title: Role of angiotensin II and reactive oxygen species in cyclosporine A-dependent hypertension.
abstract: Treatment with cyclosporine A (CysA), a potent immunosuppressive agent, is associated with systemic and renal vasoconstriction, leading to hypertension. The present study was conducted to elucidate the contribution of angiotensin II (Ang II) to CysA-induced hypertension and reactive oxygen species (ROS) generation. CysA (30 mg/kg per day SC), given for 3 weeks in rats, increased systolic blood pressure (SBP) from 119+/-2 to 145+/-3 mm Hg (n=7). Plasma and kidney Ang II levels were significantly higher in CysA-treated rats (136+/-10 fmol/mL and 516+/-70 fmol/g) than in vehicle-treated (1 mL olive oil) rats (76+/-10 fmol/mL and 222+/-21 fmol/g, n=7). CysA treatment increased AT1 receptor protein expression in the aorta (by 251+/-35%), whereas it was reduced in the kidney (by -32+/-4%). Superoxide anion production in aortic segments and kidney thiobarbituric acid-reactive substance (TBARS) contents were higher in CysA-treated rats (26+/-2 counts/min per milligram and 37+/-3 nmol/g) than in vehicle-treated rats (17+/-1 counts/min per milligram and 24+/-3 nmol/g). Concurrent administration of an AT1 receptor antagonist, valsartan (30 mg/kg per day, in drinking water), to CysA-treated rats (n=7) significantly decreased SBP (113+/-4 mm Hg) and prevented increases in vascular superoxide (16+/-2 counts/min per milligram) and kidney TBARS contents (21+/-3 nmol/g). Similarly, treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6,-tetramethylpiperidine-N-oxyl (Tempol; 3 mmol/L in drinking water, n=7), prevented CysA-induced increases in SBP (115+/-3 mm Hg), vascular superoxide (16+/-1 counts/min per milligram), and kidney TBARS contents (19+/-2 nmol/g). These data suggest that ROS generation induced by augmented Ang II levels contributes to the development of CysA-induced hypertension.
authors.affiliation: Department of Pharmacology, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. akira@kms.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: Toshiki
authors.initials: T
authors.lastname: Fukui
authors.forename: Guo-Xing
authors.initials: GX
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Yao
authors.forename: Matlubur
authors.initials: M
authors.lastname: Rahman
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Kiyomoto
authors.forename: Takatomi
authors.initials: T
authors.lastname: Shokoji
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Youichi
authors.initials: Y
authors.lastname: Abe
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure; D003404:Creatinine / Q000097:blood; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016572:Cyclosporine / Q000633:toxicity*; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008297:Male; D011507:Proteinuria / Q000175:diagnosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D012084:Renin-Angiotensin System; D013113:Spin Labels; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D057911:Angiotensin Receptor Antagonists; D000975:Antioxidants; D003497:Cyclic N-Oxides; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D013113:Spin Labels; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D016572:Cyclosporine; D003404:Creatinine; D014633:Valine; C001803:tempol