Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

• Published in: International journal of impotence research Vol. 20; no. 2; pp. 202 - 212
• Main Authors: Kovanecz, I, Rambhatla, A, Ferrini, M, Vernet, D, Sanchez, S, Rajfer, J, Gonzalez-Cadavid, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Complications and side effects; Denervation - methods; Dosage and administration; Erectile dysfunction; Erectile Dysfunction - drug therapy; Erectile Dysfunction - etiology; Gynecology. Andrology. Obstetrics; Health aspects; Male; Medical sciences; Medicine; Medicine & Public Health; Methods; Nitric oxide; original-article; Penile Erection - drug effects; Penis - blood supply; Penis - innervation; Phosphodiesterase Inhibitors - administration & dosage; Piperazines - administration & dosage; Prostatectomy; Purines - administration & dosage; Rats; Reproductive Medicine; rology; Sildenafil; Sildenafil Citrate; Smooth muscle; Sulfones - administration & dosage; Time Factors; Treatment Outcome; Urological surgery; Urology; Vascular Diseases - prevention & control; United States; smooth muscle; fibrosis; radical prostatectomy; PDE5 inhibitors; nerve damage; erectile dysfunction; Andrology; Vasodilator agent; Rat; 3',5'-Cyclic-GMP phosphodiesterase; Erection; Sexual dysfunction; Smooth muscle; Esterases; Phosphoric diester hydrolases; Radical; Surgery; Cavernous nerve; Male genital diseases; Erection disorders; Enzyme; Rodentia; Enzyme inhibitor; Surgical resection; Long term; Phosphodiesterase 5 inhibitor; Phosphodiesterase inhibitor; Vertebrata; Mammalia; Treatment; Dysfunction; Animal; Fibrosis; Hydrolases; Prostatectomy; Lesion; Sildenafil
• ISSN: 0955-9930; 1476-5489
• DOI: 10.1038/sj.ijir.3901612

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 =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.