Peripheral nerve transmission L4 Flashcards
what neurotrasmitter do most postganglionic nerves release?
NA.
is adr a neurotransmitter?
not really - more of a horemone
Adr is made in the adrenal gland and acts as a circulating hormone rather than as a neurotransmitter in the periphery and it is effectively the N-methylated version of NA.
where is Adr preduced?
This methylation takes place in the chromaffin cells of adrenal medulla in presence of the enzyme PNMT (phenylethanolamine N-methyltransferase).
what is isoprenaline?
synthetic derivertive of NA
often used experimentally
Noradrenaline (NA)
released from ________ nerve terminals (except sweat gland), also in some tracts of the CNS
Noradrenaline (NA)
released from sympathetic nerve terminals (except sweat gland), also in some tracts of the CNS
Adrenaline (Adr)
the main hormone secreted by ______ medullae
Adrenaline (Adr)
the main hormone secreted by adrenal medullae
Dopamine (DA)
precursor of ___&_____; also
a transmitter/neuromodulator in the central nervous system
Dopamine (DA)
precursor of NA & Adr; also
a transmitter/neuromodulator in the central nervous system
catecholamine biosynthesis
The starting material for catecholamine biosynthesis is….
The starting material for catecholamine biosynthesis is L-tyrosine
what is the rate limiting step in the catecholamine biosynthesis.
L-tyrosine which is present in body fluid and taken up from the circulation by catecholaminergic nerves and converted into DOPA (dihydroxyphenylalanine) by tyrosine hydroxylase (TOH).
1st step
which intermediate in the syntehsis of catecholamines is laoded into vesicels?
Dopamine - loaded using vesicular monoamine transporter (VMAT) - the process is driven by the transvesicular proton gradient.
Within these vesicles, DA is hydroxylated at its b carbon to form NA and this is catalyzed by dopamine β-hydroxylase (DBH). DBH is exclusively present ………
What is DBH an idicator of?
Within these vesicles, DA is hydroxylated at its b carbon to form NA and this is catalyzed by dopamine β-hydroxylase (DBH). DBH is exclusively present within the noradrenergic nerves and a small amount of DBH is also co-released with NA release. Unlike NA, the released DBH is not rapidly degraded or susceptible to any uptake mechanism, so its concentration in plasma and body fluids can be used as an index of overall sympathetic nerve activity.
Therefore____ is used to boost DA synthesis in the Parkinsonian brain
Therefore L-DOPA is used to boost DA synthesis in the Parkinsonian brain
as well as L-DOPA - what is often given along side to parkinson patients to ease symptoms
alot of the L_DOPA is taken up by the periphery - leading to side effecst.
carbidopa is given as well - cannot cross BBB so doesnt inhibit substantia nigra cells
but modulates peripheral sideeffects
whta is disulfiram used to treat
alcohol dependance becasue its also good at inhibiting aldehyde dehydrogenase (not to do with catecholamine syntehsis
which enzymes in catecholamine syntehsis are selective?
TOH is selective.
DDC and DBH are not particularly slecetive
how is α-Methyldopa used?
α-Methyldopa is taken into noradrenergic nerve terminals and converted successively into α-methyldopamine (α-methyl DA), and α-methylnoradrenaline (α-methyl NA), respectively. α-methyl NA is stored within the synaptic vesicles and released with (or in place of) NA as a false transmitter
it is preferentially functional
α-methyl NA adrenoreceptor binding characteristics?
less active at α1 adrenoceptors and more selective towards α2 adrenoceptors like another drug clonidine
Both α-methylnoradrenaline and clonidine cause a fall in blood pressure……. why?
Both α-methylnoradrenaline and clonidine cause a fall in blood pressure, partly by inhibition of NA release (through stimulating presynaptic α2 adrenoreceptors, see later) and partly by a central action.
- NA is stored with ATP in ____–core vesicles
- NA, ATP & usually NPY are present in _____-core vesicles
- NA is stored with ATP in clear-core vesicles neuropeptide Y .
- NA, ATP & usually NPY are present in dense-core vesicles
how is NA loaded into vescileds?
NA is stored with ATP.
NA (and DA) accumulates into these vesicle by the vesicular monoamine transporter (VMAT2, a member of the SLC protein superfamily) which uses the trans-vesicular H+ gradient as its energy source (two H+ are extruded for each amine molecule taken into the vesicle), The H+ gradient is set up by an ATP-dependent proton pump (a v-ATPase).
where is VMAT1 found?
non neural tissues - chromaffin cells and few others in the GI trcat
what does reserpine do?
