Charles R. Beamon, M.D., Hardeep S. Phull, B.A., Craig V. Comiter, M.D.*: Tucson, AZ.

(Financial Support for this Study provided by Pfizer Pharmaceuticals)

Purpose: Sildenafil citrate, an oral phosphodiesterase type-5 inhibitor, is the most commonly prescribed medication for the treatment of erectile dysfunction. In addition, it has recently been demonstrated that sildenafil reduces penile fibrosis in a rat model of Peyronie’s Disease. Furthermore, phosphodiesterase type-5 has been identified in extra-penile tissues, specifically in the rat and rabbit bladders, and inhibition of this enzyme by sildenafil citrate has been shown to induce relaxation of isolated detrusor muscle strips. We investigated if sildenafil citrate can inhibit the fibrosis and detrusor overactivity that accompany bladder outlet obstruction (BOO) in a murine model.

Materials and Methods: Eighteen Balb/CAN mice were anesthetized with ketamine (60 mg/kg), xylazine (5 mg/kg), and acepromazine (5 mg/kg) via intraperitoneal injection. Lacrilube was applied to the eyes to prevent drying. The abdomen was shaved and the mice were placed on a heating pad regulated at 37 degrees Celsius. After sterile preparation of the operative site with betadine, a midline abdominal incision was made from the umbilicus to just cephalad to the genitalia. Through the incision, the bladder and proximal urethra were exposed. A 4-0 nylon suture was tied around the proximal urethra using PE-50 tubing as a guide to partially obstruct. The abdomen was closed with 3-0 vicryl suture. Mice were survived for 6 weeks (n=9). Half of the mice (n=9) at each time point were given Sildenafil daily (10 mg/kg) in their drinking water. Urodynamics was performed through an open incision at sacrifice. The filling rate utilized was 50 ul/min with PE-50 tubing. After urodynamics the bladder was harvested, at which point it was weighed and then placed into 10% formalin for histological evaluation. Trichrome scoring was performed. Scores were given of 1 for decreased collagen, 2 for normal collagen, and 3 for increased collagen deposition when compared to our control group. Hematoxylin and eosin scoring was done in a similar fashion, with a score of 1 for atrophy, 2 for normal appearing bladder, and 3 for hypertrophy, compared to control bladders. Normal histological values were based on control animals with no obstruction or treatment.

Results: BOO caused urodynamic changes and histological changes. BOO caused detrusor muscular hypertrophy, and fibrosis with collagen deposition. Treatment with sildenafil reduced this fibrosis and muscular hypertrophy. BOO also increased the bladder capacity. Treatment with sildenafil mediated an increase in bladder capacity when compared to obstructed non-treated mice (278 ± 46 µl versus 160 ± 22 µl, p<0.03). Histologically, trichrome staining revealed that the sildenafil treated obstructed mice had less collagen deposition (median trichrome score = 1) when compared to obstructed mice who were not treated with sildenafil (median trichrome score = 3) (p<0.001). In addition, hematoxylin and eosin staining demonstrated that sildenafil-treated mice had less detrusor hypertrophy (median detrusor hypertrophy score = 2) compared to untreated obstructed mice (median detrusor hypertrophy score = 3) (p<0.01). These results correlate when untreated unobstructed mice are compared to untreated obstructed mice for both detrusor hypertrophy and collagen scoring systems (p<0.001).

Conclusions: In a mouse model of bladder outlet obstruction, treatment with six weeks of oral sildenafil citrate commencing at the time of obstructive surgery resulted in significant urodynamic and histological differences compared to obstructed mice that were not treated with sildenafil citrate. Bladder outlet obstruction was associated with a significant increase in bladder capacity and hypertrophy of the detrusor muscle, as well as a significant increase in collagen deposition in the lamina propria and detrusor muscular layer. In obstructed mice treated with six weeks of oral sildenafil citrate, beginning at the time of obstructive surgery, the bladder capacity was significantly increased, and there was significantly less collagen deposition compared to those obstructed mice that were not given sildenafil citrate. Sildenafil appears to protect the partially obstructed bladder in a mouse model by increasing bladder capacity and decreasing collagen deposition.

UroToday.com Coverage of SUFU 2007

Please log-in or register in order to submit comments.

Powered by AkoComment!