We have reported previously that the nitric oxide (NO) donor FK409 {(±)-( E )-4-ethyl-2-[( E )-hydroxyimino]-5-nitro-3-hexanamide} improved renal dysfunction as well as renal lesions in rats with ischaemia/reperfusion injury. We also found that FK409 substantially reduced endothelin-1 (ET-1) production in cultured vascular endothelial cells (ECs). Nuclear factor κB (NF-κB) is known to play a key role in the development of ischaemic disorders through regulation of the expression of a variety of genes. In the present study, we examined the effects of FK409 on ET-1 production in cultured pig aortic ECs, and the possible involvement of NF-κB in the inhibitory effect of NO on ET-1 production. FK409 significantly attenuated basal and tumour necrosis factor-α (TNF-α)-induced preproET-1 mRNA expression in ECs. In addition, FK409 diminished basal and TNF-α-stimulated NF-κB activation in ECs. Pretreatment with N -benzyloxycarbonyl-Ile-Glu( O - t -Bu)-Ala-leucinal or BAY 11-7082, both of which are suppressors of NF-κB activation, effectively attenuated basal and TNF-α-induced ET-1 mRNA expression. These findings suggest that the suppression of NF-κB activation is at least partly involved in the FK409-induced inhibition of ET-1 production in ECs. We propose that NF-κB activation plays an important role in ET-1 production.

We investigated whether the treatment with 17β-oestradiol has renal protective effects in male rats with ischaemic acute renal failure (ARF). We also examined if the effect of 17β-oestradiol is accompanied by suppression of enhanced endothelin-1 production in postischaemic kidneys. Ischaemic ARF was induced by clamping the left renal artery and vein for 45min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine and creatinine clearance were measured to test the effectiveness of the steroid hormone. Renal function in ARF rats markedly decreased 24h after reperfusion. The ischaemia/reperfusion-induced renal dysfunction was dose-dependently improved by pretreatment with 17β-oestradiol (20 or 100 µ g/kg, intravenously). Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were markedly improved by the higher dose of 17β-oestradiol. In addition, endothelin-1 content in the kidney after the ischaemia/reperfusion increased significantly by approx. 2-fold over sham-operated rats, and this elevation was dose-dependently suppressed by the 17β-oestradiol treatment. These results suggest that oestrogen exhibits protective effects against renal dysfunction and tissue injury induced by ischaemia/reperfusion, possibly through the suppression of endothelin-1 overproduction in postischaemic kidneys.