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

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Abstract
We investigated the role of angiotensin II in vascular and circulating inflammatory markers in spontaneously hypertensive rats (SHR). IL-1β, IL-6, and TNF-α 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-κB p50 subunit precursor p105 and its inhibitor (IκB) 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-1β, IL-6, and TNF-α. Hypertension was also accompanied by increased IL-1β and IL-6 plasma levels. No differences were observed in circulating TNF-α levels between SHR and WKY. SHR presented elevated aortic mRNA expression of the transcription factor NF-κB and reduction in its inhibitor, IκB. Candesartan decreased ( P < 0.05) blood pressure levels, aortic mRNA expression of IL-1β, IL-6, and TNF-α, and ( P < 0.05) IL-1β 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 IκB mRNA expression similarly. However, only candesartan reduced NF-κB 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-κB system activation; and 3 ) reduction of inflammatory mediators produced by candesartan in SHR could be partially due to both downregulation of NF-κB and upregulation of IκB.