Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans

J Am Coll Cardiol. 2007 Aug 14;50(7):626-33. doi: 10.1016/j.jacc.2007.03.060. Epub 2007 Jul 30.


Objectives: The aim of this study was to determine whether cocaine's sympathomimetic actions can be reversed by a potent centrally acting alpha2 adrenergic receptor (AR) agonist (dexmedetomidine).

Background: We recently showed that cocaine stimulates the human cardiovascular system primarily by acting in the brain to increase sympathetic nerve activity (SNA), the neural stimulus to norepinephrine release. Thus, SNA constitutes a putative new drug target to block cocaine's adverse cardiovascular effects at their origin.

Methods: In 22 healthy cocaine-naïve humans, we measured skin SNA (microneurography) and skin blood flow (laser Doppler velocimetry) as well as heart rate and blood pressure before and after intranasal cocaine (2 mg/kg) alone and in combination with dexmedetomidine or saline.

Results: During intranasal cocaine alone, SNA increased by 2-fold and skin vascular resistance increased from 13.2 +/- 2.3 to 20.1 +/- 2.2 resistance units while mean arterial pressure increased by 14 +/- 3 mm Hg and heart rate by 18 +/- 3 beats/min (p < 0.01). Dexmedetomidine abolished these increases, whereas intravenous saline was without effect. Dexmedetomidine was effective in blocking these sympathomimetic actions of cocaine even in all 7 subjects who were homozygous for the Del322-325 polymorphism in the alpha2C AR, a loss-of-function mutation that is highly enriched in blacks.

Conclusions: The data advance the novel hypothesis that central sympatholysis with dexmedetomidine constitutes a highly effective countermeasure for cocaine's sympathomimetic actions on the human cardiovascular system, even in individuals carrying the alpha2CDel322-325 polymorphism. (Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546).

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology*
  • Adult
  • Cocaine / pharmacology*
  • Dexmedetomidine / pharmacology*
  • Female
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Prospective Studies
  • Receptors, Adrenergic, alpha-2 / genetics
  • Skin / blood supply
  • Skin / drug effects*
  • Skin / innervation
  • Vascular Resistance / drug effects
  • Vasoconstrictor Agents / pharmacology*
  • Vasomotor System / drug effects*


  • ADRA2C protein, human
  • Adrenergic alpha-Agonists
  • Receptors, Adrenergic, alpha-2
  • Vasoconstrictor Agents
  • Dexmedetomidine
  • Cocaine

Associated data

  • ClinicalTrials.gov/NCT00338546