Downregulation of Brain Gα12 Attenuates Angiotensin II-Dependent Hypertension

Abstract

Background: Angiotensin II (Ang II) activates central Angiotensin II type 1 receptors to increase blood pressure via multiple pathways. However, whether central Gα proteins contribute to Ang II-induced hypertension remains unknown. We hypothesized that Angiotensin II type 1 receptors couple with Gα12 and/or Gαq to produce sympatho-excitation and increase blood pressure and downregulation of these Gα-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 Gα12 expression, but not Gαq 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 Gα12 oligodeoxynucleotide (ODN; 50 µg/day). Central Gα12 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. Gα12 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 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 Ang II-dependent hypertension in rats.

Keywords: Gα proteins; Gα12; Gαq; angiotensin II; blood pressure; brain; hypertension.

Figure 1.

Protein expression of Gα12 and Gαq in rostral ventrolateral medulla (RVLM), paraventricular nucleus (PVN), subfornical organ (SFO), and cortex of rats infused with Ang II (350 ng/kg/min, s.c.) or isotonic saline vehicle for 2 weeks. (a) Representative blots for Gα12 and Gαq in each nucleus; (b, c), quantified protein expression levels of Gα12 and Gαq. n = 4–7 in each group. *P < 0.05, compared with saline infused rats.

Figure 2.

(a) Changes in mean arterial pressure (MAP) produced by i.c.v. infusion of a scrambled (SCR) or Gα12 ODN (50 µg/day) in rats that received s.c. Ang II (350 ng/kg/min) or isotonic saline vehicle for 14 days. *P < 0.05, compared with Saline + SCR ODN and Saline + Gα12 ODN infused rats. #P < 0.05, compared with both Ang II + SCR ODN infused rats. There is interaction between treatments and time. (b–e) Spontaneous baroreflex gain (b), changes in heart rate (HR) produced by i.p. injection of atropine (c) and propranolol (d) and change in mean blood pressure (BP) produced by chlorisondamine (e) measured in four chronic treatment groups. *P < 0.05. n = 5–7 in each group. Abbreviation: ODN, oligodeoxynucleotide.

Figure 3

Representative blots and Gα12 protein expression levels in rostral ventrolateral medulla (RVLM) (a), paraventricular nucleus (PVN) (b), cortex (c) and Gαq protein level in RVLM (d) of rats (n = 5–7/group) that received continuous i.c.v. infusion of a scrambled (SCR) or Gα12 ODN (50 µg/day) during 14 days s.c. isotonic saline or Ang II (350 ng/kg/min) administration. n = 5–7 in each group. *P < 0.05. Abbreviation: ODN, oligodeoxynucleotide.

Figure 4

Changes in mean arterial pressure (MAP) produced by s.c. Ang II (350 ng/kg/min) in rats that concurrently received i.c.v. infusion of a scrambled (SCR) ODN, a Gαq ODN, or combined Gα12 and Gαq ODN (50 µg/day/ODN). n = 6–7 in each group. #P < 0.05, compared with Ang II + SCR ODN. There is no interaction between treatment and time. Abbreviation: ODN, oligodeoxynucleotide.