Inhibition of endothelial derived relaxing factor (EDRF) aggravates ischemic acute renal failure in anesthetized rats

Abstract

The relative importance of endothelial derived relaxing factor (EDRF)/nitric oxide (NO) in maintaining kidney function in normal condition and in acute renal failure (ARF) were evaluated in inactin anesthetized rats. ARF was induced by unilateral occlusion of the left renal artery (40 min) followed by reperfusion, with the contralateral kidney serving as normal control. This protocol resulted in marked reductions in renal plasma flow (RPF), glomerular filtration rate (GFR) and increases in fractional sodium excretion (FENa) and urinary protein excretion in the post-ischemic kidney in comparison to the contralateral normal kidney. Administration of the nitric oxide (NO) synthase inhibitor NG--monomethyl-L-arginine (0.25 mg/kg per min, L-NMMA) exacerbated the ischemia-induced changes in renal functions as reflected by further reductions in urine flow (V), GFR, marked sodium wasting and renal edema. Pretreatment of the animals with NO precursor L-arginine (2.5 mg/kg per min, L-Arg) abolished the detrimental effects of L-NMMA in ARF. In contrast, D-Arginine (2.5 mg/kg per min, D-Arg) failed to reverse the detrimental effects of L-NMMA. Infusion of L-Arg alone also resulted in improvements in RPF and GFR in the ischemic kidney. The results of the present study suggest that the function of the ischemic kidney is sustained by EDRF/NO and is thus more sensitive to NO synthase inhibition.

RETRACTION: Opposite Effects of Pre- and Postischemic Treatments with Nitric Oxide Donor on Ischemia/Reperfusion-Induced Renal Injury

“…Several studies have demonstrated that endogenous or exogenous NO protects the kidney against ischemia/reperfusion injury (Chintala et al, 1993;Schramm et al, 1994;Linas et al, 1997). Most recently, we noted that both exogenous and endogenous NO have protective effects Fig.…”

“…Furthermore, the inhibition of NO synthase (NOS) was seen to aggravate the postischemic ARF (Chintala et al, 1993), thereby suggesting the renoprotective role of endogenous NO in this disease. On the other hand, NO may be deleterious because of its reactivity with oxygen free radicals produced during reperfusion of the ischemic kidney to yield toxic products, such as peroxynitrates (Pryor and Squadrito, 1995).…”

“…Ischemia, followed by reperfusion, is one of the major causes of ARF (Thadhani et al, 1996). Various in vivo studies have indicated that NO biosynthesis and its action are closely related to the pathogenesis of ischemia/reperfusion-induced ARF (Conger et al, 1988(Conger et al, , 1991Chintala et al, 1993;Schramm et al, 1994;Pryor and Squadrito, 1995). Conger et al (1988Conger et al ( , 1991 demonstrated that decreased endothelium-dependent vasorelaxation and NO production were related to an impaired renal function observed after ischemia/reperfusion.…”

Effects of sodium nitrite on ischemia-reperfusion injury in the rat kidney

“…The administration of NO donors such as sodium nitroprusside, molsidomine, and FK-409 is beneficial in renal I/R injury (19,24,31,42). L-Arginine supplementation and NOS inhibitors have shown varying results (4,24,37,41,43,50). Inhibition of iNOS using antisense oligonucleotides is beneficial in renal I/R injury (37).…”

Retraction：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

“…7) In contrast, in vivo studies have shown a beneficial effect of NO in ischemic ARF models: the inhibition of NO production with a non-selective NOS inhibitor significantly deteriorated renal function of ischemic ARF rats, whereas the NOS inhibitor-induced renal dysfunction was abolished by L-arginine. 8) We have also found that renal dysfunction in ischemic ARF rats is markedly attenuated by pre-ischemic treatment with (Ϯ)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409), a NO donor, thereby suggesting that pre-ischemic treatment with the NO donor has a protective effect against renal injury in vivo models of ischemic ARF 9) ; however, it is unclear whether post-ischemic treatment with a NO donor could suppress the ischemia/reperfusion-induced renal dysfunction.…”