Antisense inhibition of brain renin-angiotensin system decreased blood pressure in chronic 2-kidney, 1 clip hypertensive rats

The systemic renin-angiotensin system (RAS) plays an important role in bloo d 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 n ormal, but the hypertension is sustained for months. We hypothesized that i n this phase the brain RAS contributes to the maintenance of high BP. To te st the hypothesis, we studied the role of brain RAS by decreasing the synth esis of angiotensinogen (AGT) and the angiotensin II (Ang II) type 1a recep tor (AT(1)R) with intracerebroventricular injections of antisense oligonucl eotides (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 A S-ODNs to AT(1)R mRNA was studied at 10 months after clipping. Intracerebro ventricular injection of AS-ODN-AGT (200 mug/kg, n=5) significantly decreas ed SEP (-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 sens e ODN and saline groups was significantly (P<0.05) higher than in the noncl ipped group. Compared with inverted ODN, intracerebroventricular injection of AS-ODN-AT(1)R (250 mug/kg, n=6) significantly decreased SEP (-26+/-8 mm Hg, P<0.05) for 3 days after injection. This was a brain effect because int ravenous AS-ODN-AT(1)R at a dose of 250 to 500 <mu>g/kg did not affect SEP. These results suggest that the brain RAS plays an important role in mainta ining the elevated SEP in chronic 2K1C hypertension.