Nitric oxide inhibits endothelin-1 production through the suppression of nuclear factor κB

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-I (ET-1) production in cultured vascular endothelial cells (ECs). Nuclear factor kappaB (NF-kappaB) 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-kappaB in the inhibitory effect of NO on ET-1 production. FK409 significantly attenuated basal and tumour necrosis factor-alpha (TNF-alpha)-induced preproET-1 mRNA expression in ECs. In addition, FK409 diminished basal and TNF-alpha-stimulated NF-kappaB activation in ECs. Pretreatment with N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal or BAY II-7082, both of which are suppressors of NF-kappaB activation, effectively attenuated basal and TNF-alpha-induced ET-1 mRNA expression. These findings suggest that the suppression of NF-kappaB activation is at least partly involved in the FK409-induced inhibition of ET-1 production in ECs. We propose that NF-kappaB activation plays an important role in ET-1 production.