Losartan Preserves Erectile Function After Bilateral Cavernous Nerve Injury via Antifibrotic Mechanisms in Male Rats

Abstract

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 SMAD signaling pathways. We evaluated the effect of treatment with the angiotensin II type 1 receptor antagonist losartan on erectile function in the rat following bilateral cavernous nerve injury. 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. 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 up-regulated expression of fibronectin (p <0.01), pSMAD2 (p <0.05) and thrombospondin-1 (p <0.05), and up-regulated total SMAD2 (p <0.05). 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.