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

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2001-02, Vol.37 (2, Part 2 Suppl), p.371-375
• Main Authors: Kagiyama, Shuntaro, Varela, Adrian, Phillips, M Ian, Galli, Sara M
• Format: Article
• Language: English
• Subjects: Angiotensin II - blood; Angiotensin II - metabolism; Angiotensin Receptor Antagonists; Angiotensinogen - antagonists & inhibitors; Angiotensinogen - biosynthesis; Angiotensinogen - genetics; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - physiology; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Cardiology. Vascular system; Chronic Disease; Experimental diseases; Hypertension - blood; Hypertension - drug therapy; Hypertension - physiopathology; Hypertension, Renovascular - physiopathology; Hypothalamus - drug effects; Hypothalamus - metabolism; Injections, Intraventricular; Male; Medical sciences; Oligonucleotides, Antisense - therapeutic use; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin - biosynthesis; Receptors, Angiotensin - genetics; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; RNA, Messenger - analysis; RNA, Messenger - antagonists & inhibitors; Time Factors
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.37.2.371

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 (AT1R) 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 AT1R 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