Antisense Inhibition of Central, But not Peripheral Renin Angiotensin System Decreased Arterial Pressure in Chronic Phase of Two-Kidney, One Clip Hypertensive Rats

Abstract

P198 Introduction: The systemic renin angiotensin system (RAS) plays an important role in blood pressure (BP) regulation during the development of two-kidney, one clip hypertension (2K1C). Its contributions decrease with time after constriction of the renal artery. During the chronic phase, the peripheral RAS returns to normal, nevertheless for months the hypertension is sustained. We hypothesized that during this phase of 2K1C hypertension, the brain RAS contributes to the maintenance of high BP. Methods: Therefore, we studied in the role of brain RAS by decreasing the synthesis of angiotensinogen (AGT) and angiotensin type 1a receptors (AT1R) with intracerebroventricular (ICV) injection of antisense oligonucleotides (AS-ODN). The response of systolic BP (SBP) to AS-ODN to AGT was studied at 6 mo(Group 1) and the response to AS-ODN to AT1R at 10 mo post clipping (Group 2). Each group was divided into AS-ODN, sense or inverted ODN, and saline subgroups. All groups were implanted with ICV cannulae one week before treatment. SBP was monitored by tail cuff method. Plasma and brain angiotensin II (AngII) content was measured by radioimmunoassay in all treated 2K1C groups and in nonclipped rats. Results: The results show that in Group 1, at 6 mo post clipping, the ICV AS-ODN to AGT (200 μg/kg, n=5) significantly decreased SBP(≈−22±6 mmHg, P<0.05)compared to sense ODN and saline group (n=5). The hypothalamic AngII content in sense ODN and saline groups was significantly (P<0.05) higher than in nonclipped rats. AS-ODN to AGT reduced the elevated hypothalamic AngII level. Plasma AngII was significantly decreased in the clipped group (40±12 pg/ml) compared with nonclipped group (75±8 pg/ml). In Group 2, 10 mo post clipping, the ICV injection of AS-ODN to AT1R (250 μg/kg, n=6) significantly decreased SBP(≈−26±8 mmHg, P<0.05) for 3 days post injection, compared to inverted ODN. In contrast, intravenous AS-ODN to AT1R in dose of 250-500 μg/kg did not affect SBP. Conclusion: These results suggest that the brain RAS plays an important role in maintaining the elevated SBP in chronic hypertension phase.