ORIGINAL ARTICLE Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats I Kovanecz 1 , A Rambhatla 1 , M Ferrini 1,2 , D Vernet 1 , S Sanchez 1 , J Rajfer 1,2,3 and N Gonzalez-Cadavid 1,2,3 1 LA Biomedical Research Institute at Harbor-UCLA Medical Center, Urology Research Laboratory, Torrance, CA, USA; 2 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA and 3 Division of Urology, Harbour-UCLA Medical Center, Torrance, CA, USA It was recently reported in the rat that vardenafil given in a continuous long-term manner was successful in preventing smooth muscle fibrosis in the penile corpora cavernosa and corporal veno- occlusive dysfunction (CVOD) that occur following bilateral cavernosal nerve resection (BCNR), a model for human erectile dysfunction after radical prostatectomy. To expand on this finding and to determine whether this effect was common to other PDE5 inhibitors, and occurred in part by stimulation of the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2), male Fischer 344 rats (N ¼ 10/group) were subjected to either BCNR or unilateral cavernosal nerve resection (UCNR) and treated with sildenafil (20 mg kg 1 day 1 ) in the drinking water daily for 45 days. Additional BCNR groups received L-NIL (6.7 mg kg 1 day 1 ) as inhibitor of iNOS activity, with or without concurrent sildenafil administration. It was determined that sildenafil, like vardenafil, (1) prevented the 30% decrease in the smooth muscle cell/collagen ratio, and the 3–4-fold increase in apoptosis and reduction in cell proliferation, and partially counteracted the increase in collagen, seen with both UCNR and BCNR; and (2) normalized the CVOD, measured by dynamic infusion cavernosometry, induced by both BCNR and UCNR. The long-term inhibition of iNOS activity exacerbated corporal fibrosis and CVOD in the BCNR rats, but sildenafil functional effects were not affected by L-NIL. These data suggest that the salutary effects of continuous long-term PDE5 inhibitors on erectile function post-cavernosal nerve resection involve their ability to prevent the alterations in corporal histology induced by cavernosal nerve damage, in a process apparently independent from endogenous iNOS induction. International Journal of Impotence Research (2008) 20, 202–212; doi:10.1038/sj.ijir.3901612; published online 20 September 2007 Keywords: erectile dysfunction; radical prostatectomy; nerve damage; PDE5 inhibitors; smooth muscle; fibrosis Introduction Erectile dysfunction is a common complication following radical prostatectomy that affects the quality of life of both the patient and his partner. In addition, many men who have been diagnosed with early stage prostate cancer and are candidates for radical prostatectomy avoid this surgery primar- ily because of the fear of developing this side effect. 1–3 The main cause of erectile dysfunction in this patient population is corporal veno-occlusive dysfunction (CVOD), which occurs when the cor- poral smooth muscle is unable to relax sufficiently and let the intracorporeal pressure adequately compress the subtunical veins, which prevents the egress of blood out of the corpora during tumescence. 4 Regardless of its cause, when the number of smooth muscle cells (SMC) decreases and/or the collagen content increases, the corporal tissue loses its normal compliance and is prone to developing CVOD. During a radical prostatectomy, the cavernosal nerves are susceptible to injury. This not only impairs Received 19 March 2007; revised 26 June 2007; accepted 29 July 2007; published online 20 September 2007 Correspondence: Dr N Gonzalez-Cadavid, Urology Research Laboratory, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Building F6, F7, Torrance, CA 90502-2064, USA. E-mail: ncadavid@ucla.edu International Journal of Impotence Research (2008) 20, 202–212 & 2008 Nature Publishing Group All rights reserved 0955-9930/08 $30.00 www.nature.com/ijir