title: Sympathoneural and adrenomedullary functional effects of alpha2C-adrenoreceptor gene polymorphism in healthy humans.
abstract: OBJECTIVE
  alpha2-Adrenoreceptors restrain sympathetic nervous outflows and inhibit release of noradrenaline from sympathetic nerves. In-frame deletion of the alpha2C-adrenoreceptor subtype (alpha2CDel322-325) 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 alpha2-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 alpha2CDel322-325 polymorphism, nine heterozygotes, and nine non-carriers. Subjects were studied during supine rest and during and after i.v. infusion of the alpha2-adrenoreceptor antagonist, yohimbine.
  
  
  RESULTS
  At rest, homozygotes for the alpha2CDel322-325 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.
  
  
  CONCLUSIONS
  In healthy people, alpha2CDel322-325 polymorphism is associated with increased sympathetic nervous and adrenomedullary hormonal activities, both during supine rest and during pharmacologically evoked catecholamine release. Polymorphisms of the alpha2C-adrenoreceptor may help explain individual differences in predisposition to a variety of disorders of catecholaminergic function, such as cardiovascular disorders, depression or anxiety disorders.
authors.affiliation: Mood and Anxiety Disorders Program, Section on Experimental Therapeutics and Pathophysiology, NIMH, NIH, Bethesda, MD, USA. alexander.neumeister@yale.edu
authors.forename: Alexander
authors.initials: A
authors.lastname: Neumeister
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Charney
authors.forename: Inna
authors.initials: I
authors.lastname: Belfer
authors.forename: Marilla
authors.initials: M
authors.lastname: Geraci
authors.forename: Courtney
authors.initials: C
authors.lastname: Holmes
authors.forename: Yehonatan
authors.initials: Y
authors.lastname: Sharabi
authors.forename: Tanya
authors.initials: T
authors.lastname: Alim
authors.forename: Omer
authors.initials: O
authors.lastname: Bonne
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.forename: Husseini
authors.initials: H
authors.lastname: Manji
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
mesh_terms: D000293:Adolescent; D000313:Adrenal Medulla / Q000473:pathology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000328:Adult; D000704:Analysis of Variance; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure; D002319:Cardiovascular System / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006333:Heart Failure; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D011110:Polymorphism, Genetic; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D012306:Risk; D013564:Sympathetic Nervous System / Q000473:pathology*; D013997:Time Factors; D015016:Yohimbine / Q000494:pharmacology
chemical_list: C547774:ADRA2C protein, human; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D009638:Norepinephrine; D004837:Epinephrine