Introduction

To investigate the mechanism of action of pioglitazone (Pio) on the major pelvic ganglion (MPG) and cavernous nerves in a rat model of bilateral cavernosal nerve crush injury (BCNI), to determine a clinically exploitable pathway to treat post-prostatectomy erectile dysfunction.

Methods

26 Sprague-Dawley rats weighing 350-400 grams were divided into four groups: (a) sham, (b) BCNI, (c) BCNI + postsurgical Pio, (d) BCNI + Pio + JB-1, an insulin-growth factor-1 (IGF-1) antagonist (JB). Sham and BCNI-only rats were treated with phosphate-buffered saline (PBS), and both Pio and JB rats received 14 days treatment of 6.5 mg Pio per day. PBS and Pio were administered by oral gavage. Sham, BCNI and Pio rats had osmotic mini pumps placed subcutaneously, which delivered saline. JB rats received 100 mg/kg JB-1 trifluoroacetate salt dissolved in saline, delivered by subcutaneous osmotic mini pump. After treatment, animals underwent surgery for endpoint cavernosal response to define hemodynamic parameters of erectile function, reported as the ratio of intracavernosal pressure to mean arterial pressure (ICP/MAP). The MPG and cavernosal nerves were resected at 2 weeks in all rats and processed for Western blot and immunohistochemistry to assess neuronal nitric oxide synthase (nNOS), IGF-1, and ERK 1/2.

Results

Animals treated with Pio after BCNI exhibited improvements in the ICP/MAP ratio, with the Pio group achieving results similar to the sham group. Animals treated with JB-1 in addition to Pio after BCNI achieved results similar to BCNI. At 7.5 V, the ICP/MAP data revealed: sham, 0.627; BCNI, 0.294; Pio, 0.582; JB, 0.286 (P < .05). Both 5V and 2.5 V demonstrated similar results. Western blot and immunohistochemistry results support the surgical data and indicate that Pio&[prime]s positive effects are mediated by intercellular IGF-1 signaling activity.

Conclusions

JB-1 reverses the beneficial effects of Pio on erectile function in rats undergoing BCNI, suggesting that Pio acts through IGF-1 signaling pathway.

Funding

None