Ethnic and Genetic Determinants of Cardiovascular Response to the Selective α ₂ -Adrenoceptor Agonist Dexmedetomidine

Abstract

Abstract-The ␣ 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 ␤3 G-protein subunit (GNB3 C825T) and in the ␣ 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 ␣ 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 g/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 PϽ0.001). 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 (PϾ0.16 for all outcomes) before or after adjustment for covariates. Neither ADRA2C del322-325 nor GNB3 C825T genotypes affected the responses to dexmedetomidine (all PϾ0.66). There is large interindividual variability in response to the selective ␣ 2 -AR agonist dexmedetomidine, and neither ethnicity nor ADRA2C and GNB3 genotypes contribute to it. Further studies to identify determinants of ␣ 2 -AR-mediated responses will be of interest. Key Words: cardiovascular physiology Ⅲ receptors, adrenergic, ␣-2 Ⅲ G-protein beta3 subunit Ⅲ dexmedetomidine Ⅲ pharmacogenetics Ⅲ ethnic groups ␣ 2 -Adrenoceptors (␣ 2 -ARs) in the central nervous system and on presynaptic sympathetic nerve terminals play a key role in the regulation of the sympathetic response and thus cardiovascular control. The systemic administration of an ␣ 2 -AR agonist causes a reduction in sympathetic tone resulting in a decrease in blood pressure and heart rate, and the ␣ 2 -AR agonist clonidine is widely used as antihypertensive medication. There is, however, substantial interindividual variability in response to ␣ 2 -AR agonists, and black hypertensive patients achieved blood pressure control with clonidine monotherapy less often than whites. 1,2 Concordant with that observation, we found that clonidine reduced blood pressure less in healthy black subjects than white subjects, despite similar decreases in norepinephrine spillover. 3 The reasons for these ethnic differences remain unclear.Functionally significant genetic variants of ␣ 2 -ARs and other proteins in their signaling pathways have been identified. The prevalence of these allelic...

Dexmedetomidine Induces Both Relaxations and Contractions, via Different α2-Adrenoceptor Subtypes, in the Isolated Mesenteric Artery and Aorta of the Rat

“…Although the constriction is consistent, there is substantial variability in sensitivity to dexmedetomidine, and the mechanism underlying this variability remains elusive (Kurnik et al, 2008;Muszkat et al, 2010). It is noteworthy that ␣ 2 -ARmediated effects are different in venous and arterial blood vessels (Wright et al, 1995;Muszkat et al, 2010).…”

Dexmedetomidine-induced cerebral hypoperfusion exacerbates ischemic brain injury in rats

“…However, Erkonen et al [29] and Mason et al [30] recently reported that dexmedetomidine tended to increase BP, particularly in children,. Furthermore, Kurnik et al [32] reported substantial individual variability in the response to dexmedetomidine. These variations may be due to differences in the expression and/or sensitivity of the alpha-2B receptor subtype.…”

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

“…Intravenous administration of the ␣ 2 -agonist dexmedetomidine to healthy subjects results in blood pressure lowering and a decrease in plasma catecholamine concentrations. These effects exhibit a considerable interindividual variability; however, the I/D polymorphism in the ␣ 2C -AR gene did not contribute to this heterogeneity (Table 4) (Kurnik et al, 2008a). Another group reported enhanced sympathetic nervous and adrenomedullary activities in carriers of the deletion variant.…”

“…No effects on investigated parameters Kurnik et al, 2008a Blood pressure and heart rate response to cold pressure test in 79 healthy subjects DD genotype associated with greater positive chronotropic response Kurnik et al, 2008b Registry study with 637 heart failure patients treated with metoprolol or carvedilol…”