FK506 and sildenafil promote erectile function recovery after cavernous nerve injury through antioxidative mechanisms
FK506 and sildenafil promote erectile function recovery after cavernous nerve injury through antioxidative mechanisms
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DOI：
10.1111/j.1743-6109.2007.00519.x
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发表时间：
2007-07-01
影响因子：
3.5
通讯作者：
Burnett, Arthur L.
中科院分区：
文献类型：
--
作者：
Lagoda, Gwen;Jin, Liming;Burnett, Arthur L.
导论.亲免疫素配体和磷酸二酯酶5型（PDE 5）抑制剂被吹捧为促进海绵体神经（CN）损伤后勃起功能的恢复。然而，其作用机制仍不清楚。比较CN损伤后亲免素配体FK 506和PDE 5抑制剂西地那非的勃起恢复作用，并确定它们是否涉及抗氧化和/或抗凋亡机制。最初的实验在成年雄性Sprague-Dawley大鼠中建立了我们的CN损伤模型的条件。随后，我们在以下14天后评价治疗效果：（i）单侧CN损伤（UNI）+盐水（媒介物对照）;（ii）UNI + FK 506（5 mg/kg，每日一次，皮下x5天）;（iii）UNI +西地那非（20 mg/kg，每8小时，皮下x7天）;（iv）UNI + FK 506/西地那非;和（v）假手术。CN电刺激后测量阴茎海绵体内压（ICP）以评估勃起功能，Western blot分析阴茎中谷胱甘肽过氧化物酶（GPX;抗氧化酶）、硝基酪氨酸（NT;氧化应激标记物）、磷酸化Akt和总Akt（抗凋亡因子）的表达。在UNI模型中，GPX表达在第1天和第7天增加，而p-Akt表达在第1天降低并在第7天恢复至基线。UNI + FK 506组GPX表达明显高于生理盐水组（P < 0.05）。各治疗组与生理盐水治疗组相比，ICP均升高（P < 0.05）。生理盐水处理后NT水平升高（P < 0.05），但FK 506和西地那非单独或联合处理后NT水平均未升高。GPX定位于阴茎神经、阴茎背静脉和动脉的平滑肌和内皮。FK 506和西地那非均通过减少氧化应激相关组织损伤保护CN损伤后的勃起功能。FK 506可能通过增加GPX活性发挥作用。需要进一步的研究来阐明与西地那非有益作用相关的机制。
Introduction. Immunophilin ligands and phosphodiesterase type 5 (PDE5) inhibitors are touted to promote erectile function recovery after cavernous nerve (CN) injury. However, the mechanisms for their effects remain unclear.Aim. To compare the erection recovery effects of the immunophilin ligand FK506 and the PDE5 inhibitor sildenafil after CN injury and determine whether they involve antioxidative and/or antiapoptotic mechanisms.Methods. Initial experiments established conditions of our CN injury model in adult male Sprague-Dawley rats. Subsequently, we evaluated treatment effects 14 days after: (i) unilateral CN injury (UNI) + saline (vehicle control); (ii) UNI + FK506 (5 mg/kg once daily, subcutaneous x5 days); (iii) UNI + sildenafil (20 mg/kg every 8 hours, subcutaneous x7 days); (iv) UNI + FK506/sildenafil; and (v) sham surgery.Main Outcome Measures. Intracavernous pressure (ICP) measurement after CN electrical stimulation to assess erectile function and Western blot analysis of expressions of glutathione peroxidase (GPX; antioxidant enzyme), nitrotyrosine (NT; oxidative stress marker), and phosphorylated and total Akt (antiapoptotic factor) in penes.Results. In the UNI model, GPX expression was increased at Days 1 and 7, while p-Akt expression decreased at Day 1 and returned to baseline at Day 7. GPX expression was significantly higher in the UNI + FK506 group compared with the saline-treated group (P < 0.05). ICP increased in all treatment groups compared with that of the saline-treated group (P < 0.05). NT levels were increased after saline treatment (P < 0.05) but not after FK506 and sildenafil treatment, alone or in combination. GPX was localized to nerves coursing through the penis and to smooth muscle and endothelium of the dorsal vein and arteries.Conclusions. Both FK506 and sildenafil protect erectile function after CN injury by decreasing oxidative stress-associated tissue damage. FK506 may act through increased GPX activity. Further research is required to elucidate mechanisms associated with the beneficial effect of sildenafil.