Abnormal regulation of the sympathetic nervous system in alpha(2A)-adrenergic receptor knockout mice

alpha(2)-Adrenergic receptors (ARs) play a key role in regulating neurotran smitter 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 dis rupting the gene for the or,AR. Mice lacking functional or,subtypes were co mpared with wild-type (WT) mice, with animals lacking the alpha(2B) or alph a(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 co ncentration (knockout, 676 +/- 31 pg/mg protein; WT, 1178 +/- 98 pg/mg prot ein), and downregulation of cardiac beta-ARs (B-max: knockout, 23 +/- 1 fmo l/mg protein; WT, 31 +/- 2 fmol/mg protein). The hypotensive effect of alph a(2) agonists was completely absent in alpha(2A)-deficient mice. Presynapti c alpha(2)-AR function was tested in two isolated vas deferens preparations . The nonsubtype-selective alpha(2) agonist dexmedetomidine completely bloc ked 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) a gonist in alpha(2A)-AR knockout mice was only 42 +/- 9%. [H-3]Norepinephrin e release studies performed in vas deferens confirmed these findings. The r esults indicate that the alpha(2A)-AR is a major presynaptic receptor subty pe regulating norepinephrine release from sympathetic nerves; however, the residual alpha(2)-mediated effect in the alpha(2A)-AR knockout mice suggest s that a second or, subtype (alpha(2B) or alpha(2C)) also functions as a pr esynaptic autoreceptor to inhibit transmitter release.