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

43 Scopus citations

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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