TY - JOUR
T1 - Dexmedetomidine as a novel countermeasure for cocaine-induced central sympathoexcitation in cocaine-addicted humans
AU - Kontak, Andrew C.
AU - Victor, Ronald G.
AU - Vongpatanasin, Wanpen
PY - 2013/2
Y1 - 2013/2
N2 - Cocaine-induced acute hypertension is mediated largely by increased central sympathetic nerve activity. We hypothesized that dexmedetomidine, a central sympatholytic, reverses cocaine-induced increases in sympathetic nerve activity, mean arterial pressure (MAP), and heart rate (HR) in cocaine-addicted subjects. First, we conducted a dose-finding study in 15 nontreatment-seeking cocaine-addicted subjects and 12 cocaine-naive healthy controls to find doses of intravenous dexmedetomidine that lower MAP and HR in the absence of acute-cocaine challenge. We then conducted a placebo-controlled treatment trial in 26 cocaine-addicted subjects to determine whether dexmedetomidine reverses MAP and HR increases after intranasal cocaine (3 mg/kg). Skin sympathetic nerve activity (measured in the second protocol) and skin vascular resistance (measured in both protocols) served as indices of cocaine-sensitive central sympathoexcitation. In doses up to 0.6 μg/kg IV, dexmedetomidine alone caused comparable dose-dependent decreases in blood pressure in cases and controls but a 1.0 μg/kg dose was required to lower HR. In cocaine-addicted subjects, low-dose dexmedetomidine (0.4 μg/kg; n=14) abolished cocaine-induced increases in skin sympathetic nerve activity (156±26 versus -15±22%, cocaine/placebo versus cocaine/dexmedetomidine; P<0.05), skin vascular resistance (+10±2 versus -2±3 U; P<0.05), and MAP (+6±1 versus -5±2 mm Hg; P<0.01) without affecting HR (+13±2 versus +9±2 bpm; P=ns). When dexmedetomidine was increased to 1 μg/kg (high dose; n=12) to reverse cocaine-induced increases in HR, MAP did not fall further and increased paradoxically in 4 of 12 subjects. Thus, in a low nonsedating dose, dexmedetomidine constitutes a putative new treatment for cocaine-induced acute hypertension but higher sedating doses can increase blood pressure unpredictably during acute-cocaine challenge and should be avoided.
AB - Cocaine-induced acute hypertension is mediated largely by increased central sympathetic nerve activity. We hypothesized that dexmedetomidine, a central sympatholytic, reverses cocaine-induced increases in sympathetic nerve activity, mean arterial pressure (MAP), and heart rate (HR) in cocaine-addicted subjects. First, we conducted a dose-finding study in 15 nontreatment-seeking cocaine-addicted subjects and 12 cocaine-naive healthy controls to find doses of intravenous dexmedetomidine that lower MAP and HR in the absence of acute-cocaine challenge. We then conducted a placebo-controlled treatment trial in 26 cocaine-addicted subjects to determine whether dexmedetomidine reverses MAP and HR increases after intranasal cocaine (3 mg/kg). Skin sympathetic nerve activity (measured in the second protocol) and skin vascular resistance (measured in both protocols) served as indices of cocaine-sensitive central sympathoexcitation. In doses up to 0.6 μg/kg IV, dexmedetomidine alone caused comparable dose-dependent decreases in blood pressure in cases and controls but a 1.0 μg/kg dose was required to lower HR. In cocaine-addicted subjects, low-dose dexmedetomidine (0.4 μg/kg; n=14) abolished cocaine-induced increases in skin sympathetic nerve activity (156±26 versus -15±22%, cocaine/placebo versus cocaine/dexmedetomidine; P<0.05), skin vascular resistance (+10±2 versus -2±3 U; P<0.05), and MAP (+6±1 versus -5±2 mm Hg; P<0.01) without affecting HR (+13±2 versus +9±2 bpm; P=ns). When dexmedetomidine was increased to 1 μg/kg (high dose; n=12) to reverse cocaine-induced increases in HR, MAP did not fall further and increased paradoxically in 4 of 12 subjects. Thus, in a low nonsedating dose, dexmedetomidine constitutes a putative new treatment for cocaine-induced acute hypertension but higher sedating doses can increase blood pressure unpredictably during acute-cocaine challenge and should be avoided.
KW - adrenergic receptor agonists
KW - adrenergic receptors
KW - cocaine
KW - sympathetic nervous system
KW - sympatholytics
UR - http://www.scopus.com/inward/record.url?scp=84873055968&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873055968&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.112.203554
DO - 10.1161/HYPERTENSIONAHA.112.203554
M3 - Article
C2 - 23283356
AN - SCOPUS:84873055968
SN - 0194-911X
VL - 61
SP - 388
EP - 394
JO - Hypertension
JF - Hypertension
IS - 2
ER -