Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-kappaB/IkappaB system.
We investigated the role of angiotensin II in vascular and circulating inflammatory markers in spontaneously hypertensive rats (SHR). IL-1beta, IL-6, and TNF-alpha 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-kappaB p50 subunit precursor p105 and its inhibitor (IkappaB) 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-1beta, IL-6, and TNF-alpha. Hypertension was also accompanied by increased IL-1beta and IL-6 plasma levels. No differences were observed in circulating TNF-alpha levels between SHR and WKY. SHR presented elevated aortic mRNA expression of the transcription factor NF-kappaB and reduction in its inhibitor, IkappaB. Candesartan decreased (P < 0.05) blood pressure levels, aortic mRNA expression of IL-1beta, IL-6, and TNF-alpha, and (P < 0.05) IL-1beta 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 IkappaB mRNA expression similarly. However, only candesartan reduced NF-kappaB 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-kappaB system activation; and 3) reduction of inflammatory mediators produced by candesartan in SHR could be partially due to both downregulation of NF-kappaB and upregulation of IkappaB.
Sanz-Rosa
David
D
Department of Physiology, School of Medicine, Universidad Complutense, Madrid 28040, Spain.
Oubiña
M Pilar
MP
Cediel
Eva
E
de Las Heras
Natalia
N
Vegazo
Onofre
O
Jiménez
Javier
J
Lahera
Vicente
V
Cachofeiro
Victoria
V
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D006973:Hypertension / Q000097:blood / Q000378:metabolism*; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D007375:Interleukin-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; C081643:candesartan