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Here is a complete, structured explanation of the diagram, using the textbook figure above as a direct companion reference.
Adrenergic Neurotransmission and Drugs Modulating It
The diagram shows an adrenergic nerve ending (the bulb-shaped presynaptic terminal) communicating with an effector cell (postsynaptic cell) below, with both alpha (α) and beta (β) receptors on the effector cell surface. The key events are synthesis, storage, release, receptor binding, and removal of noradrenaline (NA), also called norepinephrine (NE).
1. Synthesis of NA (Inside the Nerve Terminal)
The pathway runs: TYR → DOPA → Dopamine → NA
| Step | Enzyme | Note |
|---|---|---|
| TYR (Tyrosine) → DOPA | Tyrosine hydroxylase | Rate-limiting step |
| DOPA → Dopamine | Aromatic L-amino acid decarboxylase | |
| Dopamine → NA | Dopamine β-hydroxylase | Occurs inside vesicles |
- TYR enters the nerve terminal by active transport (shown by the solid circle-arrow at the top).
- α-Methyltyrosine (α M-p-Tyr) blocks tyrosine hydroxylase → inhibits NA synthesis.
- α-Methyldopa (α M-Dopa) is a false precursor; it gets converted to α-methylnoradrenaline, which displaces NA and acts as a weak false transmitter (used in hypertension).
2. Storage of NA in Vesicles
Dopamine is taken up into vesicles by the vesicular monoamine transporter (VMAT), then converted to NA inside vesicles. Vesicles protect NA from degradation by MAO.
- Reserpine - irreversibly blocks VMAT → prevents dopamine uptake into vesicles → NA stores are depleted → antihypertensive/antipsychotic effect (shown by the dashed inhibitory arrow).
3. Release of NA (Nerve Impulse-Coupled Exocytosis)
An action potential triggers calcium influx → vesicle fusion with the membrane → exocytosis of NA into the synapse (the wavy line in the diagram represents this nerve impulse-coupled release).
- Guanethidine - enters the nerve terminal and displaces NA from vesicles, then blocks exocytosis → net depletion of NA release (antihypertensive).
- Tyramine (an indirectly acting sympathomimetic found in aged cheese, wine) - also displaces NA from vesicles → releases NA into the synapse → sympathomimetic effect. Normally metabolized by gut/liver MAO. Dangerous in patients taking MAO inhibitors (MAO-I) - can cause hypertensive crisis.
4. Receptor Binding on the Effector Cell
Released NA crosses the synapse and binds to:
- α receptors (α₁ postsynaptic): vasoconstriction, mydriasis, etc.
- β receptors (β₁, β₂ postsynaptic): cardiac stimulation, bronchodilation, etc.
- α₂ presynaptic receptors (autoreceptors): feedback inhibition - NA "circles back" and inhibits its own further release (shown as the α₂ feedback arrow in the diagram).
5. Removal / Termination of NA Action
Three routes terminate NA's action:
a) Reuptake (Uptake-1) - the major pathway
NA is transported back into the presynaptic terminal by the noradrenaline transporter (NET).
- Cocaine blocks Uptake-1 → NA accumulates in synapse → enhanced sympathomimetic effect (this is the mechanism of cocaine's cardiovascular toxicity).
- Tricyclic antidepressants and SNRIs similarly block reuptake.
b) Enzymatic Metabolism by MAO
Inside the neuron, monoamine oxidase (MAO) on mitochondria degrades NA → DOH-MA (3,4-dihydroxymandelic acid), which is further metabolized.
- MAO inhibitors (MAO-I) block this → more NA available → increased sympathetic tone.
- This is why MAO-I + tyramine-rich food is dangerous (tyramine is also normally destroyed by MAO in the gut).
c) Enzymatic Metabolism by COMT
In the synaptic cleft or post-synaptically, catechol-O-methyltransferase (COMT) methylates NA → NMN (normetanephrine).
- Both MAO and COMT products are further degraded to VMA (vanillylmandelic acid) and free NA, excreted in urine. Elevated urinary VMA suggests a pheochromocytoma.
Summary Table: Drugs and Their Sites of Action
| Drug | Site of Action | Effect |
|---|---|---|
| α-Methyltyrosine | Tyrosine hydroxylase | ↓ NA synthesis |
| α-Methyldopa | False precursor | Replaces NA with weak false transmitter |
| Reserpine | VMAT (vesicular uptake) | Depletes NA stores |
| Guanethidine | Displaces NA + blocks exocytosis | ↓ NA release |
| Tyramine | Displaces NA from vesicles | ↑ NA release (indirect sympathomimetic) |
| MAO-Inhibitors | MAO enzyme | ↓ NA degradation → ↑ NA |
| Cocaine | Uptake-1 (reuptake transporter) | ↑ synaptic NA → sympathomimetic |
| COMT products | Synaptic metabolism | VMA, NMN excreted in urine |
The Effector Cell and Receptors
The bottom cell (effector organ) shows β receptors (left) and α receptors (right). NA binding to each triggers different G-protein-coupled second messenger cascades:
- α₁: Gq → IP₃/DAG → ↑ intracellular Ca²⁺ → smooth muscle contraction
- α₂: Gi → ↓ cAMP → presynaptic inhibition of NA release
- β₁/β₂: Gs → ↑ cAMP → cardiac stimulation / smooth muscle relaxation
This diagram is the foundation for understanding adrenergic pharmacology - every drug that modulates the sympathetic nervous system (antihypertensives, decongestants, antidepressants, stimulants) acts at one of these labeled steps.
- Lippincott Illustrated Reviews: Pharmacology, pp. 209-215
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