Chronic treatment with a type 5 phosphodiesterase inhibitor suppresses apoptosis of corporal smooth muscle by potentiating Akt signalling in a rat model of diabetic erectile dysfunction

Objectives: To examine whether chronic treatment with a type 5 phosphodiesterase inhibitor (PDE5I) could suppress corporal apoptosis via potentiation of Akt signalling in diabetic erectile dysfunction. Methods: Sprague-Dawley rats (12 wk old) were divided into three groups (n = 12 in each): normal control, diabetes (DM), and diabetes treated with PDE5I (DM+PDE5I). The rats in the diabetic groups received a single injection of streptozotocin (50 mg/kg), and from 8 wk after establishment of diabetes, DM and DM+PDE5I were treated with vehicle and PDE5I (SK-3530, 10 mg/kg), respectively, for 4 wk. After 12 wk of streptozotocin injections, six rats in each group underwent cavernosometry with cavernous nerve electrostimulation (2 V, 0.2 ms, 50 s, 2.5-20 Hz). The penile tissues from the remaining six rats were used for immunohistochemical evaluation of apoptosis, immunoblotting for the phosphorylation of Akt and its downstream molecule Bad, and a colorimetric assay of caspase activity. Results: Rats in the DM group showed markedly lower erectile parameters than those in the control group, whereas rats in the DM+PDE5I group showed normalized results. Despite persistent hyperglycaemia, PDE5I treatment significantly reduced the mean apoptotic index (39.6 +/- 4.6 vs. 21.3 +/- 1.7, p < 0.05). Densitometry revealed significantly higher levels of Akt and Bad phosphorylation, implying inhibition of pro-apoptotic stimuli. PDE5I treatment also significantly inhibited the activities of cavernosal caspase 3 and caspase 9, the main effectors of apoptosis. Conclusions: Chronic treatment with PDE5I activated Akt signalling, which suppressed pro-apoptotic stimuli and maintained erectile function in rat model of diabetic erectile dysfunction. (c) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.