In the adrenergic system, release of the neurotransmitter norepinephrine from sympathetic nerves is regulated by presynaptic inhibitory α₂-adrenoceptors, but it is unknown whether release of epinephrine from the adrenal gland is controlled by a similar short feedback loop. Using gene-targeted mice we demonstrate that two distinct subtypes of α₂-adrenoceptors control release of catecholamines from sympathetic nerves (α_2A) and from the adrenal medulla (α_2C). In isolated mouse chromaffin cells, α₂-receptor activation inhibited the electrically stimulated increase in cell capacitance (a correlate of exocytosis), voltage-activated Ca²⁺ current, as well as secretion of epinephrine and norepinephrine. The inhibitory effects of α₂-agonists on cell capacitance, voltage-activated Ca²⁺ currents, and on catecholamine secretion were completely abolished in chromaffin cells isolated from α_2C-receptor-deficient mice. In vivo, deletion of sympathetic or adrenal feedback control led to increased plasma and urine norepinephrine (α_2A-knockout) and epinephrine levels (α_2C-knockout), respectively. Loss of feedback inhibition was compensated by increased tyrosine hydroxylase activity, as detected by elevated tissue dihydroxyphenylalanine levels. Thus, receptor subtype diversity in the adrenergic system has emerged to selectively control sympathetic and adrenal catecholamine secretion via distinct α₂-adrenoceptor subtypes. Short-loop feedback inhibition of epinephrine release from the adrenal gland may represent a novel therapeutic target for diseases that arise from enhanced adrenergic stimulation.