Wakade - Adrenergic Pharmacology I Flashcards
Sympathetic Reflex Pathway:
Sensory Neurons:
Where are nerve endings?
NT:
Sensory Neurons: have nerve endings in effector organs and specialized structures (carotid body, aortic arch) and convey information to neurons on the spinal cord
o NT: substance P
Where does integration of the inputs from the CNS (limbic area) and local region take place?
spinal cord
NT for the integration of inputs
NT: interneurons in the spinal cord use a variety of NTs (GABA, glycine, etc.)
Presynaptic Neurons location:
Synapse in:
Take message to effector organ via:
NT:
Presynaptic Neurons: being in intermediolateral cell column and synapse in sympathetic ganglia.
Take message back to the effector organ via postgangionic neurons
o NT: ACh (cholinergic nerves)
Post-synaptic Neurons:
begin in:
carry message:
NT:
Post-synaptic Neurons: begin in sympathetic ganglia and carry message back to effector organ
o NT: NE (adrenergic nerves)
Co-Transmitters def:
2 Examples
Co-Transmitters: peptidergic transmitters that are also released along with the above principal transmitters; function under investgation
Vasoactive Intestinal Peptide (VIP): cholinergic neurons
Neuropeptide Y (NPY): adrenergic neurons
Adrenergic Neuron:
Polarity:
NE Synthesis:
- occurs
- vesicles contain
Axoplasmic Transport:
- Fast rate
- Blocked by (2 drugs)
- Slow rate
Adrenergic Neuron:
Multipolar Cell:
o Very long axon
o Beaded appearance at terminal region of axon (nerve endings/varicocities; functional unit of neuron)
NE Synthesis:
o Occurs in all regions of the neuron
o Vesicles containing NE transported down from the cell body to terminals via fast axoplasmic transport
Axoplasmic Transport:
o Fast: 100-500 mm/day
- Can be blocked by drugs that inhibit polymerization of microtubules/microfilaments
- Colchicine
- Vinca alkaloids (vinblastine, vincristine)
o Slow: 1-25 mm/day
Adrenergic Neuron:
Nerve endings:
- Contain
Synapse size:
-Examples of narrow and wider junctions
Nerve Endings:
o Contain large number of granules/vesicles containing NE (500-2000/nerve ending)
o Synapses with the target organ
Synapse Size:
o Distance between nerve ending and effector cell varies:
Narrow Synaptic Junctions: 10-50nm; produce faster and greater responses
Examples: resistance vessels, vas deferens, SA node of heart
Wider Synaptic Junctions: 100-500nm; produce slow and sluggish responses
Examples: large blood vessels like the femoral artery, GI smooth muscle
Where is the highest conc. of NE in the neuron?
The “nerve ending”
6 Events in the Life of NE:
o Synthesis o Storage o Release o Action o Inactivation o Recycling of Synaptic Vesicles
Tyrosine to epinephrine synthesis
Tyrosine (TH) –> DOPA (DOPA Decarboxylase) –> Dopamine (DBH) –> NE (PNMT) –> EPI
What is the end product of Dopaminergic Neurons of CNS?
Dopamine is the end product
What is the end product of Sympathetic Neurons of CNS?
Sympathetic Neurons: NE is the end product
What is the end product of Chromaffin Cells of Adrenal Gland
Chromaffin Cells of Adrenal Gland: EPI is the end product (hormone, not an NT)
What is the rate-limiting enzyme for entire biosynthetic pathway of catecholamines?
Tyrosine hydroxylase
Regulation of NE Synthesis by TH Activation:
Acute activation def:
-What happens when the frequency of SS nerve impulses increase?
Chronic activation def:
Activity of SNS chronically activated –>
Examples of chronically activated SNS:
Acute Activation: phosphorylation of existing enzyme
- Frequency of SS nerve impulses increased –> increased rate of NE release –> increased rate of NE synthesis (by phosphorylation of TH)
Chronic Activation: induction/synthesis of new TH molecules
- Activity of SNS chronically activated –> synthesis of TH increased (induction)
Examples of chronically activated SNS include daily exercise, long exposure to cold, and long exposure to stress
Dopamine Beta-Hydroxylase (DBH):
Location:
Marker of:
Dopamine Beta-Hydroxylase (DBH):
Location: found in the vesicles(75% in the membrane the rest in soluble contents)
Marker of Sympathetic Nerve Activity: released along with NE, and therefore concentration in plasma can be used for this purpose
Phenylethanolamine-N-Methyl Transferase (PNMT):
Location:
Mechanism:
- Methyl donor
- Induction of activity
Location: chromaffin cells of adrenal gland
Mechanism: NE methylated to form EPI
- Methyl Donor: S-adenosyl methionine
- Induction of Activity: by corticosteroids (high [glucocorticoids] perfusing adrenal medulla via adrenal cortical sinusoids)
Storage of NE and DA:
Dependent on what?
