Down-regulation of Brain Gα12 attenuates Angiotensin II Dependent Hypertension.

BACKGROUND Angiotensin II (Ang II) activates central Angiotensin II type 1 receptors to increase blood pressure via multiple pathways. However, whether central G alpha proteins contribute to Ang II-induced hypertension remains unknown. We hypothesized that Angiotensin II type 1 receptors couple with G alpha 12 and/or G alpha q to produce sympatho-excitation and increase blood pressure and downregulation of these G alpha-subunit proteins will attenuate Ang II-dependent hypertension. METHODS AND RESULTS After chronic infusion of Ang II (s.c. 350 ng/kg/min) or vehicle for 2 weeks, Ang II evoked an increase in G alpha 12 expression, but not G alpha q in the rostral ventrolateral medulla of Sprague-Dawley rats. In other studies, rats that received Ang II or vehicle infusion s.c. were simultaneously infused i.c.v. with a scrambled (SCR) or G alpha 12 oligodeoxynucleotide (ODN; 50 mu g/day). Central G alpha 12 ODN infusion lowered mean blood pressure in Ang II infused rats compared with SCR ODN infusion (14-day peak; 133 12 vs. 176 +/- 11 mm Hg). Compared to the SCR ODN group, Ang II infused rats that received i.c.v. G alpha 12 ODN showed a greater increase in heart rate to atropine, an attenuated reduction in blood pressure to chlorisondamine, and an improved baroreflex sensitivity. In addition, central G alpha 12 and G alpha q ODN pretreatment blunted the pressor response to an acute i.c.v. injection of Ang II (i.c.v., 200 ng). CONCLUSIONS These findings suggest that central G alpha 12 protein signaling pathways play an important role in the development of chronic Ang II-dependent hypertension in rats.