Involvement of the renin–angiotensin system in the development of vascular damage in a rat model of arthritis: Effect of angiotensin receptor blockers

Abstract

Objective. To explore the involvement of the renin-angiotensin system (RAS) in the development of vascular damage in adjuvant-induced arthritis (AIA) in rats.Methods. Angiotensin II (Ang II; 0.25 or 1.0 mg/kg/day) was infused in control rats and rats with AIA for 21 days, and the impact of systemic inflammation on Ang II-induced hypertension, endothelial dysfunction, and vascular hypertrophy was evaluated. Expression of angiotensin II type 1 receptor (AT 1 R) and angiotensin-converting enzyme (ACE) in the aortas of rats with AIA were examined by real-time polymerase chain reaction (PCR) and Western blot analyses. Losartan (3 mg/kg/day) or irbesartan (5 mg/kg/day), both of which are AT 1 R blockers, was administered orally to rats with AIA for 21 days. In situ superoxide production in aortas was assessed according to the fluorogenic oxidation of dihydroethidium to ethidium. The expression and activity of NAD(P)H oxidases in aortas were examined by real-time PCR analysis and lucigenin chemiluminescence assay. Endothelial function in rats with AIA treated in vivo or ex vivo with AT 1 R blockers was also determined.Results. The Ang II-induced hypertensive response, endothelial dysfunction, and vascular hypertrophy were exacerbated in rats with AIA. Expression of AT 1 R and ACE was increased in the aortas of rats with AIA. Both losartan and irbesartan decreased the levels of superoxide and the expression and activity NAD(P)H oxidases in the aortas of rats with AIA. The endothelial dysfunction in AIA was improved by the in vivo or ex vivo treatment with AT 1 R blockers.Conclusion. The locally activated RAS is involved in the increased vascular oxidative stress and endothelial dysfunction in AIA. Our findings have important implications for clinical approaches to the reduction of cardiovascular risk in patients with rheumatoid arthritis.

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

“…To confirm that the abnormal response of vessels from AIA rats to ACh was not due to decreased response of vascular smooth muscle cells to NO, we demonstrated that the relaxing effect of the NO donor SNP was not impaired in the AIA rats. This result is in accordance with recent study findings in AIA rats (12,14,36) as well as in RA patients (37)(38)(39)(40). Likewise, we verified that the contractile response of vessels from AIA rats to NE was not different from that of control rats.…”

“…In the present study, we investigated endothelial function in the AIA model, which is commonly accepted as having many histologic and clinical features in common with human RA (31) and which is widely used to predict clinical efficacy of new therapies in RA (32). In accordance with previous studies (12)(13)(14)(15)(16)(33)(34)(35), our data show that endothelial function assessed by the vasodilating response to ACh is impaired in AIA rats. We also demonstrated that endothelial dysfunction correlates with disease activity.…”

“…Only a few studies have investigated the mechanisms involved in endothelial dysfunction in animal models of arthritis. In the model of adjuvant-induced arthritis (AIA), data demonstrated that vessels from AIA rats overproduced superoxide anions (O 2 Ϫ ) (12)(13)(14) and that BH 4 supplementation decreased endothelial dysfunction (12), suggesting that the deficiency in BH 4 may contribute to the uncoupling of eNOS and subsequent production of O 2 Ϫ . However, treatment with vitamin E used as an antioxidant both improved (15) and decreased (16) endothelial function in AIA rats.…”

Antiinflammatory effect of telmisartan on chronic obstructive pulmonary disease: 8-isoprostane concentration in exhaled breath condensate

“…Antiinflammatory effects of ARBs have been demonstrated in various clinical conditions as hypertension, radiation-related delayed inflammation, and inflammatory chronic hepatitis C [20][21][22]. In animal studies performed using ARBs, valsartan decreased inflammatory cell infiltration in bronchoalveolar lavage fluid in asthmatics, and losartan suppressed inflammatory processes in sepsis, and arthritis [23][24][25]. Gemici et al [26] detected antiinflammatory effects of candesartan in an animal model of ischemic reperfusion damage.…”

“…Many studies have demonstrated antiinflammatory effects of ARBs. In these studies also including telmisartan, favourable effects of ARBs have been displayed on diabetes mellitus and cardiovascular diseases which possess inflammatory properties [10][11][12][13][14]. ARBs are known to decrease inflammation, and oxidative stress which lead to complications in cardiovascular diseases, and diabetes mellitus [15].…”