Sympathoneural adrenomedullary functional effects of α2c- adrenoreceptor gene polymorphism in healthy humans

Alexander Neumeister, Dennis S. Charney, Inna Belfer, Marilla Geraci, Courtney Holmes, Yehonatan Sharabi, Tanya Alim, Omer Bonne, David A. Luckenbaugh, Husseini Manji, David Goldman, David S. Goldstein

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: α2-Adrenoreceptors restrain sympathetic nervous outflows and inhibit release of noradrenaline from sympathetic nerves. In-frame deletion of the α2c-adrenoreceptor subtype (α2CDel322-325) increases the risk of congestive heart failure. Increased delivery of catecholamines to cardiovascular receptors might explain this increased risk. Methods: Twenty-nine healthy African-Americans genotyped for α2-adrenoreceptor subtype polymorphisms underwent 3H-noradrenaline and 3H-adrenaline intravenous infusion and arterial blood sampling for measurements of rates of entry of endogenous noradrenaline and adrenaline into arterial plasma (total body spillovers) by the tracer dilution technique. Eleven subjects were homozygotes for the α2CDel322-325 polymorphism, nine heterozygotes, and nine non-carriers. Subjects were studied during supine rest and during and after i.v. infusion of the α2-adrenoreceptor antagonist, yohimbine. Results: At rest, homozygotes for the α2cDel322-325 polymorphism had higher total body noradrenaline spillover than did heterozygotes (t=2.90, df=18, P=0.023) or non-carriers (t=3.22, df=18, P=0.010). Adrenaline spillover was higher in homozygotes than non-carriers (t=2.61, df=18, P=0.045). Administration of yohimbine produced larger, more sustained increments in noradrenaline spillover, heart rate, and anxiety in homozygotes than in the other groups. Conclusion: In healthy people, α 2cDel322-325 polymorphism is associated with increased sympathetic nervous and adrenomedullary hormonal activities, both during supine rest and during pharmacologically evoked catecholamine release. Polymorphisms of the α2c-adrenoreceptor may help explain individual differences in predisposition to a variety of disorders of catecholaminergic function, such as cardiovascular disorders, depression or anxiety disorders.

Original languageEnglish
Pages (from-to)143-149
Number of pages7
JournalPharmacogenetics and Genomics
Volume15
Issue number3
DOIs
StatePublished - Mar 2005
Externally publishedYes

Keywords

  • Genetic variant
  • Noradrenaline and adrenaline spillover
  • Yohimbine
  • α-adrenoceptor

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