—Presynaptic α₂-adrenergic receptors (α₂-AR) are distributed throughout the central nervous system and are highly concentrated in the brain stem, where they contribute to neural baroreflex control of blood pressure (BP). To explore the role of the α_2A-AR subtype in this function, we compared BP and plasma norepinephrine and epinephrine levels in genetically engineered mice with deleted α_2A-AR gene to their wild-type controls. At baseline, the α_2A-AR gene knockouts (n=11) versus controls (n=10) had higher systolic BP (123±2.5 versus 115±2.5 mm Hg, P<0.05), heart rate (730±15 versus 600±18 b/min, P<0.001), and norepinephrine (1.005±0.078 versus 0.587±0.095 ng/mL, P<0.01), respectively. When submitted to subtotal nephrectomy and given 1% saline as drinking water, both α_2A-AR gene knockouts (n=14) and controls (n=14) became hypertensive, but the former required 15.6±2.5 days versus 29.3±1.4 days for the controls (P<0.001). End-point systolic BP was similar for both at 155±2.1 versus 152±5.2 mm Hg, but norepinephrine and epinephrine levels were twice as high in the knockouts at 1.386±0.283 and 0.577±0.143 versus 0.712±0.110 and 0.255±0.032 ng/mL, respectively, P<0.05 for both. We conclude that the α_2A-AR subtype exerts a sympathoinhibitory effect, and its loss leads to a hypertensive, hyperadrenergic state.