Hypertension in Transgenic Mice With Brain-Selective Overexpression of the α2B-Adrenoceptor

BACKGROUND Previous studies have shown that the presynaptic α 2B -adrenoceptor subtype in the central nervous system has a sympathoexcitatory function and its activation leads to a hyperadrenergic hypertensive state. The purpose ofthis project was to develop a novel hyperadrenergic model, a transgenic (TG) mouse model with brain-selective overexpression of the α 2B -adrenergic receptor (α 2B -AR). METHODS We used Southern blot analysis to confirm transgene, real-time PCR to assess gene expression, western Blot analysis and immunohistology to assess protein expression and localization in brain areas. Indirect blood pressure (BP) and heart rate were recorded. RESULTS In TG mice there was a 1.8-fold increase in α 2B -AR protein expression compared to wild-type (WT) mice. Immunostaining of brain sections revealed that concentration of α 2B -AR was much more pronounced in TG than in WT mice. Systolic BP at 8 weeks of age was significantly elevated in TG 130 ± 6 mm Hg, compared with WT control nontransgenic littermates of the same age 107 ± 7 mm Hg, (P < 0.05), indicating thattheTG mice had indeed developed hypertension. CONCLUSIONS We have therefore documented that overexpression of the α 2B -AR gene leads to increased production of α 2B -AR protein in brain regions known to regulate central sympathetic outflow, thus resulting in sustained BP elevation.This is a unique model of experimental hypertension driven purely by overexpression of the α 2B -AR that would result in an overactive sympathetic system and would be suitable for testing the pharmacologic properties of potential therapeutic agents.