- binds irreversibly to VMAT2, blocking NA uptake into new vesicles
- leads to long lasting NA depletion
- new vesciles synthesis required
where does reserpine act?
periphery and brain
was reserpine used as an antihypertensive in the past?
yep
why is reserpine no longer used as an antihypertensive?
because it may cause sever depression
whicih VMAT2 inhibitors are approved now?
tetrabenazine and valbenazine
to manage abnormal involuntary movements associated with Huntington’s disease, tardive dyskinesia etc. Both these agents are pro-drugs which upon in vivo metabolism, produce the active metabolite a-dihydrotetrabenazine (DTBZ)
difference between valbenazine + tetrabenazine and reserpine?
reserpine = irreversible inhibition
valbenazine and tetrabenazine = reversible inhibiton
give 4 ways we can modulate the amount of catecholamine release?
- direct blockade of noradrenergic neurons
- triggering NA release without stimulating the nerve terminal (indirectly acting & mixed acting sympathomimetics)
- activating pre-synaptic GPCRs
- altering the amount available for relea
catecholamines are released from presynaptic nerves through…..
catecholamines are released from presynaptic nerves through Ca2+-dependent exocytosis following depolarisation.
name a compound which Direct blockade of adrenergic neurons
Guanethidine
how does guanethidine work?
at low doses and high doses
- selective uptake into noradrenergic neurones by NET
- selective actions on noradrenergic neurones
- @low doses: blocks impulse conduction in these nerves, like the local anesthetics
- @high dose: irreversibly damages noradrenergic neurons - like a neurotoxin
what did Guanethidine used to be used to treat?
previously used for hypertension, obsolete now
give some examples of indirectly-acting sympathomimetics
Indirectly acting sympathomimetics such as tyramine (a dietary amine) and dexamfetamine are capable of releasing stored transmitter from noradrenergic nerve endings by a Ca2+-independent process.
avidly taken up into noradrenergic nerve terminals by NET, then loaded into vesicles via VMAT2, displacing NA
what is dexamfetamine used to treat?
nacolepsy and ADHD
abused recreationally
what is lisdexamfetamine
inactive prodrug for dexamphetamine
when might tyramine rich foods be dangerous?
Tyramine-riched food intake in presence of MAO inhibition can lead to severe hypertensive crisis
Ephedrine - whats it used for?
a nasal decongestant as it results in NA-mediated vasoconstriction in some blood vessels to the nose.
ephedrine can directly activate adrenorecpeotrs
Tyramine, ephedrine, amphetamine, and related drugs cause a ………….. producing a sympathomimetic effect indirectly
Tyramine, ephedrine, amphetamine, and related drugs cause a relatively rapid and brief liberation of the transmitter, producing a sympathomimetic effect indirectly
describe the cheese effect?
people taking MAO inhibitors and also ingesting large quantities of tyramine-rich food
inadequate pre-systemic metabolism of tyramine ® reaches in blood in high quantities
massive NA release
widespread vasoconstriction & potentially fatal rise in blood pressure – ‘the cheese effect’
how are noradrenergic nerves modulated by pre-synatpic receptors?
. At the noradrenergic nerves the most prominent effect is mediated by α2-adrenoceptors (coupled to Gi/o) which, when stimulated, decrease the amount of NA released.
how do alpha 2 adrenoreceptors lead to decreased NA release?
α2-AR stimulation decreases cyclic AMP production
Stimulation of the α2 -ARs, via the separated bg subunit, also results in the opening of K+ channels (GIRK)s - K+ efflux which causes hyperpolarisation of the nerve terminal membrane and reduces its excitability.
how do beta 2 adrenoreceptors mediate an increase in NA release?
Beta 2 is Gs coupled
(the cyclic AMP increases Ca2+ channel activity by a PKA-mediated phosphorylation
how are catecholamines removed from the cleft?
which is more importnat?
one into the presynaptic neuron (Uptake 1) and the other into postjunctional effector cells (Uptake 2)
Uptake 1 is of primary importance as inhibiting this process enhances and prolongs the actions of released NA whereas inhibiting Uptake 2 does not affect the response.
describe the type 1 mechanisms
≥75% of the released NA is recaptured into the pre-synaptic terminus by NET
high affinity, low capacity system
also transports Na+ and Cl- & driven by the electrochemical gradient for these ions
bidirectional
what does NEt also carry back into the presynaptic terminal (along with NA)
also carries the indirectly-acting sympathomimetic agents such as
tyramine, dexamfetamine, guanethidine, ephedrine etc
what blocks NET?
