Effect of norepinephrine uptake blockers on norepinephrine kinetics

Area of Science:

• Pharmacology
• Neuroscience
• Clinical Medicine

Background:

• Norepinephrine (NE) is a key neurotransmitter and hormone.
• Understanding NE kinetics is crucial for various physiological and pathological conditions.
• The roles of neuronal and extraneuronal uptake in NE clearance are not fully elucidated.

Purpose of the Study:

• To investigate the effect of desipramine, a selective neuronal norepinephrine reuptake inhibitor, on norepinephrine kinetics.
• To assess the contribution of neuronal norepinephrine uptake to overall plasma NE clearance.
• To compare the effects of neuronal and extraneuronal NE uptake blockers on NE kinetics.

Main Methods:

• Administration of a single oral dose of desipramine (125 mg) to healthy subjects.
• Measurement of plasma norepinephrine clearance, spillover, and concentration.
• Infusion of tritiated norepinephrine to determine plasma disappearance kinetics.
• Administration of cortisol (500 mg IV), a selective extraneuronal uptake blocker, for comparison.

Main Results:

• Desipramine significantly reduced plasma norepinephrine clearance by ~20% (p<0.01).
• Desipramine decreased norepinephrine spillover to plasma but did not alter plasma NE concentration.
• The rapid-removal phase of tritiated norepinephrine disappearance (t1 1/2) was prolonged by desipramine, indicating impaired neuronal uptake.
• Cortisol had no significant effect on plasma norepinephrine clearance or NE disappearance kinetics in normal subjects.

Conclusions:

• Neuronal norepinephrine uptake plays a significant role in the overall removal of norepinephrine from plasma.
• Desipramine's effect on NE kinetics underscores the importance of neuronal reuptake mechanisms.
• Extraneuronal norepinephrine uptake appears to be negligible at physiological plasma NE concentrations.