Contribution of Brain Gαq and Gα12 Protein Pathways in Mediating Angiotensin II (Ang II) Dependent Hypertension

Our previous studies demonstrated that down‐regulation of brain Gα12 proteins blunted Ang II‐induced hypertension in rats. In this study, we examined whether brain Gαq proteins also contribute to Ang II‐dependent hypertension and whether the combined down‐regulation of brain Gαq and Gα12 proteins further attenuates the increase in blood pressure (BP) to Ang II. Methods: Sprague Dawley rats were implanted with telemetry transmitters for measurement of BP. After 3 days of baseline BP recording, rats were distributed into 3 groups (n=6/group) for i.c.v. infusion (mini‐osmotic pump) of scrambled (SCR) oligodeoxynucleotide (ODN; 50 µg/day), Gαq ODN (50 µg/day), or Gαq ODN + Gα12 ODN (50 µg/day each). Each group also received subcutaneous mini‐osmotic pump Ang II infusion (350 ng/kg/min). BP recording was then performed daily for 14 days. Results: After 7 days of Ang II treatment, Gαq ODN infusion decreased mean blood pressure (MBP) compared to that of SCR ODN (day 7, 151±7 vs 170±10 mmHg), and i.c.v. Gαq ODN + Gα12 ODN infusion reduced MBP further (133±4 mmHg, n=6). At day 14, there was no significant difference in MAP between Ang II + Gαq ODN and Ang II + SCR ODN (163±8 vs 176±12 mmHg), but there remained a significant decrease in MBP in the Gαq ODN + Gα12 ODN group (142±6 mmHg). Conclusions These findings demonstrate that brain Gαq protein pathways mediate the early phase increase in BP produced by systemic administration of Ang II, whereas brain Gα12 pathways supersede in the late phase. Therapeutically, these findings also demonstrate that down‐regulation of both brain Gαq and Gα12 protein pathways is necessary to maximally attenuate Ang II‐dependent hypertension. AHA 14POST20450173 to JG; 12GRNT12060613 and P20 GM103514 to DRK