TY - JOUR
T1 - Ethnic and genetic determinants of cardiovascular response to the selective α2-adrenoceptor agonist dexmedetomidine
AU - Kurnik, Daniel
AU - Muszkat, Mordechai
AU - Sofowora, Gbenga G.
AU - Friedman, Eitan A.
AU - Dupont, William D.
AU - Scheinin, Mika
AU - Wood, Alastair J.J.
AU - Stein, C. Michael
PY - 2008/2
Y1 - 2008/2
N2 - The α2-adrenoceptor agonist clonidine reduces blood pressure more effectively in White than Black Americans despite similar degrees of sympatholysis. Functional genetic variation in receptor signaling mechanisms, for example in the β3 G-protein subunit (GNB3 C825T) and in the α2C-adrenoceptor subtype (ADRA2C del322-325), may affect drug responses. We examined the hypothesis that there are ethnic differences in the responses to the highly selective α2-agonist, dexmedetomidine, and that these genetic variants contribute to interindividual variability in drug responses. In a placebo-controlled, single-masked study, 73 healthy subjects (37 whites and 36 blacks) received 3 placebo infusions and then 3 incremental doses of dexmedetomidine (cumulative dose, 0.4 μg/kg), each separated by 30 minutes. Blood pressure, heart rate, and plasma catecholamine concentrations were determined after each infusion. We measured dexmedetomidine concentrations after the last infusion and determined ADRA2C del322-325 and GNB3 C825T genotypes. Dexmedetomidine lowered blood pressure and plasma catecholamine concentrations significantly (all P<0.001). There was substantial interindividual variability in the reduction of systolic blood pressure (range, 1 to 34 mm Hg) and plasma norepinephrine concentrations (range, 24 to 424 pg/mL). However, there were no differences between black and white subjects in dexmedetomidine responses (P>0.16 for all outcomes) before or after adjustment for covariates. Neither ADRA2C del322-325 nor GNB3 C825T genotypes affected the responses to dexmedetomidine (all P>0.66). There is large interindividual variability in response to the selective α2-AR agonist dexmedetomidine, and neither ethnicity nor ADRA2C and GNB3 genotypes contribute to it. Further studies to identify determinants of α2-AR-mediated responses will be of interest.
AB - The α2-adrenoceptor agonist clonidine reduces blood pressure more effectively in White than Black Americans despite similar degrees of sympatholysis. Functional genetic variation in receptor signaling mechanisms, for example in the β3 G-protein subunit (GNB3 C825T) and in the α2C-adrenoceptor subtype (ADRA2C del322-325), may affect drug responses. We examined the hypothesis that there are ethnic differences in the responses to the highly selective α2-agonist, dexmedetomidine, and that these genetic variants contribute to interindividual variability in drug responses. In a placebo-controlled, single-masked study, 73 healthy subjects (37 whites and 36 blacks) received 3 placebo infusions and then 3 incremental doses of dexmedetomidine (cumulative dose, 0.4 μg/kg), each separated by 30 minutes. Blood pressure, heart rate, and plasma catecholamine concentrations were determined after each infusion. We measured dexmedetomidine concentrations after the last infusion and determined ADRA2C del322-325 and GNB3 C825T genotypes. Dexmedetomidine lowered blood pressure and plasma catecholamine concentrations significantly (all P<0.001). There was substantial interindividual variability in the reduction of systolic blood pressure (range, 1 to 34 mm Hg) and plasma norepinephrine concentrations (range, 24 to 424 pg/mL). However, there were no differences between black and white subjects in dexmedetomidine responses (P>0.16 for all outcomes) before or after adjustment for covariates. Neither ADRA2C del322-325 nor GNB3 C825T genotypes affected the responses to dexmedetomidine (all P>0.66). There is large interindividual variability in response to the selective α2-AR agonist dexmedetomidine, and neither ethnicity nor ADRA2C and GNB3 genotypes contribute to it. Further studies to identify determinants of α2-AR-mediated responses will be of interest.
KW - Cardiovascular physiology
KW - Dexmedetomidine
KW - Ethnic groups
KW - G-protein beta3 subunit
KW - Pharmacogenetics
KW - Receptors, adrenergic, α-2
UR - http://www.scopus.com/inward/record.url?scp=38549107556&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.107.098939
DO - 10.1161/HYPERTENSIONAHA.107.098939
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C2 - 18071056
AN - SCOPUS:38549107556
SN - 0194-911X
VL - 51
SP - 406
EP - 411
JO - Hypertension
JF - Hypertension
IS - 2
ER -