IκB kinase 2 inhibition corrects defective nitrergic erectile mechanisms in diabetic mouse corpus cavernosum

ObjectivesOxidative or glyco-oxidative stress-induced activation of the transcription factor, nuclear factor (NF)-κB, is associated with the neurovascular complications of diabetes mellitus. Antioxidant treatment has beneficial effects in diabetic patients; however, delineating a possible role for NF-κB deactivation against direct antioxidant effects has been difficult. NF-κB is negatively regulated by the inhibitor of κB (IκB) complex that, in turn, is activated by specific kinases. Thus, the aim was to investigate the effects of the IκB kinase 2 inhibitor, AS602868, on corpus cavernosum function in diabetic mice.MethodsDiabetes was induced by streptozotocin; the duration was 6 weeks. Intervention AS602868 treatment (100 mg/kg/day) was given for 2 weeks after 4 weeks of untreated diabetes. Corpora cavernosum were isolated in organ baths for measurement of agonist-evoked or electrical stimulation-evoked smooth muscle tensions.ResultsThe maximal nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was reduced approximately 30% by diabetes (P <0.001). AS602868 treatment completely reversed the deficit (P <0.001). Maximal nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 32% by diabetes (P <0.05). This was completely restored by IκB kinase 2 inhibition (P <0.01). Furthermore, AS602868 treatment also completely corrected (P <0.01) an approximate 20% diabetic deficit (P <0.001) in maximal endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside.ConclusionsInhibition of IκB kinase 2 can correct nitric oxide-dependent indexes of diabetic erectile dysfunction. This suggests that NF-κB activation is important in the development of diabetic cavernosum nitrergic neuropathy and vasculopathy.