Central Sympatholysis as a Novel Countermeasure for Cocaine-Induced Sympathetic Activation and Vasoconstriction in Humans

Dileep V. Menon, Zhongyun Wang, Paul J. Fadel, Debbie Arbique, David Leonard, Jia Ling Li, Ronald G. Victor, Wanpen Vongpatanasin

Research output: Contribution to journalArticle

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Abstract

Objectives: The aim of this study was to determine whether cocaine's sympathomimetic actions can be reversed by a potent centrally acting α2 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 α2C 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 α2CDel322-325 polymorphism. (Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546).

Original languageEnglish (US)
Pages (from-to)626-633
Number of pages8
JournalJournal of the American College of Cardiology
Volume50
Issue number7
DOIs
StatePublished - Aug 14 2007

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Vasoconstriction
Cocaine
Dexmedetomidine
Sympathomimetics
Cardiovascular System
Skin
Heart Rate
Adrenergic Agonists
Laser-Doppler Flowmetry
Vascular Resistance
Adrenergic Receptors
Norepinephrine
Arterial Pressure
Blood Pressure
Mutation
Brain
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Nursing(all)

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Central Sympatholysis as a Novel Countermeasure for Cocaine-Induced Sympathetic Activation and Vasoconstriction in Humans. / Menon, Dileep V.; Wang, Zhongyun; Fadel, Paul J.; Arbique, Debbie; Leonard, David; Li, Jia Ling; Victor, Ronald G.; Vongpatanasin, Wanpen.

In: Journal of the American College of Cardiology, Vol. 50, No. 7, 14.08.2007, p. 626-633.

Research output: Contribution to journalArticle

Menon, Dileep V. ; Wang, Zhongyun ; Fadel, Paul J. ; Arbique, Debbie ; Leonard, David ; Li, Jia Ling ; Victor, Ronald G. ; Vongpatanasin, Wanpen. / Central Sympatholysis as a Novel Countermeasure for Cocaine-Induced Sympathetic Activation and Vasoconstriction in Humans. In: Journal of the American College of Cardiology. 2007 ; Vol. 50, No. 7. pp. 626-633.
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AU - Menon, Dileep V.

AU - Wang, Zhongyun

AU - Fadel, Paul J.

AU - Arbique, Debbie

AU - Leonard, David

AU - Li, Jia Ling

AU - Victor, Ronald G.

AU - Vongpatanasin, Wanpen

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AB - Objectives: The aim of this study was to determine whether cocaine's sympathomimetic actions can be reversed by a potent centrally acting α2 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 α2C 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 α2CDel322-325 polymorphism. (Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546).

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