title: Opposite effects of pre- and postischemic treatments with nitric oxide donor on ischemia/reperfusion-induced renal injury.
abstract: We have demonstrated previously that preischemic treatment with FK409 [(+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide], a spontaneous nitric oxide (NO) donor, markedly improves ischemia/reperfusion-induced renal injury. However, there is conflicting information (renoprotective or cytotoxic) as to the contribution of NO to ischemic acute renal failure (ARF). In the present study, we investigated the effect of postischemic treatment with FK409 (1, 3, and 10 mg/kg i.v.) at 6 h after reperfusion on ischemic ARF, in comparison with the preischemic treatment effect. Ischemic ARF was induced by clamping of the left renal artery and vein for 45 min, followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in ARF rats markedly decreased at 24 h after reperfusion. Histopathological examination of the kidney of ARF rats revealed severe renal damage. In contrast to the renoprotective effect by preischemic treatment, postischemic treatment with FK409 aggravated the ischemia/reperfusion-induced renal dysfunction and histological damage. Immunohistochemical analysis of renal sections obtained from ARF rats revealed positive staining for nitrotyrosine, a biomarker of peroxynitrite formation, in injured tubular cells, and more intense staining was observed in renal tissues from the animals that received postischemic treatment with FK409. On the other hand, the formation of nitrotyrosine, neutrophil infiltration into renal tissues, and renal superoxide production, all of which were enhanced in ARF rats, were efficiently attenuated by the preischemic treatment with FK409. These results demonstrate that, although preischemic treatment with an NO donor is renoprotective, postischemic treatment with the same agent aggravates the ischemia/reperfusion-induced renal injury, probably through peroxynitrite overproduction.
authors.affiliation: Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ueda
authors.forename: Masanori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yoshimi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D058186:Acute Kidney Injury / Q000517:prevention & control*; D000818:Animals; D001806:Blood Urea Nitrogen; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D009574:Nitro Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications* / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
chemical_list: D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; C061872:FK 409; D052247:Nitric Oxide Synthase Type II