Abnormal Regulation of the Sympathetic Nervous System in α2A-Adrenergic Receptor Knockout Mice

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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 (α2A, α2B, and α2C). Here we describe the physiological consequences of disrupting the gene for the α2A-AR. Mice lacking functional α2Asubtypes were compared with wild-type (WT) mice, with animals lacking the α2B or α2C subtypes, and with mice carrying a point mutation in the α2A-AR gene (α2AD79N). Deletion of the α2A 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 (Bmax: knockout, 23 ± 1 fmol/mg protein; WT, 31 ± 2 fmol/mg protein). The hypotensive effect of α2 agonists was completely absent in α2A-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 α2B-AR knockout, α2C-AR knockout, α2AD79N mutant, and WT mice. The maximal inhibition of vas deferens contraction by the α2 agonist in α2A-AR knockout mice was only 42 ± 9%. [3H]Norepinephrine release studies performed in vas deferens confirmed these findings. The results indicate that the α2A-AR is a major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves; however, the residual α2-mediated effect in the α2A-AR knockout mice suggests that a second α2 subtype (α2B or α2C) also functions as a presynaptic autoreceptor to inhibit transmitter release.