Bilateral Cavernous Nerve Resection Research Articles

(154) Microarray and Pathway Analysis of Corpora Cavernosal Tissue from Peyronie’s and Prostatectomy Patients with Erectile Dysfunction in Comparison to a Rat Cavernous Nerve Resection Model

Abstract Introduction Prostatectomy patients are at high risk of developing erectile dysfunction (ED) that is refractory to PDE5 inhibitors. The cavernous nerve (CN), which innervates the penis, is frequently damaged during prostatectomy, causing loss of neurotransmission, remodeling of penile architecture, including abundant smooth muscle apoptosis and fibrosis, resulting in ED. Objective In this study we perform microarray and pathway analysis to identify signaling mechanisms that are altered with ED and penile remodeling, in order to develop novel therapies for ED prevention and treatment. Methods Corpora cavernosal tissue was obtained from Peyronie’s (control, n=3) and prostatectomy (control, n=3) patients that underwent prosthesis implant to treat ED. Sprague Dawley rat penis was obtained from rats that underwent bilateral CN resection (n=5) or sham surgery (controls, n=5), and corpora cavernosa was dissected after two days. RNA was extracted using TRIzol, DNase treated, and purified by Qiagen mini kit. Microarray was performed using the Human Gene 2.0 ST Array and the RU34 rat array. Differentially expressed genes were identified in corpora cavernosa from prostatectomy patients using several analytical tools (ShinyGO, WebGestalt) and databases (GO, Reactome). Comparison of patient and rat pathway analysis was performed. Two technical replicates were examined. A two-fold change was used as threshold for differential expression. FDR<0.05 was considered significant for enrichment terms. Results Microarray identified 197 differentially expressed protein-coding genes in corpora cavernosa from prostatectomy patients, with 100 genes up, and 97 genes down regulated. 112 of the 197 DEGs were non-protein-coding genes of which 26 had documented associations (9 up-regulated and 17 down-regulated; 13 associated with cell proliferation). Thus, the overall changed expression of these documented non-protein-coding genes would be expected to favor a reduction in cell growth compared with Peyronie’s control. For the rat ED model, microarray detected 182 differentially expressed protein-coding genes. Over Representation Enrichment Analysis showed enrichments for cell death, stress and cellular development. Examination of the role of individual genes found altered signaling for both proliferation and cell death, indicating while apoptosis is abundant at this time frame in the rat ED model, proliferation also occurs initially, prior to apoptotic dominance. Conclusions Prostatectomy patients display alterations in gene expression in their corpora cavernosa that are consistent with decreased growth, likely impacting tissue repair and regenerative processes. Non-protein-coding RNAs may play a crucial role in ED development in prostatectomy patients. In our CN resection rat ED model, which represents altered signaling early in the architectural remodel process that occurs after CN injury, both cell death and proliferation are the acute response followed by apoptosis domination. Microarray and pathway analysis identify strategic points for clinical intervention for ED therapy development. Disclosure No

MP27-02 MICROARRAY ANALYSIS OF CORPORA CAVERNOSAL TISSUE FROM PEYRONIE'S AND PROSTATECTOMY PATIENTS WITH ERECTILE DYSFUNCTION IN COMPARISON TO A RAT CAVERNOUS NERVE RESECTION MODEL