NET can be blocked by cocaine, tricyclic antidepressants (eg imipramine)
DAT = specific uptake 1 for DA (also blocked by ______)
DAT ® specific uptake 1 for DA (also blocked by cocaine)
SERT = specific uptake 1 for 5-HT (blocked by….
SERT ® specific uptake 1 for 5-HT (blocked by the SSRIs such as fluoxetine)
what modulates uptake 1 for cateccholamines?
phosphorylation by various kinases
In the periphery, Uptake _ is primarily responsible for the termination of transmitter action.
In the periphery, Uptake 1 is primarily responsible for the termination of transmitter action.
oxidopamine (6-Hydroxydopamine) (6-OHDA)
what does it do?
a synthetic neurotoxic organic compound that is experimentally used (injected into brain areas) to selectivity destroy dopaminergic (and noradrenergic) neurons in the brain.
6-OHDA induced nigrostriatal damage is one of the popular methods to induce Parkinsonism in experimental animals
upatke via NET
metabolised to compounds which damamge neurones - eg hydrogen peroxide
describe uptake 2 method for catecholamine uptake
remaining 25% of released NA = taken up by neighbouring non- neuronal cells
a lower affinity, but higher capacity system
transporter called ENT (extraneuronal amine transporter
not Na+-dependent
also transports DA, 5-HT and Histamine
ENT also transports ,…
also transports DA, 5-HT and Histamine
inhibiotsr of ENT (uptake 2 method)
normetanephrine, a metabolite of NA, corticosteroids (such as corticosterone and hydrocortisone) and the irreversible α-AR blocking agent - phenoxybenzamine (which will also block NET at much higher concentrations).
describe phenoxybenzamine
- irreversible α-adrenoceptor antagonist, also inhibits NET & EMT
- used to manage hypertension due to phaeochromocytoma
where does most catecholamine metabolism take palce?
the same cells where the amines are synthesized and stored.
due to leak from vesicular storage granules
VMAT2 effectively sequesters about ___% of the amines leaking into the cytoplasm back into storage vesicles; about ___% escapes sequestration and is metabolized.
VMAT2 effectively sequesters about 90% of the amines leaking into the cytoplasm back into storage vesicles; about 10% escapes sequestration and is metabolized.
what 2 enzymes metabolise catecholamines?
monoamine oxidase (MAO) and catechol O-methyltransferase (COMT).
does the order pf metabolism of catecholamines matter?
no - either MAO or COMT can act first
where does MAO occur
. MAO occurs in the outer membrane of mitochondria and it is abundant in noradrenergic nerve terminals but is also present in liver, intestinal epithelium and other tissues
what does MAO do in the liver?
MAO in the liver inactivates circulating monoamines such as tyramine
MAO isoforms?
what do each do?
MAO exists in two isoforms, MAO-A and MAO-B.
The two isoforms somewhat differ in their distribution, substrate specificity and pharmacology. MAO-A degrades 5-HT, NA and DA, while MAO-B degrades DA more rapidly than the other monoamines
MAO-A degrades…
MAO-A degrades 5-HT, NA and DA
MAO-B degrades …
MAO-B degrades DA more rapidly than the other monoamines.
Non-selective or selective MAO-A inhibitors are used in _____________ whilst selective MAO-B inhibitors is used in the treatment of…..
Non-selective or selective MAO-A inhibitors are used in depression and anxiety disorders whilst selective MAO-B inhibitors is used in the treatment of Parkinson’s disease.
MAO A specific inhibitors?
Clorgyline
Moclobemide
MAO B specific inhibitors
Selegiline
non specific MAO inhibitors?
Pargyline
Tranylcypromine
Isocarboxazid
describe COMT
cytosolic enzyme
not in noradrenergic neurones - but is found in liver, gut kidney ect
a membrane-bound form is present in adrenal medullary chromaffin cells
diagnostic test of patietns with tumours of adrenal chromaffin tissue?
. In patients with tumours of chromaffin tissue of the adrenal medulla (Phaeochromocytoma - a rare cause of hypertension), the urinary excretion of VMA is markedly increased, this being used as a diagnostic test for this condition.
COMT inhibitor?
Entacapone is an inhibitor of COMT which can be used in Parkinson’s disease in combination with L-DOPA and Carbidopa.
