Endothelial rehabilitation: The impact of chronic PDE5 inhibitors on erectile function and protein alterations in cavernous tissue of diabetic rats

Background: Diabetic men generally have reduced efficacy with PDE-5 inhibitors (PDE5i) for the treatment of erectile dysfunction (ED). Objective: To determine whether chronic vardenafil exposure alters cavernous protein expression predicting improved erectile function in diabetes. Design: Forty-two adult male Sprague Dawley rats with streptozotocin-induced (SO mg/kg IP) diabetes for 4 wk, were exposed to either vehicle or vardenafil for 6 wk. Assessments compared the impact of vardenafil given at 1 h and 20 h to erectile function and cellular alterations and downstream translation of cavernous protein profiles were aimed. Intervention: Vehicle or vardenafil 0.5 mg/kg/day by oral gavage for 6 wk. Measurements: Erectile function, penile tissue morphology, protein expression and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI) protein profiling were determined. Results and Limitations: A significant increase of intracavernous pressure was seen in both treatment arms compared to diabetic rats not receiving vardenafil. Immunohistochemical staining showed improved endothelial and smooth muscle cell staining with chronic vardenafil use. Western blot analysis demonstrated increased endothelial cell eNOS and smooth muscle a-actin protein content. SELDI protein profiling showed enhanced proteins expression at molecular weights of 14.7, 20, 41.9, 66.2, and 83.9 kDa in the chronically treated vardenafil group. Conclusions: Vardenafil was effective in treating diabetic-induced ED with the greatest effect achieved through chronic dosing, with no additive effect measured with the final acute dose. Changes noted in the histology and protein expression indicate that vardenafil may have a protective effect in this disease state. This finding may serve as a basis for further work evaluating the utility of chronic vardenafil dosing in diabetic men. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.