You have accessJournal of UrologyCME1 Apr 2023MP27-02 MICROARRAY ANALYSIS OF CORPORA CAVERNOSAL TISSUE FROM PEYRONIE'S AND PROSTATECTOMY PATIENTS WITH ERECTILE DYSFUNCTION IN COMPARISON TO A RAT CAVERNOUS NERVE RESECTION MODEL Timothy Searl, Samuel Ohlander, Kevin McVary, and Carol Podlasek Timothy SearlTimothy Searl More articles by this author , Samuel OhlanderSamuel Ohlander More articles by this author , Kevin McVaryKevin McVary More articles by this author , and Carol PodlasekCarol Podlasek More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003255.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostatectomy patients are at high risk of erectile dysfunction (ED) that is refractory to PDE5 inhibitors. Cavernous nerve (CN) damage causes loss of innervation, smooth muscle apoptosis, and fibrosis, resulting in ED. We performed microarray and pathway analysis to identify mechanisms that are altered with ED, to find new targets for ED treatment. METHODS: Corpora cavernosal (CC) tissue was obtained from Peyronie’s (control, n=3) and prostatectomy (control, n=3) patients undergoing prosthesis implant to treat ED. For our rat CN injury model, Sprague Dawley rats underwent bilateral CN resection (n=5) or sham surgery (controls, n=5) and C.C. tissue was harvested 2 days post surgery. RNA was extracted from CC tissue using TRIzol, DNase treated, and purified with Qiagen mini kit. Microarray analysis (HG 2.0 ST, RU34), and pathway analysis was performed (ShinyGO, WebGestalt. Ingenuity). A 2-fold change was used as threshold for differentially expressed genes (DEGs). FDR<0.05 was considered significant for enrichment terms. RESULTS: There were 197 DEGs in CC from prostatectomy patients. 112 of the 197 DEGs were non-protein-coding genes. The overall changed expression of these non-protein-coding genes expected to favor a reduction in cell growth compared with Peyronie’s control. In the rat, microarray detected 182 protein coding DEGs. Pathway Analysis identified changes in cell death, stress and cellular development. Examination of the role of individual genes found changes in proliferation and cell death. CONCLUSIONS: Prostatectomy patients display alterations in gene expression in their corpora cavernosa that are consistent with decreased growth, likely impacting tissue repair and regenerative processes. Non-protein-coding RNAs may play a crucial role in ED in prostatectomy patients. In the acute rat CN resection model, cell death and proliferation are followed by apoptosis domination. Prostatectomy patient results show penile remodeling continues in patients long after the acute surgical injury to the CN takes place, offering the opportunity for clinical intervention to reverse penile remodeling and improve erectile function. Source of Funding: NIH/NIDDK DK101536 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e362 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Timothy Searl More articles by this author Samuel Ohlander More articles by this author Kevin McVary More articles by this author Carol Podlasek More articles by this author Expand All Advertisement PDF downloadLoading ...

883 Ganglion cell size after bilateral cavernous nerve resection and reconstruction

883 Ganglion cell size after bilateral cavernous nerve resection and reconstruction

Involvement of Rho-Kinase/LIM Kinase/Cofilin Signaling Pathway in Corporal Fibrosis after Cavernous Nerve Injury in Male Rats.

The molecular mechanism of corporal fibrosis leading to erectile dysfunction (ED) following cavernous nerve (CN) injury is poorly understood. To determine whether the LIMK2/cofilin pathway, the downstream effectors of ROCK1, was involved in ED and corporal fibrosis following bilateral CN injury in male rats. Forty-eight 10-week-old male Sprague-Dawley rats were equally divided into three groups: sham surgery (S); bilateral CN crush injury (I); and bilateral CN resection (R). Within each groups, two subgroups were analyzed at 1 and 4 weeks postoperatively. Electrostimulation was performed to assess erectile function by the ratio of maximal intracavernous pressure to mean arterial pressure (ICP/MAP) and areas under the ICP curve to MAP (AUC/MAP). Penile tissue was processed for Masson's trichrome staining, Western blot (ROCK1, total LIMK2, phospho-LIMK2, total cofilin, phospho-cofilin), immunohistochemistry (alpha-SM actin [α-SMA]), and double immunofluorescent staining (ROCK1, phospho-LIMK2, vimentin). At each time point, both I and R groups showed a significantly lower percent of ICP/MAP and AUC, and decreased SM cell/collagen ratio and expression of α-SMA than S group. Densitometry revealed a significantly higher expression of ROCK1 in I and R groups compared with S group at all time points. The LIMK2 phosphorylation in I and R groups significantly increased at 1 week, but not at 4 weeks. The cofilin phosphorylation in R group significantly increased to that in S group starting at 1 week, while that in I group was increased significantly at 4 weeks. The double immunofluorescent staining noted that coexpression of vimentin with ROCK1 or phospho-LIMK2 in I and R groups was significantly increased mainly in the subtunical area at 1 week but not at 4 weeks. The ROCK1/LIMK2/cofilin pathway may be involved in ED related to corporal fibrosis, and it appears to be functional particularly in the early period after CN injury.

