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

Sanz-Rosa, David, M. Pilar Oubiña, Eva Cediel, Natalia de las Heras, Onofre Vegazo, Javier Jiménez, Vicente Lahera, and Victoria Cachofeiro. Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NFB/I B system. Am J Physiol Heart Circ Physiol 288: H111–H115, 2005. First published August 12, 2004; doi:10.1152/ajpheart.01061. 2003.—We investigated the role of angiotensin II in vascular and circulating inflammatory markers in spontaneously hypertensive rats (SHR). IL-1 , IL-6, and TNFaortic 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 ) or antihypertensive triple therapy (TT; in mg kg 1 day : 20 hydralazine 7 type 1 hydrochlorothiazide 0.15 reserpine) for 10 wk. Likewise, aortic expression of NFB p50 subunit precursor p105 and its inhibitor (I B) 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 TNFlevels between SHR and WKY. SHR presented elevated aortic mRNA expression of the transcription factor NFB and reduction in its inhibitor, I B. 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 TTtreated animals. The treatments increased I B mRNA expression similarly. However, only candesartan reduced NFB 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 NFB system activation; and 3) reduction of inflammatory mediators produced by candesartan in SHR could be partially due to both downregulation of NFB and upregulation of I B.