Losartan Preserves Erectile Function After Bilateral Cavernous Nerve Injury via Antifibrotic Mechanisms in Male Rats
Losartan Preserves Erectile Function After Bilateral Cavernous Nerve Injury via Antifibrotic Mechanisms in Male Rats
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DOI：
10.1016/j.juro.2009.01.097
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发表时间：
2009-06-01
影响因子：
6.6
通讯作者：
Burnett, Arthur L.
中科院分区：
文献类型：
--
作者：
Canguven, Onder;Lagoda, Gwen;Burnett, Arthur L.
目的：血管紧张素II是一种已知的平滑肌血管收缩和纤维化介质。它上调血小板反应蛋白-1，一种潜在转化生长因子-β的主要激活剂。转化生长因子-β通过细胞内SALAD信号通路诱导血管纤维化。我们评估了血管紧张素11 1型受体拮抗剂氯沙坦对大鼠双侧海绵体神经损伤后勃起功能的影响。材料和方法：将36只成年雄性大鼠随机分为6组，每组10只，其中假手术组（假手术组）仅暴露海绵体神经并给予溶剂，假手术组（假手术组）给予小剂量氯沙坦（10 mg/kg/天），组3-假手术加高剂量氯沙坦（40 mg/kg/天），组4-双侧海绵体神经损伤（使用止血钳挤压3分钟）加媒介物，组5-双侧海绵体神经损伤加低剂量氯沙坦和组6-双侧海绵体神经损伤加高剂量氯沙坦。术后7天，通过电刺激海绵体神经和监测海绵体内压来测量勃起功能。结果：双侧海绵体神经损伤后阴茎勃起功能较假手术后明显下降（P <0.01），而双侧海绵体神经损伤后阴茎勃起功能明显下降（P < 0.01），阴茎勃起功能下降（P < 0.01）。与溶剂对照组相比，低剂量和高剂量氯沙坦在双侧海绵体神经损伤后保留了勃起功能（分别为p < 0.01和p < 0.05）。阴茎海绵体神经损伤后，纤维连接蛋白、pSMAD 2、pSMAD 3、转化生长因子β 1、血小板反应蛋白1和α-肌动蛋白表达上调，总SMAD 2和SMAD 3表达下调。结论：双侧海绵体神经损伤后，阴茎组织纤维化激活物可能导致阴茎勃起功能下降，其中纤维连接蛋白（FN）、pSMAD 2（p <0.05）和血小板反应蛋白-1（p <0.05）的表达上调，总SMAD 2表达上调。血管紧张素II 1型受体拮抗剂可能会抵消这种作用，并促进勃起功能的保护与阴茎纤维化的条件。
Purpose: Angiotensin II is a known mediator of smooth muscle vasoconstriction and fibrosis. It up-regulates thrombospondin-1, a major activator of latent transforming growth factor-beta. Transforming growth factor-beta induces vascular fibrosis via intracellular SALAD signaling pathways. We evaluated the effect of treatment with the angiotensin 11 type 1 receptor antagonist losartan on erectile function in the rat following bilateral cavernous nerve injury.Materials and Methods: A total of 36 adult male rats were divided equally into 6 groups, including group 1-sham surgery with cavernous nerve exposure only plus vehicle, group 2-sham surgery plus oral low dose losartan (10 mg/kg per day), group 3-sham surgery plus high dose losartan (40 mg/kg per day), group 4-bilateral cavernous nerve injury (3-minute crush using a hemostat clamp) plus vehicle, group 5-bilateral cavernous nerve injury plus low dose losartan and group 6-bilateral cavernous nerve injury plus high dose losartan. Seven days following surgery erectile function was measured by electrically stimulating the cavernous nerves and monitoring intracavernous pressure. Penile tissue was collected for Western blot analysis of fibronectin, transforming growth factor-beta, thrombospondin-1, alpha-actin, and phosphorylated and total SMAD2 and SMAD3 expression.Results: Erectile function was significantly decreased after bilateral cavernous nerve injury compared with that after sham surgery (p < 0.01). Low and high dose losartan preserved erectile function after bilateral cavernous nerve injury compared to that in vehicle controls (p < 0.01 and < 0.05, respectively). Fibronectin, pSMAD2, pSMAD3, transforming growth factor-beta-1, thrombospondin-1 and alpha-actin expression was up-regulated, and total SMAD2 and SMAD3 expression was down-regulated in the penis after bilateral cavernous nerve injury. Each dose of losartan after bilateral cavernous nerve injury significantly attenuated the upregulated expression of fibronectin (p < 0.01), pSMAD2 (p < 0.05) and thrombospondin-1 (p < 0.05), and up-regulated total SMAD2 (p < 0.05).Conclusions: These data suggest that fibrotic activators in the penis may cause decreased erectile function after bilateral cavernous nerve injury. Angiotensin II type 1 receptor antagonism may counteract this effect and promote erectile function preservation for conditions associated with penile fibrosis.