Antisense Inhibition of Brain Renin-Angiotensin System Decreased Blood Pressure in Chronic 2-Kidney, 1 Clip Hypertensive Rats

Abstract

The systemic renin-angiotensin system (RAS) plays an important role in blood pressure (BP) regulation during the development of 2-kidney, 1 clip (2K1C) hypertension. Its contributions decrease with time after constriction of the renal artery. During the chronic phase, the peripheral RAS returns to normal, but the hypertension is sustained for months. We hypothesized that in this phase the brain RAS contributes to the maintenance of high BP. To test the hypothesis, we studied the role of brain RAS by decreasing the synthesis of angiotensinogen (AGT) and the angiotensin II (Ang II) type 1a receptor (AT 1 R) with intracerebroventricular injections of antisense oligonucleotides (AS-ODNs). The response of systolic BP (SBP) to AS-ODNs to AGT mRNA was studied in 2K1C rats at 6 months after clipping, and the response to AS-ODNs to AT 1 R mRNA was studied at 10 months after clipping. Intracerebroventricular injection of AS-ODN-AGT (200 μg/kg, n=5) significantly decreased SBP (−22±6 mm Hg, P <0.05) compared with the sense ODN (n=5) and saline (n=3) groups. Intracerebroventricular injection of AS-ODN-AGT reduced the elevated hypothalamic Ang II level. The hypothalamic Ang II content in sense ODN and saline groups was significantly ( P <0.05) higher than in the nonclipped group. Compared with inverted ODN, intracerebroventricular injection of AS-ODN-AT 1 R (250 μg/kg, n=6) significantly decreased SBP (−26±8 mm Hg, P <0.05) for 3 days after injection. This was a brain effect because intravenous AS-ODN-AT 1 R at a dose of 250 to 500 μg/kg did not affect SBP. These results suggest that the brain RAS plays an important role in maintaining the elevated SBP in chronic 2K1C hypertension.