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CLINICAL RESEARCH: AUTONOMIC FUNCTION

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

Hypertension Division and the Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Manuscript received December 12, 2006; revised manuscript received March 14, 2007, accepted March 28, 2007.

^_* Reprint requests and correspondence: Dr. Wanpen Vongpatanasin, Divisions of Hypertension and Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, J4.134, Dallas, Texas 75390-8586. (Email: wanpen.vongpatanasin{at}utsouthwestern.edu).

Objectives: The aim of this study was to determine whether cocaine’s sympathomimetic actions can be reversed by a potent centrally acting 2 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 2C 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 2CDel322-325 polymorphism. (Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546 [ClinicalTrials.gov] )

Abbreviations and Acronyms   2 AR = alpha 2 adrenergic receptor   2CDel322-325 = deletion 322-325 polymorphism of the alpha 2C AR   DNA = deoxyribonucleic acid   MAP = mean arterial pressure   NE = norepinephrine   OAAS = observer’s assessment of alertness/sedation scale   PCR = polymerase chain reaction   SNA = sympathetic nerve activity

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