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Knockdown of angiotensin AT1 receptors with siRNA prevents pressor response to angiotensin II at the subfornical organ
Author(s) -
Rossi Noreen F.,
MaliszewskaScislo Maria,
Rishi Arun K.,
Levi Edi,
Hatfield James S.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.842.6
Subject(s) - subfornical organ , angiotensin ii , gene knockdown , angiotensin ii receptor type 1 , renin–angiotensin system , pressor response , receptor , angiotensin receptor , pharmacology , medicine , chemistry , endocrinology , blood pressure , gene , biochemistry , heart rate
The subfornical organ (SFO) possesses abundant angiotensin AT 1 receptors (AT 1 R). Injection of Ang II into SFO activates its neurons and elicits a robust pressor response. Since the SFO lies outside the blood brain barrier, plasma Ang II may activate its AT 1 R. We hypothesized that selective knockdown of AT 1 R in SFO (1) will decrease the pressor response to exogenous microinjected Ang II and (2) will exert a depressor effect in two‐kidney one‐clip (2K1C) hypertensive rats. Male Sprague Dawley rats (12 wk old) were equipped with vascular catheters and an intracerebral cannula directed at SFO. Ang II (10 pmol) was injected into conscious rats 1 day before and 3 and 7 days after injection of 32 ng of a 1:1 mixture of siRNAs to AT 1a R and AT 1b R isoforms or vehicle. A similar siRNA injection was done in 2K1C rats equipped with telemetry. Prior to AT 1 R knockdown, Ang II elicited a 17.0±1.1 mmHg increase in mean arterial pressure (MAP). This pressor response was significantly attenuated 3 days (3.5±1.2 mmHg) and 7 days (5.1±3 mmHg) after siRNA. The pressor response to vasopressin was not changed. MAP in 2K1C rats 6 wk post clipping, decreased from 133 to 115 mmHg at 3 days, and remained lower than preinjection levels for 21 days of observation. Immunohistochemical staining with anti‐AT 1 R antibody showed appreciable loss of AT 1 R in SFO region that did not extend to the choroid or ependyma of the nearby 3 rd ventricle. These findings further support that activation of AT 1 R in SFO contributes to elevations in systemic arterial pressure in 2K1C rats.