Rectification of cavernosal fibrosis and veno‐occlusive dysfunction by administration of suberoylanilide hydroxamic acid in a rat model of cavernosal nerve injury: Comparison with a PDE5 inhibitor

Abstract

Cavernosal fibrosis, which is induced by cavernosal nerve (CN) injury and progresses with time, is the main cause of cavernosal veno-occlusive dysfunction (CVOD) after radical prostatectomy. To determine whether daily oral administration of suberoylanilide hydroxamic acid (SAHA; vorinostat) for 5-weeks from the immediate post-injury period after CN injury would rectify CVOD by suppressing cavernosal fibrosis and normalizing HDAC pathway in a rat model of CN crush injury (CNCI) and to compare the results with those obtained using chronic administration of PDE5-inhibitors (a positive control). Fifty-six 12-week-old rats were randomized into the four groups: sham surgery (S), CNCI (I), and CNCI treated with daily administration of 25.0mg/kg SAHA (V) or 20.0mg/kg udenafil (P). Group-V and Group-P received the respective treatment for 5-weeks from the following day after CNCI. At 5weeks after surgery, dynamic infusion cavernosometry (DIC), histological staining, and Western blot analysis were performed. Group-I had a significantly decreased papaverine response, higher maintenance rate or drop rate, lower smooth muscle (SM)/collagen ratio, decreased SM content, and increased protein expression of HDAC2, HDAC3, TGF-β1, and collagen-1, compared with Group-S. The three DIC parameters in Group-V and Group-P significantly improved compared to those in Group-I. Except for the maintenance rate, the improvement in papaverine response and drop rate in Group-V was not significantly different from that in Group-P. Group-V and Group-P showed the rectification of SM/collagen ratio and protein expression of TGF-β1 or collagen-1. SM content was improved in Group-P, but not in Group-V. Group-V showed the normalization of protein expression of both HDAC2 and HDAC3, whereas protein expression of only HDAC2 was partially restored in Group-P. Treatment strategies targeting the HDAC pathway might be helpful to alleviate CVOD induced by CN injury. According to our data, chronic administration of SAHA improves post-injury CVOD by suppressing cavernosal fibrosis via rectifying the HDAC/TGF-β1 pathway in nerve-injured rats, comparable to that with PDE5 inhibitors.