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 language | English (US) |
|---|---|
| Pages (from-to) | 626-633 |
| Number of pages | 8 |
| Journal | Journal of the American College of Cardiology |
| Volume | 50 |
| Issue number | 7 |
| DOIs | |
| State | Published - Aug 14 2007 |
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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 journal › Article
}
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
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
VL - 50
SP - 626
EP - 633
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 7
ER -