Down-regulation of Brain Gα12 attenuates Angiotensin II Dependent Hypertension

Abstract

Abstract Background Angiotensin II (Ang II) activates central Angiotensin II type 1 receptors (AT1R) to increase blood pressure (BP) via multiple pathways. However, whether central Gα proteins contribute to Ang II induced hypertension remains unknown. We hypothesized that AT1R couple with Gα12 and/or Gαq to produce sympatho-excitation and increase BP and downregulation of these Gα subunit proteins will attenuate Ang II dependent hypertension. Methods & Results After chronic infusion of Ang II (s.c. 350 ng/kg/min) or vehicle for 2-weeks, Ang II evoked an increase in Gα12 expression, but not Gαq in the RVLM 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 Gα12 oligodeoxynucleotide (ODN; 50 μg/day). Central Gα12 ODN infusion lowered mean BP in Ang II infused rats compared with SCR ODN infusion (14- day peak; 133 ± 12 vs 176 ± 11 mmHg). Compared to the SCR ODN group, Ang II infused rats that received i.c.v. Gα12 ODN showed a greater increase in heart rate to atropine, an attenuated reduction in BP to chlorisondamine, and an improved baroreflex sensitivity. In addition, central Gα12 and Gαq 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 Gα12 protein signaling pathways play an important role in the development of chronic AngII-dependent hypertension in rats.