OBJECTIVES: The aim of this study was to determine whether cocaine's sympathomimetic actions can be reversed by a potent centrally acting alpha2 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 alpha2C 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 alpha2CDel322-325 polymorphism. (Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546).
RCT Entities:
OBJECTIVES: The aim of this study was to determine whether cocaine's sympathomimetic actions can be reversed by a potent centrally acting alpha2 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 alpha2C 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 alpha2CDel322-325 polymorphism. (Study to Improve Scientific Understanding of the Cardiovascular Actions of Cocaine; http://clinicaltrials.gov/ct/show/NCT00338546?order=1; NCT00338546).
Authors: Erik J Mersereau; Shelby L Poitra; Ana Espinoza; Dane A Crossley; Tristan Darland Journal: Comp Biochem Physiol C Toxicol Pharmacol Date: 2015-04-03 Impact factor: 3.228
Authors: Kristen Metzler-Wilson; Kumika Toma; Dawn L Sammons; Sarah Mann; Andrew J Jurovcik; Olga Demidova; Thad E Wilson Journal: J Neurophysiol Date: 2015-07-01 Impact factor: 2.714
Authors: Swaminatha V Gurudevan; Michael D Nelson; Florian Rader; Xiu Tang; Joshua Lewis; Jimmy Johannes; J Todd Belcik; Robert M Elashoff; Jonathan R Lindner; Ronald G Victor Journal: Circulation Date: 2013-06-28 Impact factor: 29.690