Abnormal regulation of the sympathetic nervous system in α2A-adrenergic receptor knockout mice

alpha(2)-Adrenergic receptors (ARs) play a key role in regulating neurotransmitter release in the central and peripheral sympathetic nervous systems. To date, three subtypes of alpha(2)-ARs have been cloned (alpha(2A), alpha(2B), and alpha(2C)). Here we describe the physiological consequences of disrupting the gene for the or,AR. Mice lacking functional or,subtypes were compared with wild-type (WT) mice, with animals lacking the alpha(2B) or alpha(2C) subtypes, and with mice carrying a point mutation in the alpha(2)-AR gene (alpha(2A)D79N). Deletion of the alpha(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 downregulation of cardiac beta-ARs (B-max: knockout, 23 +/- 1 fmol/mg protein; WT, 31 +/- 2 fmol/mg protein). The hypotensive effect of alpha(2) agonists was completely absent in alpha(2A)-deficient mice. Presynaptic alpha(2)-AR function was tested in two isolated vas deferens preparations. The nonsubtype-selective alpha(2) agonist dexmedetomidine completely blocked the contractile response to electrical stimulation in vas deferens from alpha(2B)-AR knockout, alpha(2C)-AR knockout, alpha(2A)D79N mutant, and WT mice. The maximal inhibition of vas deferens contraction by the alpha(2) agonist in alpha(2A)-AR knockout mice was only 42 +/- 9%. [H-3]Norepinephrine release studies performed in vas deferens confirmed these findings. The results indicate that the alpha(2A)-AR is a major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves; however, the residual alpha(2)-mediated effect in the alpha(2A)-AR knockout mice suggests that a second or, subtype (alpha(2B) or alpha(2C)) also functions as a presynaptic autoreceptor to inhibit transmitter release.