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Prostaglandin E2 (PGE2) Type 1 Receptors (EP1R) in the Subfornical Organ (SFO) Contribute to Slow‐Pressor AngII Sympathoexcitation and Hypertension (HTN) via NADPH Oxidase (Nox)‐Dependent Signaling
Author(s) -
Cao Xian,
Wang Gang,
Peterson Jeffrey,
Burmeister Melissa,
Sharma Ram,
Iadecola Costantino,
Davisson Robin
Publication year - 2010
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.24.1_supplement.1049.1
Subject(s) - losartan , angiotensin ii , endocrinology , nadph oxidase , medicine , subfornical organ , chemistry , antagonist , prostaglandin e2 , receptor , receptor antagonist , oxidative stress
The SFO is a critical forebrain region that mediates slow‐pressor AngII‐induced sympathoexcitation and HTN via reactive oxygen species (ROS) formation. We have shown that the HTN and sympathetic outflow caused by slow‐pressor AngII are abolished in EP1R null mice. Here we tested the hypothesis that EP1R in the SFO contribute to these AngII responses by activating Nox‐dependent ROS signaling. Real‐time PCR revealed that EP1R is the predominant PGE2 receptor in SFO at baseline compared to EP2R, EP3R or EP4R (p<.05; n=3). Slow‐pressor AngII infusion for 2 wks (600ng/kg/min, sc) caused a gradual increase in EP1R mRNA selectively in SFO, which peaked (1.89±.3‐fold day 0, p<.05; n=3) before BP began to rise. ICV infusion of the EP1R antagonist SC‐51089 (6ug/hr) prevented AngII‐induced HTN (ΔMAP: 5±5 vs vehicle 35±9 mmHg, p<.05, n=6–7) and ROS formation in SFO (1.07±.2 vs vehicle 2.3±.4, p<.05, n=6–8) during week 2. In vitro, AngII and PGE2 dose‐dependently elicited increases in ROS production in isolated SFO cells with EC50 = 63 nM and 53.2 nM, respectively. The AT1 antagonist losartan blocked the response to AngII but not PGE2. Both responses were eliminated in SFO cells treated with gp91ds‐tat or derived from Nox2 or EP1R null mice. This suggests that activation of EP1R is a critical step that links AT1 and Nox signaling in the SFO, which may contribute to sympathetic activation in this model of AngII HTN. ( HL096571 )