Erectile function recovery in patients after non-nerve sparing radical prostatectomy.

Few studies have looked at erectile function recovery (EFR) rates in men undergoing non-nerve sparing resection during radical prostatectomy (RP). Existing studies show great variation in EFR rates owing to multiple factors that minimize their utility in counselling RP patients. We investigated the EFR rate and its predictors in unilateral cavernous nerve resection and bilateral cavernous nerve resection patients 24months after RP. We conducted a population-based, prospective cohort study of 966 patients who underwent RP at a tertiary cancer centre from 2008 to 2012. Cavernous nerve condition was evaluated on a 4-point nerve sparing score and assigned to one of three groups: bilateral sparing, unilateral resection (UNR) and bilateral nerve resection (BNR). EF was assessed pre-RP and 24-30months post-op using a validated 5-point patient-reported scale (1=fully rigid; 5=no tumescence). EFR was defined as a post-op EF grade of 1-2. Statistical analysis included descriptive statistics, anova, chi-square, Fisher's exact test and logistic regression. Mean baseline EF was 1.84±1.3 and 2.74±1.5 for UNR and BNR patients respectively. Thirty-three percent of UNR patients and 13% of BNR patients exhibited EFR. Age, baseline EF were predictors of EFR. Multivariable analysis showed baseline EF was a significant predictor of EFR at 24months for UNR. For BNR patients, pre-RP EF was the only factor predictive of EFR. Patients undergoing nerve resection still have a significant chance of achieving true EFR, with UNR surgery patients showing more potential for improvement than patients undergoing BNR surgery. Age and baseline EFR characterize recovery prospects in these two groups. Physicians should thus measure and account for baseline EF in addition to age and the degree of nerve resection when advising patients about expectations for successful EF following RP.

Erectile functional restoration with genital branch of genitofemoral nerve to cavernous nerve transfer after bilateral cavernous nerve resection in the rat.

To investigate the feasibility of erectile function restoration by genital branch of genitofemoral nerve (GN) to cavernous nerve (CN) transfer in rats. Thirty adult (3 months) male Sprague-Dawley rats were divided into 3 groups (n = 10 per group). Rats in sham group underwent sham operation, rats in nerve resection (NR) group underwent bilateral GN and CN resection to make a 2.5-mm gap, and rats in nerve transfer (NT) group underwent nerve anastomosis bilaterally between proximal stump of GN and distal stump of CN after nerve resection. Three months postoperatively, mating test observed 70% rats with intromission behaviors in NT group but only 10% rats in NR group. Electrostimulating the GN of NT group rats resulted in a significant increase in intracavernous pressure, and the ratio of intracavernous pressure increase to mean arterial pressure in NT group was significantly higher than that in NR group. Seven days after Fluoro-Gold injection into the penile crus, Fluoro-Gold-labeled neurons were found in ventral horn of L1 and L2 in NT group, indicating that a new erectile efferent pathway might be established. Axon counting and ultrastructure observation confirmed axonal regeneration in NT group. Furthermore, NT group had a higher expression of nitric oxide synthase in the dorsal penile nerve than that in NR group. The results have demonstrated that nerve regeneration can be obtained, and erectile function may be restored after GN to CN nerve transfer in bilateral CN resection rats, which provides an innovative and promising treatment for neurogenic erectile dysfunction.

