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

Abstract

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.

Angiotensin AT1 receptor antagonists exert anti‐inflammatory effects in spontaneously hypertensive rats

“…Further, AT1 antagonism decreased the secretion of MCP-1 from PBMCs and the level of CCR2 in PBMCs. Previous studies of animal models of hypertension have also shown AT1 antagonists alleviating the detrimental effects of Ang II on endothelial cells and reducing the level of inflammatory response in vessels (Cheng et al, 2005;Sanz-Rosa et al, 2005).…”

“…MCP-1 acts as a central mediator of the inflammatory response in hypertensive vascular disease (Usui et al, 2000;Sanz-Rosa et al, 2005;Willemsen et al, 2007). In response to Ang II, monocytes increase MCP-1 secretion, which plays an essential role in increased inflammation in the vessel (Ni et al, 2004).…”

Potassium channel changes of peripheral blood T-lymphocytes from Kazakh hypertensive patients in Northwest China and the inhibition effect towards potassium channels by telmisartan

“…Other studies have shown that upregulation of inflammatory mediators in hypertensive patients can be used to predict the development of hypertension. The inflammatory process in hypertensive patients is characterised by expression of cytokines (interleukin [IL]-6, IL-1, and tumour necrosis factor alpha [TNF-a]), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and the corresponding activation of nuclear factor-kB (NF-kB) [6][7][8]. T lymphocytes are also thought to play a critical role in the pathogenesis of hypertension and vascular remodelling [9].…”

“…Transcriptional factor Foxp3, which is expressed in T lymphocytes (including T helper cells [Th1, Th2, Th17] and suppressor T cells [including regulatory T cells]), has been reported to be critical for the production of angiotensin II, which plays a key role in the progression of essential hypertension [9]. Other studies have shown that the anti-inflammatory effects of angiotensin II receptor blocker (ARB) may be involved in the ability of these agents to lower blood pressure (BP) [6,13,14].…”

Participação do receptor tipo Toll 4 na reatividade vascular em ratos espontaneamente hipertensos.

“…De fato, diversos estudos têm demonstrado que os níveis circulantes de moléculas inflamatórias, como citocinas, quimiocinas, HSP60 e 70, Ang II e proteína C reativa, encontram-se elevados em SHR e em pacientes hipertensos (39)(40)(41). Em alguns casos, a detecção dos níveis plasmáticos de proteína C reativa pode colaborar com o prognóstico da hipertensão em pacientes (42).…”