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Related Experiment Videos

S-nitrosothiols inhibit neuronal norepinephrine transport

D M Kaye1, S D Wiviott, L Kobzik

  • 1Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

The American Journal of Physiology
|February 1, 1997
PubMed
Summary

Nitric oxide (NO) and related compounds reduce norepinephrine (NE) uptake in sympathetic neurons by affecting the NE transporter. This suggests NO may regulate neurotransmitter levels in the nervous system.

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Nitric oxide (NO) and its congeners (NOx) are known to influence catecholamine turnover in the brain.
  • The specific impact of NOx on norepinephrine (NE) uptake by sympathetic neurons remains largely uncharacterized.

Purpose of the Study:

  • To investigate whether NOx affect norepinephrine (NE) uptake mediated by the uptake-1 transporter in sympathetic neurons.
  • To elucidate the potential mechanisms underlying NOx-mediated modulation of NE transport.

Main Methods:

  • Utilized PC-12 cells and primary cultures of rat superior cervical ganglia to assess [3H]NE uptake.
  • Employed S-nitroso-acetylpenicillamine (SNAP) as an NO donor and N-monomethyl-L-arginine (L-NMMA) as a nitric oxide synthase (NOS) inhibitor.
  • Investigated the role of cyclic guanosine monophosphate (cGMP) and sulfhydryl compounds like cysteine in mediating the observed effects.

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Main Results:

  • S-nitroso-acetylpenicillamine (SNAP) significantly reduced desipramine-sensitive [3H]NE uptake in PC-12 cells and superior cervical ganglia, indicating selective inhibition of uptake-1.
  • Coculture with endothelial cells expressing NOS2 or endogenous NO production in PC-12 cells also decreased [3H]NE uptake in an L-NMMA-sensitive manner.
  • The inhibitory effect of SNAP was attenuated by cysteine, suggesting a role for S-nitrosation, while cGMP elevation did not mimic the uptake inhibition.

Conclusions:

  • Endogenous nitric oxide (NO) sources modulate the activity of the uptake-1 catecholamine transporter in postganglionic sympathetic neurons.
  • This modulation likely occurs via S-nitrosothiol-mediated nitrosation of regulatory sites on the NE transporter.
  • These findings highlight a novel mechanism for regulating neurotransmitter levels in the sympathetic nervous system.