Erectile Function Restoration After Repair of Resected Cavernous Nerves by Adipose-Derived Stem Cells Combined with Autologous Vein Graft in Rats

Cavernous nerve (CN) injury is the main cause of erectile dysfunction (ED) following radical prostatectomy. The recovery of erectile function following this procedure remains challenging. Here, we investigated the ability of adipose-derived stem cells (ADSCs) combined with autologous vein graft to improve erectile function in a rat model of bilateral long CN resection. Sprague-Dawley rats (n = 36) were randomized into four groups. Group A underwent sham operation. In Groups B, C, and D, an 8-mm segment of CN was excised bilaterally. In Group B and C, a 10-mm segment of autologous saphenous vein was interposed bilaterally at the site of injury, and the two nerve stumps were inserted into the vein lumen. 50 μL ADSCs were injected into each vein in Group B, and 50 μL of phosphate-buffered saline was injected in Group C. Group D underwent no repair. Erectile function assessed after 3 months by measuring intracavernosal pressure demonstrated significant recovery in erectile function in Group B with minimal recovery in Group C or D. Immunohistochemical staining showed that the nNOS-positive area was significantly larger in Group B than in Group D. ADSCs combined with autologous vein graft treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum. This procedure, therefore, provided a means of regenerating CN tissue and restoring autonomic erectile function after long bilateral CN resection (0.8 cm) in rats.

1023 INVOLVEMENT OF RHO-KINASE/LIM-KINASE/COFILIN SIGNALING PATHWAY IN ERECTILE DYSFUNCTION AND CORPORAL FIBROSIS AFTER CAVERNOUS NERVE INJURY IN MALE RATS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research (II)1 Apr 20131023 INVOLVEMENT OF RHO-KINASE/LIM-KINASE/COFILIN SIGNALING PATHWAY IN ERECTILE DYSFUNCTION AND CORPORAL FIBROSIS AFTER CAVERNOUS NERVE INJURY IN MALE RATS Min Chul Cho, Sang Hoon Song, Sung Yong Cho, Kwanjin Park, Soo Woong Kim, and Jae-Seung Paick Min Chul ChoMin Chul Cho Goyang, Korea, Republic of More articles by this author , Sang Hoon SongSang Hoon Song Seoul, Korea, Republic of More articles by this author , Sung Yong ChoSung Yong Cho Seoul, Korea, Republic of More articles by this author , Kwanjin ParkKwanjin Park Seoul, Korea, Republic of More articles by this author , Soo Woong KimSoo Woong Kim Seoul, Korea, Republic of More articles by this author , and Jae-Seung PaickJae-Seung Paick Seoul, Korea, Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.608AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Molecular mechanism of corporal fibrosis leading to erectile dysfunction (ED) after cavernous nerve (CN) injury is poorly understood. Recently, we demonstrated that sphingosine-1-phosphate/RhoA/ROCK1 pathway could be involved in corporal fibrosis after CN injury. Activation of ROCK1 is followed by activation of downstream target kinases, LIM-kinase2 (LIMK2) and cofilin, resulting in fibroblast-to-myofibroblast differentiation, a pathophysiologic feature of fibrosis. Thus, the aim of this study was to determine whether LIMK2/cofilin pathway, the downstream effector of ROCK1, was involved in ED and corporal fibrosis after CN injury in male rats. METHODS Forty eight 10-week-old male Sprague-Dawley rats were equally divided into 3 groups: sham surgery (S); bilateral CN crush injury (I); and bilateral CN resection (R). Within each of 3 groups, two subgroups were analyzed as a function of time (1 and 4 weeks postoperatively). At 1 and 4 weeks postoperatively, electrostimulation was performed to assess erectile function by maximal intracavernous pressure (ICP)/mean arterial pressure (MAP) ratio and areas under the curve (AUC). Western blot (ROCK1, phospho/total LIMK2, phospho/total cofilin), immunohistochemistry (α-SMA and phospho-LIMK2) and Masson's trichrome staining were performed. RESULTS At each time point, both I and R groups showed significantly lower ICP/MAP ratio and AUC than S group. Mean ICP/MAP and AUC showed a trend toward higher level in I group than R group, which was not significantly different. At all time points, I and R groups had a significantly decreased SM cell/collagen ratio and expression of α-SMA compared to the S group and a trend toward decreasing over the study period. On immunohistochemical staining, the LIMK2 expression in both I and R groups was significantly higher than that in S group at 1 week, but not at 4 weeks. Densitometry revealed a significantly higher expression of ROCK1 in I and R group compared to S group at 1 and 4 weeks. The ratio of phospho/total LIMK2 protein expression in I and R groups was significantly decreased at 1 week, but not significantly different from that in S group at 4 weeks. The ratio of phospho/total cofilin protein expression in R group significantly decreased starting from 1 week, while that in I group significantly decreased as late as 4 weeks. CONCLUSIONS Our data suggest that LIMK2/cofilin pathway can be involved in ED and corporal fibrosis associated with loss of SM after CN injury, and appears to be functional particularly in the early phase after CN injury. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e419-e420 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Min Chul Cho Goyang, Korea, Republic of More articles by this author Sang Hoon Song Seoul, Korea, Republic of More articles by this author Sung Yong Cho Seoul, Korea, Republic of More articles by this author Kwanjin Park Seoul, Korea, Republic of More articles by this author Soo Woong Kim Seoul, Korea, Republic of More articles by this author Jae-Seung Paick Seoul, Korea, Republic of More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Is It Possible to Recover Erectile Function Spontaneously after Cavernous Nerve Injury? Time-Dependent Structural and Functional Changes in Corpus Cavernosum Following Cavernous Nerve Injury in Rats

