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Ethnic and genetic determinants of cardiovascular response to the selective alpha 2-adrenoceptor agonist dexmedetomidine.

Kurnik D, Muszkat M, Sofowora GG, Friedman EA, Dupont WD, Scheinin M, Wood AJ, Stein CM
Hypertension. 2008 51 (2): 406-11

PMID: 18071056 · DOI:10.1161/HYPERTENSIONAHA.107.098939

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.

MeSH Terms (21)

Adrenergic alpha-2 Receptor Agonists Adrenergic alpha-Agonists Adult African Continental Ancestry Group Blood Pressure Cardiovascular System Cytosine Dexmedetomidine European Continental Ancestry Group Female Genetic Variation Genotype Heterotrimeric GTP-Binding Proteins Humans Male Norepinephrine Osmolar Concentration Receptors, Adrenergic, alpha-2 Sequence Deletion Single-Blind Method Thymine

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