receptors keeping it in a resting state of bradycardia
what is a adrenergic receptor
receptor that binds to NE
includes most sympathetics except sweat glands
what is a cholinergic receptor
binds to ACh
includes all parasympathetics
also includes sympathetic control of sweat glands
also includes somatic control of skeletal muscles
what is the baroreceptor(vagal reflex)
if blood pressure too high, baroreceptors in the aorta or the carotid will send signal to the brain
this will cause decrease in HR and vasodilation
rank order of EPI vs NE in β1
rank order of EPI vs NE in β2
rank order of EPI vs NE in β3
— = great nonselective β agonist (β1 and β2)
Isoproterenol
Low doses of EPI → — effects predominate
β
spill over
NE does not activate — very well
β2
EPI ⫸ NE
↑ HR + force of contraction with ’no change’ in vascular resistance → —
increased blood pressure
Vasodilation of blood vessels with ’no change’ in cardiac output will make —
decreased blood pressure
which catecholamine
NE
which catecholamine
epi
which catecholamine
ISO
which catecholamine
dopamine
if you give epi what will happen in general to a1, B1, B2, a2 receptors
low dose NE will do what to the heart
Activate β1 in heart =↑HR ↑FC ↑CO
will cause vagal reflex that causes↶ of HR and CO
FC (force of contraction remains ACh, no effect on ventricles)
low dose NE will do what to vasculature?
Activate α1 cause vasoconstriction → ↑ peripheral resistance
Low NE does not activate β2 well and is overwhelmed by α1 activation
low dose NE will do what to vagal reflex
Initially a significant increase in Mean BP ( ↑ SP and DP)
Vagal Reflex → Bradycardia (decrease heart rate)
will have same effect as high dose epi
low dose NE
low dose NE
or high dose Epi or high dose DA
they have the same effect
low dose EPI does what to heart
Activate β 1 in heart → ↑ in HR, FC, CO
low dose EPI does what to vasculature
activates β2 causes vasodilation →↓ peripheral resistance
remember at low epi effect on B receptors predominate
what happens to vagal reflex with low dose epi
No significant increase in Mean BP
No Vagal Reflex
low dose epi
low dose epi
iso
high dose epi will look the same as —
high and low dose NE
this is because at high dose EPI, ⍺1 receptors will win causing vasoconstriction
what happens to heart with high dose Epi
activates β1 in heart → increased HR, FC, CO
FC remains ACh no effect on ventricles
will have same effect as NE
what happens to vasculature with high dose epi
Activate α1 causes vasoconstriction →. increased peripheral resistance
Activate β2 to try to cause vasodilation but activation of α1 ‘wins’
will have same effect as NE
what happens to vagal reflex with high dose epi
Initially a significant increase in Mean BP ( ↑SP and DP)
Vagal Reflex → Bradycardia (decrease heart rate)
will have same effect as NE ( NE does not activate B2 well)
high dose epi or low dose NE or high dose Dopamine
iso will do what to the heart
activate β1 in heart → increased HR, FC and CO
iso will do what to vasculature?
Activate β2 causes vasodilation →decreased peripheral resistance
iso will do what to vagal reflex
Significant decrease in PR and increase in HR
No Vagal Reflex (Mean BP unchanged)
low or high dose iso
low or high dose iso
DA has highest affinity for DA receptors but also has some affinity for — and even lower
affinity for — adrenergic receptors
α1 α2 β1
β2
At LOW concs, Dopamine can activate — to some degree but does not activate — receptors at all
α1 α2 β1
β2
At — concs, DA activates α1 α2 β1 but also now activates some β2 receptors
HIGH
Effects of LOW vs HIGH Dopamine concentrations reminiscent of LOW vs HIGH —
epi
low dose dopamine effect on heart
minimal activation of β1 in heart = increased HR, FC, CO
similar to low dose epi and iso
low dose dopamine does what to vasculature
No activation of β2 receptors so no β2 -mediated vasodilation
Minimal activation of α1 receptors in vasculature- minimal vasoconstriction
Significant D1-mediated vasodilation of mesenteric (gut), renal, and coronary vascular beds decreasing peripheral resistance
low dose dopamine does what to vagal reflex
no vagal reflex
mean BP unchanged
low dose dopamine
high dose dopamine will do what to heart
Significant activation β1 in heart = increased HR, FC, CO
high dose dopamine will do what to vagal reflex
Vagal Reflex →Bradycardia (decrease heart rate)
high dose dopamine, high dose epi, NE