Purpose: There has been a scarcity of integrated, long-term (＞4 week) studies on structural and functional alterations in the penis according to the period following cavernous nerve (CN) injury. The aim of this study was to investigate time-dependent structural and functional changes in the corpus cavernosum following CN injury in a rat model. Materials and Methods: Ninety male Sprague-Dawley rats (10 weeks old) were divided into 4 groups: normal control (C), sham (S), bilateral CN resection (R), and bilateral CN crush injury (I) groups. At 1, 4, and 12 weeks after the procedure, erectile function was assessed by electrostimulation. The terminal deoxynucleotidyl transferase-mediated 2’-deoxyuridine 5’-triphosphate nick end labeling (TUNEL) assay was performed for detection of apoptosis. Masson’s trichrome staining and immunohistochemistry were performed for detection of alpha smooth muscle actin (α-SMA). Western blot analysis was then performed. Results: The R and I groups showed persistent impairment of erectile function at all three points in time. Apoptosis peaked at 1 week after resection or crush injury and then gradually subsided. The smooth muscle cell/collagen ratio and expression of α-SMA gradually decreased over time after CN resection or crush injury. Myosin phosphatase target subunit 1 phosphorylation progressively increased over time after CN resection or crush injury. On the other hand, expression of phospho-protein kinase B, phospho-endothelial nitric oxide synthase, and neuronal nitric oxide synthase transiently decreased at 1 week after resection or crush injury and then recovered to the control values. Conclusions: Our results suggest that persistent up-regulation of the RhoA/Rho-kinase pathway and structural change such as decreased smooth muscle cell and increased cavernosal fibrosis might play an important role in persistent erectile dysfunction following CN injury.

Inhibition of Interleukin‐6 Attenuates Erectile Dysfunction in a Rat Model of Nerve-Sparing Radical Prostatectomy

The precise mechanisms underlying erectile dysfunction (ED) occurring after cavernous nerve (CN)-sparing surgery remain to be determined. Aim. To evaluate the expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) after CN injury, and the effect of inhibiting IL-6 bioactivity on nerve injury-related ED. Male Sprague-Dawley rats were divided into three groups: sham operation; bilateral CN dissection without crushing or cutting; and bilateral CN resection. In the interventional experiment, male rats underwent bilateral CN dissection, and anti-rat IL-6 antibody in phosphate-buffered saline (PBS) or vehicle alone was injected intraperitoneally immediately and 24 hours after CN dissection. One, 3, 7, 28, and 56 days after surgery, the expression of IL-6 and IL-6R in the major pelvic ganglion (MPG) was examined by real-time polymerase chain reaction. In the interventional experiment, erectile function was assessed by determining intracavernous pressure divided by arterial pressure (ICP/AP) during electrical pelvic nerve stimulation at 4 weeks after surgery in the anti-IL-6-injected rats and PBS-injected rats. The degree of nerve injury was also evaluated by retrograde dye tracing with Fluorogold. The expression levels of IL-6 and IL-6R were increased in the early period of CN injury, as compared with the sham group. IL-6 expression on day 1 was particularly enhanced. Four weeks after CN dissection, the anti-IL-6 group had greater ICP/AP and more FG-positive cells than the PBS group. Expression levels of IL-6 in the MPG were increased in the acute phase following CN injury. Inhibition of IL-6 bioactivity attenuated ED following CN dissection. Thus, the suppression of excess inflammatory responses in the acute phase may lead to improvements in ED occurring after nerve-sparing radical prostatectomy.

