Abstract

α₂-Adrenergic receptors (ARs) play a key role in regulating neurotransmitter release in the central and peripheral sympathetic nervous systems. To date, three subtypes of α₂-ARs have been cloned (α_2A, α_2B, and α_2C). Here we describe the physiological consequences of disrupting the gene for the α_2A-AR. Mice lacking functional α_2Asubtypes were compared with wild-type (WT) mice, with animals lacking the α_2B or α_2C subtypes, and with mice carrying a point mutation in the α_2A-AR gene (α_2AD79N). Deletion of the α_2A subtype led to an increase in sympathetic activity with resting tachycardia (knockout, 581 ± 21 min⁻¹; WT, 395 ± 21 min⁻¹), depletion of cardiac tissue norepinephrine concentration (knockout, 676 ± 31 pg/mg protein; WT, 1178 ± 98 pg/mg protein), and down-regulation of cardiac β-ARs (B _max: knockout, 23 ± 1 fmol/mg protein; WT, 31 ± 2 fmol/mg protein). The hypotensive effect of α₂ agonists was completely absent in α_2A-deficient mice. Presynaptic α₂-AR function was tested in two isolated vas deferens preparations. The nonsubtype-selective α₂ agonist dexmedetomidine completely blocked the contractile response to electrical stimulation in vas deferens from α_2B-AR knockout, α_2C-AR knockout, α_2AD79N mutant, and WT mice. The maximal inhibition of vas deferens contraction by the α₂ agonist in α_2A-AR knockout mice was only 42 ± 9%. [³H]Norepinephrine release studies performed in vas deferens confirmed these findings. The results indicate that the α_2A-AR is a major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves; however, the residual α₂-mediated effect in the α_2A-AR knockout mice suggests that a second α₂ subtype (α_2B or α_2C) also functions as a presynaptic autoreceptor to inhibit transmitter release.