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