914 TIME-DEPENDENT STRUCTURAL AND FUNCTIONAL CHANGES IN CORPUS CAVERNOSUM FOLLOWING CAVERNOUS NERVE INJURY IN RATS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research1 Apr 2011914 TIME-DEPENDENT STRUCTURAL AND FUNCTIONAL CHANGES IN CORPUS CAVERNOSUM FOLLOWING CAVERNOUS NERVE INJURY IN RATS Sung Yong Cho, Soo Woong Kim, and Jae-Seung Paick Sung Yong ChoSung Yong Cho Seoul, Korea, Republic of More articles by this author , Soo Woong KimSoo Woong Kim Seoul, Korea, Republic of More articles by this author , and Jae-Seung PaickJae-Seung Paick Seoul, Korea, Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.805AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Erectile dysfunction (ED) is still a frequent complication following radical prostatectomy (RP) despite the advent of surgical techniques. Post-RP ED mainly results from injury to cavernous nerve (CN). It is postulated that damage to the erectile tissue secondary to neuropraxia also plays an important role. This study was designed to investigate time-dependent structural and functional changes in corpus cavernosum following CN injury in rat model. METHODS Ninety male Sprague-Dawley rats (10 weeks old) were divided into 4 groups: normal control (C), sham (S), bilateral CN resection (R), and bilateral CN crush injury (I) group. At 1, 4, 12 weeks after procedure, electric pelvic ganglion stimulation was done to assess erectile function by maximal intracavernous pressure (ICP)/mean arterial pressure (MAP) ratio. Penile tissue was assessed for apoptosis with immunohistochemistry. Expression of phospho-myosin phosphatase target subunit 1 (MYPT1), protein kinase B (Akt), and phospho-endothelial nitric oxide synthase (eNOS) were evaluated by Western blot. RESULTS There was no difference in ICP/MAP between C and S groups in each time period (mean ICP/MAP: 0.78–0.85). Bilateral CN resection caused persistent impairment of erectile function throughout the experimental period (mean ICP/MAP: 0.15–0.24). Bilateral CN crush injury also resulted in deterioration of erectile function, however, mean ICP/MAP gradually increased over the time course (1-week: 0.23, 4-week: 0.33, 12-week: 0.39). The mean apoptotic index in R group was significantly higher than that in C or S group at all time points. The apoptotic index in I group was significantly high after 1-week of injury, however, the apoptotic index gradually decreased over the time. MYPT1 phosphorylation significantly increased after 1-week of injury and gradually increased according the duration of injury both in R and I groups. Both R and I group showed transient decrease in expressions of phospho-Akt and phospho-eNOS at 1-week of injury. CONCLUSIONS These results suggest that CN injury itself plays a more important role than structural and functional alterations in corpus cavernosum secondary to neuropraxia in the pathogenesis of post-RP ED. However, further investigations are needed to elucidate the role of up-regulation of RhoA/Rho-kinase pathway in post-RP ED. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e366 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sung Yong Cho Seoul, Korea, Republic of More articles by this author Soo Woong Kim Seoul, Korea, Republic of More articles by this author Jae-Seung Paick Seoul, Korea, Republic of More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Udenafil Enhances the Recovery of Erectile Function and Ameliorates the Pathophysiological Consequences of Cavernous Nerve Resection

