Elsevier

European Urology

Volume 58, Issue 5, November 2010, Pages 773-780
European Urology

Sexual Medicine
Molecular Mechanisms of Vacuum Therapy in Penile Rehabilitation: A Novel Animal Study

https://doi.org/10.1016/j.eururo.2010.07.005Get rights and content

Abstract

Background

Penile rehabilitation (PR) is widely applied after radical prostatectomy. Vacuum erectile device (VED) therapy is the one of three PR methods used in the clinical setting that improve erectile function (EF) and is the only PR method which may preserve penile length. However, its unknown mechanism hampered doctors’ recommendations and patients’ compliance.

Objectives

To assess the effects of VED therapy on erectile dysfunction (ED) in a rat model of bilateral cavernous nerve crush (BCNC) and to investigate the molecular mechanism of VED in postprostatectomy ED.

Design, setting, and participants

This was an experimental study using Sprague-Dawley rats in three groups: sham, BCNC, and BCNC plus VED.

Intervention

Intervention included BCNC, electrical stimulation of the cavernous nerve (CNS), and VED therapy.

Measurements

At the end of a 4-wk period, CNS was used to assess EF by maximum intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio and duration (area under the curve [AUC]). For the structural analyses, whole rat penis was harvested. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay was used for the assessment of apoptotic indices (AI). Immunohistochemistry was performed for endothelial nitric oxide synthase (eNOS), α-smooth muscle actin (ASMA), transforming growth factor beta 1 (TGF-β1), and hypoxia inducible factor-1α (HIF-1α). Staining for Masson’s trichrome was utilized to calculate the smooth muscle/collagen ratios.

Results and limitations

EF was improved with VED therapy measured by ICP/MAP ratios and AUC. VED therapy reduced HIF-1α expression and AI significantly compared with control. Animals exposed to VED therapy had decreased TGF-β1 expression, increased smooth muscle/collagen ratios, and preserved ASMA and eNOS expression.

Conclusions

To our knowledge, this is the first scientific study to suggest that VED therapy in the BCNC rat model preserves EF through antihypoxic, antiapoptotic, and antifibrotic mechanisms.

Introduction

Prostate cancer is the most common solid-organ cancer in men and one of the leading causes of death [1]. With early detection and radical prostatectomy (RP), the 15-yr overall, actuarial, cancer-specific survival rate has reached 90% [2], [3]. Unfortunately, RP is associated with at least transient erectile dysfunction (ED), with ED rates ranging from 20% to 90% depending upon the study reviewed [1], [2], [3], [4]. It is postulated that the development of post-RP ED is due predominantly to a combination of temporary cavernous nerve (CN) injury and damage to the erectile tissue secondary to neuropraxia and potentially the absence of cavernosal oxygenation [5].

To improve the patients’ quality of life and the acceptance of the RP, penile rehabilitation (PR) after RP is now widely applied in clinical practice [3]. Currently, PR methods include the use of phosphodiesterase type 5 inhibitors, intracavernosal injection/intraurethral suppository, the vacuum erectile device (VED), or combination therapy [3].

Vacuum therapy utilizes negative pressure to distend the corporal sinusoids and to increase blood inflow to the penis. Clinical data indicated that vacuum therapy is the only PR method that may preserve penile length, improves patient and partner sexual satisfaction, and allows earlier return of spontaneous erection [3], [6]. However, its unknown mechanism hampered doctors’ recommendation and patients’ compliance [3].

To explore the underlying mechanism of VED therapy after RP, we applied our newly designed rat-specific VED [7] to the bilateral cavernous nerve crush (BCNC) rat model. The BCNC rat model is believed to simulate the neural injury that occurs during RP and is designed to study the mechanisms of ED after RP as well as to explore ED-minimizing strategies [8].

Section snippets

Animal grouping, bilateral cavernous nerve crush, and vacuum erectile device therapy

Fifteen Sprague-Dawley rats (Harlan Laboratories, Houston, TX, USA), initially weighing 200–250 g, were randomly and equally divided into three groups: (1) sham (CN expose surgery only, no nerve crushing, no VED therapy); (2) control (BCNC procedure, no VED therapy); and (3) treatment group (BCNC procedure; VED therapy beginning at 2 wk after BCNC surgery, 5 min twice daily with a 1 min interval, Monday–Friday, total VED treatment time: 4 wk). The BCNC procedure was reported previously [8]. The

Erectile function assessment

EF was assessed by tracing the ICP under the CNS, and in the meantime measuring the AP. The typical ICP tracings of sham, BCNC, and BCNC with daily VED therapy are shown in Fig. 1A–C. The analysis is presented in ICP/MAP ratios and AUCs (Fig. 1D and E). The ICP/MAP ratios in the sham group were 0.61 ± 0.02 at 5.0 V and 0.71 ± 0.03 at 7.5 V, which were significantly higher compared with all other groups (p < 0.01). BCNC dramatically decreased the ICP/MAP ratios: 0.25 ± 0.02 at 5 V and 0.32 ± 0.03 at 7.5 V.

Discussion

The rat BCNC as an RP-induced ED model has been widely accepted in PR research. It was first reported by Quinlan et al in 1989 and documented in prior experiments using this animal model in the assessment of functional and structural changes of erectile tissue under various interventions [8]. Our study showed a dramatic reduction in ICP/MAP ratios and AUC in animals after BCNC when compared with the sham group. The reduced ICP/MAP ratios and AUC were associated with significantly reduced smooth

Conclusions

We have demonstrated that VED therapy in the BCNC model preserves EF and acts by preserving smooth muscle content and endothelial integrity via antihypoxia, antiapoptosis, and antifibrosis mechanisms. The daily VED therapy effect on EF recovery is consistent with patients’ results and without significant side effects. This scientific evidence, although from an animal model, may motivate physicians’ recommendations and improve patients’ compliance in the clinical setting.

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