Estimation of intrasynaptic norepinephrine concentrations in humans.

Area of Science:

• Pharmacology
• Neuroscience
• Cardiovascular Physiology

Background:

• Norepinephrine is a key neurotransmitter in the sympathetic nervous system.
• Understanding synaptic norepinephrine levels is crucial for cardiovascular regulation.
• Previous estimations of synaptic norepinephrine concentrations during pressor responses were limited.

Purpose of the Study:

• To estimate the concentration of norepinephrine in the synaptic cleft associated with a specific pressor response in humans.
• To determine the relationship between arterial plasma norepinephrine and blood pressure changes.
• To investigate the impact of pharmacological blockade on this relationship.

Main Methods:

• Measurement of blood pressure and arterial plasma norepinephrine levels.
• Norepinephrine (NE) infusion and yohimbine-induced endogenous NE release.
• Combined blockade of ganglionic, alpha 2-adrenergic receptors, and neuronal norepinephrine uptake (Uptake1).

Main Results:

• A linear relationship was observed between pressor response and log norepinephrine concentration during infusions.
• A 20 mm Hg pressor response was associated with 3647 pg/ml arterial norepinephrine during NE infusion.
• Pharmacological blockade significantly reduced the norepinephrine concentration required for a 20 mm Hg pressor response to 684 pg/ml (combined blockade) and 467 pg/ml (yohimbine-induced release).

Conclusions:

• The estimated synaptic cleft norepinephrine concentration for a 20 mm Hg sympathetically mediated pressor response is approximately 560 pg/ml (3.3 nM).
• This concentration falls between plasma norepinephrine levels during infusion and endogenous release.
• These findings provide a quantitative estimate of neurochemical events during sympathetic activation.