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      The effect of mirodenafil on the penile erection and corpus cavernosum in the rat model of cavernosal nerve injury

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          Abstract

          Impotence is one of the common complications after the radical prostatectomy. One of the main reasons of this complication is due to the dysfunction of the veins in corpus cavernosum. Recent studies have shown that the erectile function is improved after the long-term therapy of phosphodiesterase type 5 inhibitor among patients with post-prostatectomy erectile dysfunction. In this study, we evaluated the effects of mirodenafil on the penile erection and corpus cavernosum tissues in the rat model of cavernosal nerve injury. Rats were divided into four groups: (1) control group, (2) bilateral cavernosal nerve injury group, (3) mirodenafil 10 mg therapy group after the nerve injury and (4) mirodenafil 20 mg therapy group after the nerve injury. After we identified the nerve from the pelvic nerve complex on the lateral side of the prostate, the rats in the control group were sutured without causing any nerve injury and in other groups we damaged the nerve by compressing it with a vessel clamp. Then, 10 and 20 mg kg −1 of mirodenafil were orally administered to two experimental groups. After 8 weeks, the intracavernosal pressure (ICP) was recorded. The immunohistochemical staining and western blot were performed, and the effect of mirodenafil on the expression of cyclic guanosine monophosphate (cGMP) was evaluated through enzyme-linked immunosorbent assay. The ICP of nerve-injured group was decreased compared with the control group; however, the ICP of the mirodenafil-administered groups was improved compared with the nerve-injured group. The Masson's trichrome staining confirmed that the smooth muscle (SM) component was increased in the mirodenafil-administered groups. The nitric oxide synthase expression and cGMP of mirodenafil-administered groups was increased compared with the nerve-injured group. Long-term therapy of mirodenafil may improve the erectile function after the radical prostatectomy by preserving the SM content and inhibiting the fibrosis of the corpus cavernosum.

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          Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial.

          This study was aimed at assessing prospectively the effect of postoperative intracavernous injections of alprostadil on the recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy. A total of 30 potent patients with clinically localized prostate cancer (clinical stage B1 or B2, Gleason sum 7 or greater, prostatic specific antigen less than 20 ng./ml.) underwent nerve-sparing radical retropubic prostatectomy and was subsequently randomized to alprostadil injections 3 times per week for 12 weeks (group 1, 15 patients) or observation without any erectogenic treatment (group 2, 15 patients). Patients were assessed at the 6-month followup by sexual history, physical examination, color Doppler sonography of the cavernous arteries and polisomnographic recording of nocturnal erections. In group 1, 12 patients (80%) completed the entire treatment schedule and were evaluated at the long-term followup. Eight patients in this group (67%) reported the recovery of spontaneous erection sufficient for satisfactory sexual intercourse, compared with 3 patients (20%) in group 2. The difference between the 2 groups was statistically significant (p <0.01). In group 1, all but 1 patient reporting normal postoperative erections also showed normal erections at nocturnal testing, whereas color Doppler sonography demonstrated normal penile hemodynamics in all of them. In these patients, failures were the result of cavernous veno-occlusive dysfunction (2 cases, 17%) and cavernous nerve injury (2 cases, 17%). In group 2, patients with normal erections showed both normal nocturnal testing and penile hemodynamics, whereas failures were the result of cavernous veno-occlusive dysfunction (8 cases, 53%), cavernous arterial insufficiency (2 cases, 13%) or cavernous nerve injury (3 cases, 20%). Complications in patients treated with alprostadil injections accounted for 2 cases (13%) of a penile nodule and 1 further case (6%) of prolonged penile erection. Complications were not seen in group 2 patients. Early postoperative administration of alprostadil injections significantly increases the recovery rate of spontaneous erections after nerve-sparing radical retropubic prostatectomy. It is our belief that programmed vasoactive injections improve cavernous oxygenation, thereby limiting the development of hypoxia-induced tissue damage. The potential complications related to the use of intracavernous injections must be clearly explained to patients.
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            Vardenafil prevents fibrosis and loss of corporal smooth muscle that occurs after bilateral cavernosal nerve resection in the rat.

