Human response to alpha2-adrenergic agonist stimulation studied in an isolated vascular bed in vivo: Biphasic influence of dose, age, gender, and receptor genotype.
OBJECTIVE
Activation of alpha 2 -adrenergic receptors regulates a broad spectrum of physiologic responses, including blood pressure (centrally and peripherally), sedation, analgesia, insulin release, renal function, cognition, and behavior. The purpose of this study was to explore systematically the local vascular responses in humans triggered by a highly selective alpha 2 -adrenergic agonist (azepexole [B-HT 933]) and whether such responses are dose-dependent or influenced by age, gender, or allelic variation at the drug's receptor.


METHODS
We evaluated dorsal hand vein vascular responses to the infusion of a wide spectrum of doses of azepexole, assessing any venodilation, as well as the maximal extent of venoconstriction (B max ) and the dose that produced a half-maximal effect (K d ), in 50 healthy normotensive adults of both genders and 4 ethnicities. Genomic deoxyribonucleic acid from the study subjects was evaluated at polymorphisms of the alpha 2B -adrenergic receptor gene (ADRA2B).


RESULTS
We found previously unreported initial venodilation to low doses (10-100 ng/min) of azepexole, followed by progressive, intense venoconstriction to higher doses (200-100,000 ng/min) of the drug. Younger individuals (aged <30 years) had less venodilation than older individuals (aged >30 years) with low doses of azepexole but had a greater extent of venoconstriction at higher doses of azepexole (ANOVA, P = .001). Men had less venodilation than women with low doses of azepexole but greater venoconstriction with higher doses (ANOVA, P = .036). Several common polymorphisms (>10% minor allele frequency) at ADRA2B (insertion/deletion polymorphism [Glu 322-325 ], G-98C, C1182A, and C1776A) did not show an association with either B max or K d for the drug response. The A36G (Thr12Thr) synonymous single nucleotide polymorphism displayed a nonsignificant trend (P = .073) toward higher K d in A/G heterozygotes compared with A/A homozygotes.


CONCLUSIONS
Local infusion into the human dorsal hand vein of a highly selective alpha 2 -adrenergic agonist, azepexole, produces biphasic responses, with venodilation at a low dose and intense venoconstriction at a higher concentration. These responses to azepexole show prominent differences as a function of age and gender but appear not to depend on common allelic variations at the ADRA2B receptor.
King
Danuta
D
Department of Medicine and Center for Molecular Genetics (0838), University of California at San Diego, and VA San Diego Healthcare System, 9500 Gilman Dr, La Jolla, CA 92093-0838, USA.
Etzel
Jason P
JP
Chopra
Shagun
S
Smith
Joshua
J
Cadman
Peter E
PE
Rao
Fangwen
F
Funk
Stephen D
SD
Rana
Brinda K
BK
Schork
Nicholas J
NJ
Insel
Paul A
PA
O'Connor
Daniel T
DT
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000367:Age Factors; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006225:Hand / Q000098:blood supply; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010597:Pharmacogenetics / Q000379:methods; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000235:genetics; D012737:Sex Factors; D014661:Vasoconstriction; D014664:Vasodilation; D014680:Veins / Q000187:drug effects* / Q000473:pathology / Q000502:physiology
C547771:ADRA2B protein, human; C547774:ADRA2C protein, human; D000316:Adrenergic alpha-Agonists; D001381:Azepines; D018341:Receptors, Adrenergic, alpha-2; C015603:azepexole