TY - JOUR
T1 - Central Sympatholysis as a Novel Countermeasure for Cocaine-Induced Sympathetic Activation and Vasoconstriction in Humans
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
N1 - Funding Information:
This work was supported by grants to Dr. Victor from the National Institute on Drug Abuse (RO-1 DA10064) and the American Society of Hypertension (Texas chapter) and to Drs. Vongpatanasin and Victor from the Donald W. Reynolds Foundation.
PY - 2007/8/14
Y1 - 2007/8/14
N2 - 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).
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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U2 - 10.1016/j.jacc.2007.03.060
DO - 10.1016/j.jacc.2007.03.060
M3 - Article
C2 - 17692748
AN - SCOPUS:34547561841
SN - 0735-1097
VL - 50
SP - 626
EP - 633
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 7
ER -