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(Hypertension. 2003;41:1136.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Cyclosporin A Disrupts Bradykinin Signaling Through Superoxide

Michael Vetter; Zi-Jiang Chen; Geen-Dong Chang; Danian Che; Shiguo Liu; Chung-Ho Chang

From the Department of Medicine, Division of Hypertension, Case Western Reserve University (M.V., Z.-J.C., D.C., S.L., C.-H.C.), Cleveland, Ohio; the Department of Medicine, Reproductive Research Center, Shandong Provincial Hospital, Shandong University (Z.-J.C.), Jinan, Peoples Republic of China; and the Graduate Institute of Biological Sciences, National Taiwan University (G.-D.C.), Taipei, Taiwan.

Correspondence to Dr Chung-Ho Chang, Department of Medicine, Division of Hypertension, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Room W165, Cleveland, OH 44106. E-mail cxc13{at}po.cwru.edu

Cyclosporin A (CsA) is used to reduce transplant rejection rates. Chronic use, however, has a destructive toxic effect on the kidney, resulting in hypertension. In this study, we investigated the effects of CsA treatment on the bradykinin/soluble guanylate cyclase signaling cascade and the involvement of superoxide in LLC-PK1 porcine kidney proximal tubule cells. Treatment with 1 µmol/L CsA for 24 hours increased basal cGMP levels by 41%, whereas CsA inhibited bradykinin-stimulated cGMP production by 26%. Western blotting showed increased expression of eNOS, but no other protein in the bradykinin/soluble guanylate cyclase (sGC) pathway was affected. Using lucigenin-dependent chemiluminescence, we found that CsA treatment significantly increased superoxide production. Production of O₂^- was not significantly reduced by 10 µmol/L oxypurinol or 30 µmol/L ketoconazole. However, it was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium chloride (10 µmol/L) as well as the O₂^- scavenger superoxide dismutase (SOD) (100 U). On treatment with 50 µmol/L quercetin, 10 mmol/L N-acetyl-cysteine, both antioxidants, as well as the O₂^- scavenger Tiron (10 mmol/L), concomitant with 1 µmol/L CsA for 24 hours the activation of cGMP production, was restored in combination with a reduction in O₂^-. Incubation with 100 µmol/L menadione, a reactive oxygen generator, and 10 nmol/L bradykinin showed similar effects on the level of cGMP as with CsA. CsA treatment was found to increase nitrotyrosine levels. These findings suggest that CsA activates a NADPH oxidase that releases O₂^- and disrupts the bradykinin/soluble guanylate cyclase pathway, probably by binding with NO to form peroxynitrite (ONOO^-).

Key Words: cyclosporin • bradykinin • nitric oxide • cyclic GMP • antioxidants

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