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(Hypertension. 2003;42:754.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Role of Angiotensin II and Reactive Oxygen Species in Cyclosporine A–Dependent Hypertension

Akira Nishiyama; Hiroyuki Kobori; Toshiki Fukui; Guo-Xing Zhang; Li Yao; Matlubur Rahman; Hirofumi Hitomi; Hideyasu Kiyomoto; Takatomi Shokoji; Shoji Kimura; Masakazu Kohno; Youichi Abe

From the Department of Pharmacology (A.N., G.-X.Z, L.Y., M.R., H.H., S.K., Y.A.) and the Second Department of Internal Medicine (T.F., H.Kiyomoto, T.S., M.K.), Kagawa Medical University, Kagawa, Japan; and the Department of Physiology (H.Kobori), Tulane University Health Sciences Center, New Orleans, La.

Correspondence to Akira Nishiyama, MD, PhD, Department of Pharmacology, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. E-mail akira{at}kms.ac.jp

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.

Key Words: angiotensin antagonist • antioxidants • receptors, angiotensin II • renin

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