NOX-100

We investigated whether nitric oxide (NO) exposure alters the balance between NO and endothelium-derived hyperpolarizing factor (EDHF) released from rat renal arteries. To produce states of acutely or chronically excessive NO, lipopolysaccharide (LPS) was administered intraperitoneally to rats in a single dose of 4 mg/kg (LPS-single group) or in stepwise doses of 0.5, 1.0 and 2.0 mg/kg every other day (LPS-repeated group). On the day after LPS treatment, the protein levels of inducible NO synthase (iNOS) and endothelial NOS (eNOS) were measured, and the relaxation responses were determined in the renal arteries. The protein levels of iNOS markedly increased in both LPS-treated groups, while those of eNOS significantly increased in the LPS-repeated group compared with those in the respective control groups. In both LPS-treated groups, the relaxations in response to acetylcholine (ACh) and sodium nitroprusside remained unchanged. The ACh-induced relaxations in the presence of N(G)-nitro-L-arginine methyl ester, a NOS inhibitor, or by 1H-[1, 2, 4-] oxadiazole [4, 3-a] quinoxalin-1-one, a soluble guanylyl cyclase inhibitor, i.e. EDHF-mediated relaxations were significantly impaired in the LPS-repeated group but not in the LPS-single group, indicating increase in NO-mediated relaxation in the LPS-repeated group. These changes in the protein levels and EDHF-mediated relaxations induced by ACh observed in the LPS-repeated group were restored by treatment with NOX-100, a NO scavenger. These results suggest that persistent but not acute excessive NO exposure in rats impairs EDHF-mediated relaxation in renal arteries, leading to a compensatory upregulation of the eNOS/NO pathway.

Immunotherapy improves experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), while excessive production of nitric oxide (NO) has been implicated in the pathogenesis of this disease. Here, we show that disease progression in SJL/J mice with EAE is improved after treatment with either a subtherapeutic dose of cyclosporine A (CsA) or NOX-100, a nitric oxide scavenger. Importantly, the impact of subtherapeutic doses of CsA in combination with NOX-100 on disease progression in EAE was greater than that attained with either agent alone and led to near total protection. CNS inflammation and gene expression of proinflammatory cytokines and iNOS were also significantly reduced after treatment. These observations point to the potential therapeutic utility of NOX-100 as a dose-reducing agent for CsA in the treatment of MS.