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Effect of AT₁ receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-B/IB system

²Medical Department, AstraZeneca Farmacéutica Spain, and ¹Department of Physiology, School of Medicine, Universidad Complutense, Madrid, Spain

Submitted 10 November 2003 ; accepted in final form 4 August 2004

We investigated the role of angiotensin II in vascular and circulating inflammatory markers in spontaneously hypertensive rats (SHR). IL-1, IL-6, and TNF- aortic mRNA expression and plasma levels were measured in adult SHR untreated or treated with the angiotensin II receptor antagonist candesartan (2 mg·kg^–1·day^–1) or antihypertensive triple therapy (TT; in mg·kg^–1·day^–1: 20 hydralazine + 7 type 1 hydrochlorothiazide + 0.15 reserpine) for 10 wk. Likewise, aortic expression of NF-B p50 subunit precursor p105 and its inhibitor (IB) were measured. Age-matched Wistar-Kyoto rats (WKY) served as normotensive reference. High blood pressure levels were associated with increased (P < 0.05) aortic mRNA expression of IL-1, IL-6, and TNF-. Hypertension was also accompanied by increased IL-1 and IL-6 plasma levels. No differences were observed in circulating TNF- levels between SHR and WKY. SHR presented elevated aortic mRNA expression of the transcription factor NF-B and reduction in its inhibitor, IB. Candesartan decreased (P < 0.05) blood pressure levels, aortic mRNA expression of IL-1, IL-6, and TNF-, and (P < 0.05) IL-1 and IL-6 plasma concentration. However, although arterial pressure decrease was comparable for the treatments, TT only partially reduced the increments in inflammatory markers. In fact, candesartan-treated rats showed significantly lower levels of circulating and vascular inflammatory markers than TT-treated animals. The treatments increased IB mRNA expression similarly. However, only candesartan reduced NF-B mRNA expression. In summary, 1) SHR presented a vascular inflammatory process; 2) angiotensin II, and increased hemodynamic forces associated with hypertension, seems to be involved in stimulation of inflammatory mediators through NF-B system activation; and 3) reduction of inflammatory mediators produced by candesartan in SHR could be partially due to both downregulation of NF-B and upregulation of IB.

angiotensin II; cytokines

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