Objective Feedback regulation of norepinephrine release from sympathetic nerves is essential to control blood pressure, heart rate and contractility. Recent experiments in gene-targeted mice have suggested that α_2C-adrenoceptors may operate in a similar feedback mechanism to control the release of epinephrine from the adrenal medulla. As heterozygous polymorphisms in the human α_2C-adrenoceptor gene have been associated with cardiovascular disease including hypertension and chronic heart failure, we have sought to characterize the relevance of α_2C-gene copy number for feedback control of epinephrine release in gene-targeted mice.

Methods Adrenal catecholamine release, basal hemodynamics and susceptibility to develop heart failure after transverse aortic constriction were tested in mice with two copies (+/+), one copy (+/−) or no functional α_2C-adrenoceptor gene (α_2C−/−).

Results Heterozygous α_2C-receptor deletion (α_2C+/−) resulted in a 43% reduction of adrenal α_2C mRNA copy number and in a similar decrease in α₂-receptor-mediated inhibition of catecholamine release from isolated adrenal glands in vitro. Urinary excretion of epinephrine was increased by 74±15% in α_2C+/− and by 142±23% in α_2C−/− mice as compared with wild-type control mice. Telemetric determination of cardiovascular function revealed significant tachycardia but no hypertension in α_2C-adrenoceptor-deficient mice. α_2C+/− mice were more susceptible to develop cardiac hypertrophy, failure and mortality after left-ventricular pressure overload than α_2C+/+ mice.

Conclusion Adrenal α₂-mediated feedback regulation of epinephrine secretion differs fundamentally from sympathetic feedback control. A single adrenoceptor subtype, α_2C, operates without a significant receptor reserve to prevent elevation of circulating epinephrine levels. This genetic model may provide an experimental basis to study the pathophysiology of α_2C-adrenoceptor dysfunction in humans.