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

Objectives alpha(2)-Adrenoreceptors restrain sympathetic nervous outflows and inhibit release of noradrenaline from sympathetic nerves. In-frame deletion of the alpha(2C)-adrenoreceptor subtype (alpha(2C)Del322-325) 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 alpha(2)-adrenoreceptor subtype polymorphisms underwent H-3-noradrenaline and H-3-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 alpha(2C)Del322-325 polymorphism, nine heterozygotes, and nine non-carriers. Subjects were studied during supine rest and during and after i.v. infusion of the alpha(2)-adrenoreceptor antagonist, yohimbine. Results At rest, homozygotes for the alpha(2C)Del322-325 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, alpha(2C)Del322-325 polymorphism is associated with increased sympathetic nervous and adrenomedullary hormonal activities, both during supine rest and during pharmacologically evoked catecholamine release. Polymorphisms of the alpha(2C)-adrenoreceptor may help explain individual differences in predisposition to a variety of disorders of catecholaminergic function, such as cardiovascular disorders, depression or anxiety disorders. Pharmacogenetics and Genomics 15:143-149 (c) 2005 Lippincott Williams & Wilkins.