It reduces metabolism of L-DOPA in the periphery so that more L-DOPA could reach the CNS where it is needed to produce DA for the Parkinson’s patient and less side effects occur from activation of dopamine receptors present in various peripheral tissues.
which 2 drugs avoid COMT metabolism by not strictly being a catechol?
salbutamol and terbutaline
2 things wihch block NET
cocaine, tricyclic antidepressants block NET
what do Na and Adr boind?
specific adrenoceptors
are all adrenoreceptors GPCRs?
yes
5 adreno receptors?
2 alpha
3 beta
describe the potency of isoprenaline?
Isoprenaline (ISO) is a synthetic catecholamine, it barely activates a adrenoceptor subtypes but it possesses significantly higher potency at b adrenoceptor subtypes compared to Adr and NA.
order of stimualtion for alpha adreno receptors?
α-receptors: NA >= Adr >>> isoprenaline
order of stimulation for beta adrenorecepotrs?
β-receptors: isoprenaline > Adr >= NA
how does alpha 1 adrenoreceptor lead to smooth muscle activation
- a1-ARs
- PLCB activation
- IP3
- Calcium
- Ca2+ - CaM
- MLCK activation
- MLC phosphorylation
- smooth muscle contraction
how does alpha 1 adrenoreceptors lead to increased secretion
- a1-ARs
- PLCB activation
- IP3
- Ca2+
- secretion
9 effects of Alpha 1 adrenoreceptors
- Dilatation of pupils (mydriasis)
- Constriction of blood vessels supplied to vicera, brain and skin
- Salivary secretion
- Decreased gastrointestinal motility and tone (due to relaxation of smooth muscles)
- Localized (e.g. in palms of hands) secretion of sweat
- Piloerection (goose bumps)
- Contraction of trigone and sphincter muscles of urinary bladder
- Ejaculation of sperms
- Increased glycogenolysis and gluconeogenesis
describe how alpha 2 adrenoreceptors work?
- a2-ARs
- Gi/o coupled
- decrease cAMP
- (plus signalling from beta gamma subunit)
4 effecst of Alpha 2 adrenoreceptor
- Inhibition of neurotransmitter release (mentioned earlier)
- Platelet aggregation
- vasoconstriction
- Inhibition of insulin release from pancreatic b cell
how do b1-ARs work?
- Gs coupled
- cAMP increases (adenylyl cyclase activated)
- activates PKA
also directly opens L-type calcium channels (LTCC) in the plasma membrane (heart)
where is b1-ARs mainly expressed?
the heart
b1-ARs
effect in:
nodal cells
ventricles?
- in nodal cells: increased heart rate (ve chronotropic effect)
- in ventricles: increased force of myocardial contraction (+ve inotropic effect)
2 things B1 adrenoreceptors do?
- Increased force of myocardial contraction
- Increased heart rate
how does B2 adrenoreceptor wokr?
- Gs coupled
- increases cAMP
- activates PKA
This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel CaV1.2
PKA phosphrylates MLCK -> smooth muscle relaxation
4 effects of B2 adrenoreceptor
- Relaxation of tracheal and bronchial smooth muscle
- Relaxation of smooth muscle of blood vessels supplied to heart and skeletal muscle
- Relaxation of uterine smooth muscle (for non-pregnants)
- Hepatic glycogenolysis
b3-ARs how do they work?
same as B2
Gs coupled
increase cAMP, PKa activation
3 effects of B3 adrenoreceptors?
- adipocytes = breakdown of fat (lipolysis)
- thermogenesis
- relaxation of bladder detrusor muscle
describe effects on noadrenaline (NA) on b.p. and pulse
NA predominantly acts via a-ARs
- increases peripheral ressitance due to constriction
- . Both systolic and diastolic blood pressures increase to an extent high enough to trigger reflex bradycardia that decreases the pulse rate
describe Adr effects on BP and pulse
Adr has both a- and b-ARs mediated
- Adr increases the force as well as frequency of myocardial contractions = increased pulse rate
- It constricts arterioles in the skin, mucous membranes, and viscera (α1 -AR-mediated effects) but this is to some extent compensated by vasodilatation of skeletal muscle vascular bed which also reduces peripheral resistance (β2-AR-mediated effects)
- net effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure.
describe effects on isoprenaline (ISO) on b.p. and pulse
ISO only manifests b-ARs mediated effects
- produces intense stimulation of the heart, increasing heart rate, contractility, and cardiac output
- dilates arterioles of skeletal muscle - decreasing peripheral resistance
why is isoprenaline so Beta specific?
such preference or selectivity towards b-ARs stem from a bulkier (= isopropyl) substituent at the amino N atom.
fat
mamba
