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

Matthew R Nangle, Mary A Cotter, Norman E Cameron

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)214-218
Number of pages5
JournalUrology
Volume68
Issue number1
Early online date27 Jun 2006
DOIs
Publication statusPublished - Jul 2006

Keywords

  • FACTOR-KAPPA-B
  • ALPHA-LIPOIC ACID
  • SMOOTH-MUSCLE
  • OXIDATIVE STRESS
  • ALDOSE REDUCTASE
  • RELAXATION
  • ACTIVATION
  • CELLS
  • RATS
  • VASODILATION

Cite this

IκB kinase 2 inhibition corrects defective nitrergic erectile mechanisms in diabetic mouse corpus cavernosum. / Nangle, Matthew R; Cotter, Mary A; Cameron, Norman E.

In: Urology, Vol. 68, No. 1, 07.2006, p. 214-218.

Research output: Contribution to journalArticle

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title = "IκB kinase 2 inhibition corrects defective nitrergic erectile mechanisms in diabetic mouse corpus cavernosum",
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.",
keywords = "FACTOR-KAPPA-B, ALPHA-LIPOIC ACID, SMOOTH-MUSCLE, OXIDATIVE STRESS, ALDOSE REDUCTASE, RELAXATION, ACTIVATION, CELLS, RATS, VASODILATION",
author = "Nangle, {Matthew R} and Cotter, {Mary A} and Cameron, {Norman E}",
note = "To Dr. Michel Dreano of Serono International SA for the gift of AS602868 and helpful discussions.",
year = "2006",
month = "7",
doi = "10.1016/j.urology.2006.01.065",
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T1 - IκB kinase 2 inhibition corrects defective nitrergic erectile mechanisms in diabetic mouse corpus cavernosum

AU - Nangle, Matthew R

AU - Cotter, Mary A

AU - Cameron, Norman E

N1 - To Dr. Michel Dreano of Serono International SA for the gift of AS602868 and helpful discussions.

PY - 2006/7

Y1 - 2006/7

N2 - 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.

AB - 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.

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KW - ALPHA-LIPOIC ACID

KW - SMOOTH-MUSCLE

KW - OXIDATIVE STRESS

KW - ALDOSE REDUCTASE

KW - RELAXATION

KW - ACTIVATION

KW - CELLS

KW - RATS

KW - VASODILATION

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DO - 10.1016/j.urology.2006.01.065

M3 - Article

VL - 68

SP - 214

EP - 218

JO - Urology

JF - Urology

SN - 0090-4295

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ER -