Ethnic and genetic determinants of cardiovascular response to the selective alpha 2-adrenoceptor agonist dexmedetomidine.
The alpha(2)-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 beta 3 G-protein subunit (GNB3 C825T) and in the alpha(2C)-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 alpha(2)-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 microg/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 alpha(2)-AR agonist dexmedetomidine, and neither ethnicity nor ADRA2C and GNB3 genotypes contribute to it. Further studies to identify determinants of alpha(2)-AR-mediated responses will be of interest.
Kurnik
Daniel
D
Department of Medicine, Division of Clinical Pharmacology, 542 RRB, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Muszkat
Mordechai
M
Sofowora
Gbenga G
GG
Friedman
Eitan A
EA
Dupont
William D
WD
Scheinin
Mika
M
Wood
Alastair J J
AJ
Stein
C Michael
CM
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000097:blood / Q000494:pharmacology*; D000328:Adult; D044383:Black People / Q000235:genetics*; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D003596:Cytosine; D020927:Dexmedetomidine / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D009638:Norepinephrine / Q000097:blood; D009994:Osmolar Concentration; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D017384:Sequence Deletion; D016037:Single-Blind Method; D013941:Thymine; D044465:White People / Q000235:genetics*; D001741:Black or African American
C547774:ADRA2C protein, human; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; C454420:G-protein beta3 subunit; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine; D003596:Cytosine; D020962:Heterotrimeric GTP-Binding Proteins; D013941:Thymine; D009638:Norepinephrine