Protective effect of nitric oxide on ischemia/reperfusion-induced renal injury and endothelin-1 overproduction.
To elucidate the role of nitric oxide (NO) in the pathogenesis of ischemic acute renal failure, we examined the effects of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409) and N(G)-nitro-L-arginine methyl ester (L-NAME) as a NO donor and a non-selective NO synthase inhibitor on ischemia/reperfusion-induced renal injury and renal endothelin-1 content. Ischemic acute renal failure 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 acute renal failure rats markedly decreased and histological examination revealed severe renal damage. In addition, increases in renal endothelin-1 contents were evident in the acute renal failure rats at 2, 6, and 24 h after reperfusion, respectively. Pretreatment with FK409 (1 or 3 mg/kg, i.v.) attenuated ischemia/reperfusion-induced renal dysfunction, histological damage, and endothelin-1 overproduction after reperfusion. In contrast, pretreatment with L-NAME (1 or 10 mg/kg, i.v.) aggravated renal injuries of acute renal failure rats at 24 h after reperfusion, and the effect is accompanied by further increases in the renal endothelin-1 content at 2 and 6 h, but not at 24 h, after reperfusion. These results suggest that suppressive effects of NO on the renal endothelin-1 overproduction induced by ischemia/reperfusion in an early phase are probably responsible for the protective effect of NO against ischemic acute renal failure.
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Hayato
H
Kurata
Masanori
M
Takaoka
Yasuhiro
Y
Kubo
Tomoaki
T
Katayama
Hidenobu
H
Tsutsui
Junji
J
Takayama
Mamoru
M
Ohkita
Yasuo
Y
Matsumura
D000818:Animals; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000096:biosynthesis*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015427:Reperfusion Injury / Q000503:physiopathology*; D013997:Time Factors
D019332:Endothelin-1; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D020011:Protective Agents; D009569:Nitric Oxide; C061872:FK 409; D019331:NG-Nitroarginine Methyl Ester