Storage of NE and DA:
o Voltage and pH dependent
Vesicular Monoamine Transporter (VMAT): storage/vesicular pump
Requires Co-Factors:
Two Types:
Location/Transport:
Requires Co-Factors: Mg2+ and ATP
Two Types: depending on location and substrate specificity
VMAT 1: located in the periphery (mostly in endocrine cells)
o Transport 5HT, histamine and catecholamines
VMAT 2: located in CNS and neuronal cells
o Transport 5HT, histamine and catecholamines
NE in Storage Vesicles:
Coupled to:
What else is found in the vesicle?
Coupled to ATP (~4 NE:1 ATP)
DBH and acidic proteins (chromogranins): Ascorbic acid, Ca++, enkephalins
Storage of EPI:
In adrenal medulla chromaffin cells: storage similar to NE
Chromogranins:
Unique to adrenal medulla?
Found where?
What can be used as a marker for some tumors of endocrine tissues?
Not unique to adrenal medulla secretion granules and adrenergic nerve synaptic vesicles
Found in various endocrine tissues:
- Pancreatic islets
- Medullary cells of thyroid
- Anterior pituitary gland
Overexpression of chromogranin A can be used as a marker for some tumors of endocrine tissues
- Function of chromogranin A unknnown
Release of Catecholamines:
Basics:
Release of Catecholamines:
Basics:
Membrane depolarization
Ca++ channels on neuron open, allowing Ca++ to enter neurons
Increase in Ca++ in the neuron –> docking/fusion of vesicles and exocytosis
Release of Catecholamines requires participation of various proteins (associated with plasma membrane, cytosol and vesicles): (3)
VAMP (vesicle)
t-SNARE (plasma membrane)
SNAP (cytosol)
Exocytosis: (3)
Transient fusion of membranes of neuron and storage vesicles
Contents of vesicles (including DBH, chromogranins, ATP, ascorbic acid etc.) are released
Substances of high molecular weight (ie. inulin) taken up from extracellular space into storage granules
Role of Ca++:
Depolarization –>?
What are activated at >-20mV and are open for 50-200ms
Transient:
Depolarization of membrane results in opening of N-type Ca++ channels on cells
N-Type: activated at >-20mV and are open for 50-200ms
Massive amount of Ca++ that enters is transient (a few seconds)
- Channels rapidly close
- Pumps and intracellular buffering systems bring Ca++ back to normal levels
Negative Feedback of NE on Nerve Terminals: Purpose
What does NE bind on its releasing neuron?
2 mechanisms that shut off subsequent release:
Therapeutic use:
Negative Feedback of NE on Nerve Terminals: to inhibit its own release during subsequent stimulation period
NE binds Alpha2 Receptors: activation shuts off subsequent release mechanism by one of 2 mechanisms
- Decreases cAMP
- Inhibits entry of Ca++
Therapeutic Use: specific agonists of presynaptic alpha2 receptors block NE release and reduce SS neurotransmission (ie. to control high blood pressure)
Fate of NE in the Adrenergic Synapse: (3)
Diffusion
Extraneuronal uptake
Neuronal uptake via NE transporter (NET)
NE diffusion
Where does it diffuse?
Metabolized by what emzymes?
Some NE diffuses into lymphatics or capillaries
Eventually reaches the liver and is metabolized by:
Catechol-O-methyl transferase (COMT)
Monoamine oxidase (MAO)
Extraneuronal Uptake of NE
Passes through:
Process is inhibited by:
Metabolized by:
Some passes through the membrane of the effector cells (process specific for catecholamines)
Process is inhibited by supra-physiological amounts of estrogen and corticosteroids
Metabolized by COMT in the effector cell –> nor-metanephrine (inactive product) –> diffuses out of cell
- Eliminated in urine, OR
- Further metabolized in the liver by MAO
Neuronal Uptake via NE Transporter (NET):
% removed by this method:
Involves
70% of NE removal by this method
NE taken back up into the nerve terminals that released it initially (reuptake)
Involves an amine pump in the nerve cell membrane
Affinity and blockage of NET receptors
Affinity of NET Receptors:
NE>EPI
Isoproterenol (ISO) not transported by NET (synthetic catecholamine)
Blockage of NET Receptors:
- Cocaine
- TCAs (anti-depressants
