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

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)754-760
Number of pages7
JournalHypertension
Volume42
Issue number4
DOIs
Publication statusPublished - 2003 Oct

Keywords

  • Angiotensin antagonist
  • Antioxidants
  • Receptors, angiotensin II
  • Renin

ASJC Scopus subject areas

  • Internal Medicine

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