Which mechanism explains the antihypertensive action of reserpine?

• A Irreversible blockade of alpha-1 receptors on vascular smooth muscle
• B Stimulation of central alpha-2 autoreceptors reducing sympathetic outflow
• C Inhibition of the vesicular monoamine transporter, depleting norepinephrine stores in adrenergic nerve endings ✓
• D Inhibition of norepinephrine synthesis by blocking tyrosine hydroxylase

Explanation

Reserpine irreversibly binds and inhibits VMAT2, the transporter that packages norepinephrine and other monoamines into synaptic vesicles. Stored transmitter leaks into the cytoplasm and is degraded by MAO, producing a slow, prolonged depletion of norepinephrine from peripheral adrenergic nerves and the CNS. This depletion lowers blood pressure but also causes depression, its major limiting toxicity. Alpha-1 blockade describes prazosin, central alpha-2 stimulation describes clonidine, and tyrosine hydroxylase inhibition describes metyrosine.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

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