Radical prostatectomy is the treatment of choice for prostate cancer patients. Despite the introduction of nerve-sparing surgical techniques, its success is not entirely guaranteed and the majority of patients report compromised erectile function following surgical procedures. This study was performed to investigate the effect of repeated dosing of udenafil, a novel phosphodiesterase type 5 inhibitor, on penile hypoxia and fibrosis induced by bilateral cavernous nerve resection (BCNR) in rats. Thirty male Sprague-Dawley rats (300-320 g) were used in this study. The animals were divided into three groups; group I consisted of sham-operated animals (N = 10), animals in group II underwent BCNR alone (N = 10), and animals in group III were orally treated with 10 mg/kg udenafil b.i.d. for 8 weeks following BCNR (N = 10). The expression of transforming growth factor-beta1, hypoxia-inducible factor-1 alpha, endothelial nitric oxide synthase, neuronal nitric oxide synthase, and endothelin B receptor in penile tissue was examined at gene level. Additionally, erectile function, measured by intracavernous pressure (ICP), and pathological changes in the corpus cavernosum were examined. While fibrosis, apoptosis, and the expression of TGF-beta1, HIF-1 alpha, and ET(B) were significantly increased, and the expression of eNOS and nNOS were significantly decreased in group II, compared with the sham-operated animals, repeated dosing of udenafil significantly ameliorated these changes. Erectile function was profoundly impaired in animals that underwent BCNR alone, and udenafil treatment significantly attenuated this impairment as measured by ICP. These results demonstrate that long-term administration of udenafil ameliorates penile hypoxia and fibrosis induced by cavernous nerve resection. This study also suggests the potential beneficial role of repeated dosing of udenafil in the recovery of erectile function in patients with neuronal erectile dysfunction.

Nerve injury‐related erectile dysfunction following nerve‐sparing radical prostatectomy: A novel experimental dissection model

To establish a new experimental rat model in order to define the mechanisms of erectile dysfunction (ED) and to evaluate the changes of neuronal nitric oxide synthase (nNOS) in the pelvic ganglia following nerve-sparing radical prostatectomy. Sprague-Dawley rats were randomized to sham operation, bilateral cavernous nerve dissection (BCND) and bilateral cavernous nerve resection (BCNR) groups. In the BCND group, the cavernous nerves were only dissected bilaterally from the major pelvic ganglion (MPG) to the apex of the prostate without crushing or cutting. At 1, 2, 4 and 8 weeks after surgery, we examined intracavernous pressure along with arterial pressure (ICP/AP), retrograde dye tracing using Fluorogold (FG) and expression of nNOS in the MPG. Intracavernous pressure and arterial pressure in the BCND group was significantly decreased at 2 and 4 weeks after surgery compared with the sham group, and improved at 8 weeks. The number of FG-positive cells in the MPG also recovered at 8 weeks. ICP/AP and FG-positive cells in the BCNR group were greatly decreased until 8 weeks. The percentage of nNOS-positive cells per total cells was not different between the sham and BCND groups during the experimental period, whereas that in the BCNR group gradually decreased with time. We established a novel rat model, in which cavernous nerve dissection alone caused nerve injury-related ED. We believe that this cavernous nerve dissection model might help clarify the mechanism of nerve injury-related ED and the recovery from ED after nerve-sparing radical prostatectomy.

Tadalafil Increases Akt and Extracellular Signal-Regulated Kinase 1/2 Activation, and Prevents Apoptotic Cell Death in the Penis Following Denervation

