Effects of pre- and post-ischemic treatments with FK409, a nitric oxide donor, on ischemia/reperfusion-induced renal injury and endothelin-1 production in rats.
We have demonstrated that ischemic acute renal failure (ARF) is attenuated by pre-ischemic treatment with a spontaneous nitric oxide (NO) donor, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409). In the present study, we evaluated the effect of post-ischemic treatment with FK409 on ARF, compared with the pre-ischemic treatment effect. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 h after reperfusion, renal function in untreated ARF rats markedly decreased. In addition, increases in renal contents of endothelin-1 (ET-1), a deleterious mediator in the pathogenesis of ischemic ARF, were evident in untreated ARF rats at 24 h after reperfusion. Pre-ischemic treatment with FK409 (1 or 3 mg/kg, i.v.) at 5 min before ischemia attenuated ischemia/reperfusion-induced renal dysfunction and increased ET-1 contents after reperfusion. In contrast, post-ischemic treatment with FK409 (3 or 10 mg/kg, i.v.) at 6 h after reperfusion aggravated the renal injury, but did not affect the increased ET-1 content after reperfusion. These results suggest that pre-ischemic treatment with FK409 exerts renoprotective effects on ischemic ARF, probably through the suppression of renal ET-1 overproduction, whereas post-ischemic treatment with the NO donor worsens the ischemia/reperfusion-induced renal injury, through mechanisms unrelated to the ET-1 production after reperfusion.
Nakajima
Atsushi
A
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
Ueda
Kyoko
K
Takaoka
Masanori
M
Kurata
Hayato
H
Takayama
Junji
J
Ohkita
Mamoru
M
Matsumura
Yasuo
Y
D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D019332:Endothelin-1 / Q000096:biosynthesis*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control*
D019332:Endothelin-1; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; C061872:FK 409; D003404:Creatinine