Ethnic and genetic determinants of cardiovascular response to the selective α2-adrenoceptor agonist dexmedetomidine

Daniel Kurnik, Mordechai Muszkat, Gbenga G. Sofowora, Eitan A. Friedman, William D. Dupont, Mika Scheinin, Alastair J.J. Wood, C. Michael Stein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)406-411
Number of pages6
JournalHypertension
Volume51
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

Keywords

  • Cardiovascular physiology
  • Dexmedetomidine
  • Ethnic groups
  • G-protein beta3 subunit
  • Pharmacogenetics
  • Receptors, adrenergic, α-2

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