Abstract
Objectives
Oxidative or glyco-oxidative stress-induced activation of the transcription factor, nuclear factor (NF)-¿B, is associated with the neurovascular complications of diabetes mellitus. Antioxidant treatment has beneficial effects in diabetic patients; however, delineating a possible role for NF-¿B deactivation against direct antioxidant effects has been difficult. NF-¿B is negatively regulated by the inhibitor of ¿B (I¿B) complex that, in turn, is activated by specific kinases. Thus, the aim was to investigate the effects of the I¿B 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 I¿B 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 I¿B kinase 2 can correct nitric oxide-dependent indexes of diabetic erectile dysfunction. This suggests that NF-¿B activation is important in the development of diabetic cavernosum nitrergic neuropathy and vasculopathy.
Oxidative or glyco-oxidative stress-induced activation of the transcription factor, nuclear factor (NF)-¿B, is associated with the neurovascular complications of diabetes mellitus. Antioxidant treatment has beneficial effects in diabetic patients; however, delineating a possible role for NF-¿B deactivation against direct antioxidant effects has been difficult. NF-¿B is negatively regulated by the inhibitor of ¿B (I¿B) complex that, in turn, is activated by specific kinases. Thus, the aim was to investigate the effects of the I¿B 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 I¿B 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 I¿B kinase 2 can correct nitric oxide-dependent indexes of diabetic erectile dysfunction. This suggests that NF-¿B activation is important in the development of diabetic cavernosum nitrergic neuropathy and vasculopathy.
| Original language | English |
|---|---|
| Pages (from-to) | 214-218 |
| Number of pages | 5 |
| Journal | Urology |
| Volume | 68 |
| Issue number | 1 |
| Early online date | 27 Jun 2006 |
| DOIs | |
| Publication status | Published - Jul 2006 |
Bibliographical note
To Dr. Michel Dreano of Serono International SA for the gift of AS602868 and helpful discussions.Keywords
- FACTOR-KAPPA-B
- ALPHA-LIPOIC ACID
- SMOOTH-MUSCLE
- OXIDATIVE STRESS
- ALDOSE REDUCTASE
- RELAXATION
- ACTIVATION
- CELLS
- RATS
- VASODILATION
