Sympathoneural and adrenomedullary functional effects of ??2C-adrenoreceptor gene polymorphism in healthy humans

Mood and Anxiety Disorders Program, Section on Experimental Therapeutics and Pathophysiology, NIMH, NIH, Bethesda, MD, USA.
Pharmacogenetics and Genomics (Impact Factor: 3.45). 04/2005; 15(3):143-9. DOI: 10.1097/01213011-200503000-00002
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "The lack of clear genetic linkages may be due to the finding that both variant forms of α2 ARs exist as multiple haplotypes, and expression of specific haplotypes may be more important determinants of cardiovascular disease risk (Small et al. 2004; Small et al. 2006). Despite the lack of a clear linkage to cardiovascular disease, it has been demonstrated that human α2C Δ322- 325 AR homozygotic volunteers have the pathophysiological trait of increased sympathoneural drive (Neumeister et al. 2005). Subsequent pharmacological analysis of α2C Δ322-325 ARs using intact HEK293 cells suggested no loss-of-function phenotype, suggesting that if this variant form did have a linkage to pathophysiological conditions (such as increased sympathoneural drive), other cellular mechanisms of receptor dysfunction must play a role. "
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    • "However, the contribution of genetic factors to the ethnic differences in health is often very small and the results are often difficult to replicate (Cooper and Zhu 2001, Cruickshank et al. 2001, Cooper 2003, Li et al. 2006). For example, sequence variations in the human a 2 adrenergic receptor genes (ADRA2A and ADRA2C) were implicated as a cause of hypertension in African-American subjects (Lockette et al. 1995, Neumeister et al. 2005). From a stratified random population sample of 1767 subjects, however, Li et al. (2006) found no association of either variant with hypertension in African-Americans. "
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    • "Yohimbine, a drug that blocks the a2 receptors (i.e., a receptor antagonist), increases alcohol self-administration and induces reinstatement of alcohol seeking (Le et al. 2005; Marinelli et al. 2007). The recent finding that an a2c receptor polymorphism (Del322-325) reduces feedback inhibition of sympathetic NE release (Neumeister et al. 2005) as well as evidence from studies in mice bred to have an inactivated a2c receptor (i.e., knockout mice) (Sallinen et al. 1999), suggest that interventions targeting this receptor might modulate stress and anxiety responses. "
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