Despite techniques to preserve the cavernous nerves during radical prostatectomy erectile dysfunction remains a complication. We determined whether bilateral cavernous nerve resection induces apoptosis in the penis. We also determined whether treatment with the phosphodiesterase-5 inhibitor tadalafil prevents apoptosis as well as the specific mechanisms involved. Mice were subjected to cavernous nerve resection or sham surgery. Penises were processed for the identification of apoptotic cells, changes in phosphorylation of several protein kinases and immunolocalization of specific kinases. Mice were also placed on tadalafil or vehicle after cavernous nerve resection and the penises were processed as described. Statistical analysis was performed with the Mann-Whitney U test for comparisons among groups or Student's t test. An increase in apoptotic cavernous smooth muscle and endothelial cells was evident by 2 weeks, which further increased 4 and 6 weeks after cavernous nerve resection. Apoptosis coincided with an increase in the phosphorylation of c-jun N-terminal kinase and p38 mitogen activated protein kinase. Phospho-c-jun N-terminal kinase was immunolocalized to endothelial and smooth muscle cells. Treatment with tadalafil decreased the number of apoptotic cells and increased the phosphorylation of the 2 survival associated kinases Akt and extracellular signal-regulated kinase 1/2. These results provide a rationale for the early use of phosphodiesterase-5 inhibition following radical prostatectomy or extensive pelvic surgery, during which there may be injury to the cavernous nerves, to aid in the return of erectile function.

Bilateral Cavernous Nerve Interposition Grafting During Radical Retropubic Prostatectomy: Memorial Sloan-Kettering Cancer Center Experience

Cavernous nerve graft is an option for men requiring bilateral cavernous nerve resection for cancer control during radical prostatectomy. We determined the success rate and identified determinants of success of bilateral cavernous nerve grafting following resection of the 2 nerves during radical prostatectomy in patients who were potent preoperatively. We retrospectively reviewed the records of 44 consecutive patients who underwent bilateral nerve grafting from 1999 to 2004. Postoperative erectile function was defined as the achievement of erections satisfactory for intercourse with or without oral medication. We calculated cumulative erectile function recovery rates using Kaplan-Meier curves. The log rank test was used to compare variables affecting erectile function recovery with p <0.0083 considered significant after adjusting for the number of variables evaluated using the Bonferroni correction. The overall 5-year cumulative recovery of erectile function permitting penetration was 34% and the rate of consistent penetration was 11%. None of the analyzed variables were significantly associated with recovery of postoperative erectile function, including patient age (p = 0.3), incomplete bilateral cavernous nerve resection (p = 0.045), sural nerve grafts compared to genitofemoral or ilioinguinal nerves as donor sites (p = 0.067), post-radiation salvage radical prostatectomy (p = 0.15), neoadjuvant hormone therapy (p = 0.7) and comorbidities (p = 0.15) or medications (p = 0.4) affecting EF. Bilateral cavernous nerve grafts might be beneficial in select patients. A definitive answer awaits the performance of a multi-institutional, randomized, controlled trial.

SCHWANN CELL SEEDED GUIDANCE TUBES RESTORE ERECTILE FUNCTION AFTER ABLATION OF CAVERNOUS NERVES IN RATS

Dissection of the cavernous nerves eliminates spontaneous erections. We evaluated the ability of Schwann cell seeded nerve guidance tubes to restore erections after bilateral cavernous nerve resection in rats. Sections (5 mm) of the cavernous nerve were excised bilaterally, followed by immediate bilateral microsurgical reconstruction. In 10 animals per group (20 study nerves) reconstruction was performed by genitofemoral nerve interposition, interposition of silicone tubes or interposition of silicone tubes seeded with homologous Schwann cells. As the control 10 animals (20 study nerves) underwent sham operation (positive control) and bilateral nerve ablation (without reconstruction) was performed in a further 10 (negative control). Erectile function was evaluated 3 months postoperatively by relaparotomy, electrical nerve stimulation and intracavernous pressure recording. After 3 months neurostimulation resulted in an intact erectile response in 90% (18 of 20) of Schwann cell grafts, while treatment with autologous nerves (30% or 6 of 20) or tubes only (50% or 10 of 20) was less successful (p <0.01). Whereas untreated ablated rats showed no inducible erections (0% or 0 of 20), all sham operated animals had an intact erectile response (100% or 20 of 20). Maximum intracavernous pressure upon electrostimulation was significantly elevated using Schwann cell grafts compared to results in the other treatment groups (p <0.001). Morphological evaluation revealed advanced regeneration within Schwann cell grafts. Schwann cell seeded guidance tubes restore erectile function after the ablation of cavernous nerves in rats and they are superior to autologous nerve grafts.