            Impotence, specifically corporal veno-occlusive dysfunction (CVOD), occurs after radical prostatectomy. It results from the effects of cavernosal nerve damage, which causes smooth muscle (SM) loss and an increase in collagen within the corpora. Recent reports have suggested that long-term treatment with phosphodiesterase-5 inhibitors after radical prostatectomy may prevent such changes. We aimed to determine whether bilateral cavernosal nerve resection (BCNX) in the rat leads to CVOD and whether long-term phosphodiesterase-5 inhibition ameliorates these histologic and functional impairments. Rats (n = 7 to 11/group) underwent either the sham operation, BCNX, or BCNX plus 30 mg/L vardenafil in the drinking water. Before the rats were killed 45 days later, CVOD was assessed by dynamic infusion cavernosometry. The corpora underwent histochemistry/immunohistochemistry with quantitative image analysis for SM/collagen ratio, collagen III/I ratio, alpha-SM actin, inducible nitric oxide synthase (iNOS), proliferating cell nuclear antigen, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling as a marker of apoptosis. Compared with the sham group, the BCNX rats demonstrated CVOD as measured by the drop rate, a 60% reduction in the SM/collagen ratio, a twofold increase in iNOS expression, and a threefold increase in intracorporeal apoptosis. Compared with the BCNX group, vardenafil increased both iNOS and proliferating cell nuclear antigen expression (SM cell replication), with normalization of the dynamic infusion cavernosometry drop rate and SM/collagen ratio. Long-term treatment with vardenafil may prevent CVOD after radical prostatectomy by preserving SM content and inhibiting corporal fibrosis possibly by its effect on iNOS.
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              Phosphodiesterase type 5 inhibitors for erectile dysfunction.

              The cyclic nucleotide signalling pathway mediates the smooth-muscle relaxing effects of nitric oxide necessary for normal erectile function. Down-regulation of this pathway is central to the pathophysiology of many forms of erectile dysfunction (ED), which is often associated with other chronic diseases (e.g. hypertension, type 2 diabetes mellitus) and treatments (e.g. certain drugs, radical prostatectomy). Conversely, selective inhibition of the enzyme that catalyses the degradation of cGMP (phosphodiesterase type 5, PDE-5) promotes erectile responses to sexual stimulation. The successful launch and commercialization of the selective PDE5 inhibitor (PDE5I) sildenafil transformed the treatment of ED, not only by providing an effective, well tolerated oral ED therapy, but also by fostering greater candour about the problem among men. Sildenafil is highly effective in promoting erectile responses across a wide spectrum of severity and causes of ED, including patients with ED that is often refractory to treatment. The recent advent of vardenafil, which has the highest in vitro potency of all available PDE5Is, and tadalafil, which has a prolonged half-life that may enable couples to have sexual activity with less planning, represent further advances. Other PDE5Is offering further potential improvements are under active investigation.
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                Author and article information

                Journal
                Int J Impot Res
                International Journal of Impotence Research
                Nature Publishing Group
                0955-9930
                1476-5489
                September 2010
                23 September 2010
                : 22
                : 5
                : 291-297
                Affiliations
                [1 ]simpleDepartment of Urology, College of Medicine, The Catholic University of Korea , Seoul, Korea
                [2 ]simpleDepartment of Urology, College of Medicine, The Jeju National University of Korea , Jeju, Korea
                Author notes
                [* ]simpleDepartment of Urology, The Catholic University of Korea, Seoul St Mary's Hospital , BanPoDong 505, Seoul 150-713, Republic of Korea. E-mail: ksw1227@ 123456catholic.ac.kr
                Article
                ijir201019
                10.1038/ijir.2010.19
                2959156
                20861845
                0c5510b0-edae-41e4-9040-028367d21303
                Copyright © 2010 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 21 September 2009
                : 15 April 2010
                : 24 May 2010
                Categories
                Original Article

                Sexual medicine
                erectile dysfunction,corpus cavernosum,mirodenafil
                Sexual medicine
                erectile dysfunction, corpus cavernosum, mirodenafil

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