title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Sakuta
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Morita
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: David A
authors.initials: DA
authors.lastname: Fox
authors.forename: Naoki
authors.initials: N
authors.lastname: Kashihara
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000453:epidemiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000502:physiology; D006984:Hypertrophy; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D040242:Risk Reduction Behavior; D013777:Tetrazoles / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000077405:Irbesartan; D019808:Losartan