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

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Abstract

BACKGROUND:

Previous studies have shown that the presynaptic α2B-adrenoceptor subtype in the central nervous system has a sympathoexcitatory function and its activation leads to a hyperadrenergic hypertensive state. The purpose of this project was to develop a novel hyperadrenergic model, a transgenic (TG) mouse model with brain-selective overexpression of the α2B-adrenergic receptor (α2B-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 α2B-AR protein expression compared to wild-type (WT) mice. Immunostaining of brain sections revealed that concentration of α2B-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 that the TG mice had indeed developed hypertension.

CONCLUSIONS:

We have therefore documented that overexpression of the α2B-AR gene leads to increased production of α2B-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 α2B-AR that would result in an overactive sympathetic system and would be suitable for testing the pharmacologic properties of potential therapeutic agents.

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