title: IkappaB kinase 2 inhibition corrects defective nitrergic erectile mechanisms in diabetic mouse corpus cavernosum.
abstract: OBJECTIVE
  Oxidative or glyco-oxidative stress-induced activation of the transcription factor, nuclear factor (NF)-kappaB, is associated with the neurovascular complications of diabetes mellitus. Antioxidant treatment has beneficial effects in diabetic patients; however, delineating a possible role for NF-kappaB deactivation against direct antioxidant effects has been difficult. NF-kappaB is negatively regulated by the inhibitor of kappaB (IkappaB) complex that, in turn, is activated by specific kinases. Thus, the aim was to investigate the effects of the IkappaB kinase 2 inhibitor, AS602868, on corpus cavernosum function in diabetic mice.
  
  
  METHODS
  Diabetes 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.
  
  
  RESULTS
  The 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 IkappaB 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.
  
  
  CONCLUSIONS
  Inhibition of IkappaB kinase 2 can correct nitric oxide-dependent indexes of diabetic erectile dysfunction. This suggests that NF-kappaB activation is important in the development of diabetic cavernosum nitrergic neuropathy and vasculopathy.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen School of Medical Sciences, Foresterhill, Aberdeen, Scotland, United Kingdom.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nangle
authors.forename: Mary A
authors.initials: MA
authors.lastname: Cotter
authors.forename: Norman E
authors.initials: NE
authors.lastname: Cameron
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006145:Guanethidine / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D016328:NF-kappa B / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010410:Penile Erection / Q000502:physiology*; D010413:Penis / Q000098:blood supply / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D020030:Nitric Oxide Donors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D001285:Atropine; D051550:I-kappa B Kinase; D006145:Guanethidine