title: Dual Strategy With Oral Phosphodiesterase Type 5 Inhibition and Intracavernosal Implantation of Mesenchymal Stem Cells Is Superior to Individual Approaches in the Recovery of Erectile and Cavernosal Functions After Cavernous Nerve Injury in Rats.
abstract: BACKGROUND
  Novel effective therapeutic strategies are necessary for treating erectile dysfunction secondary to cavernous nerve injury (CNI).
  
  
  OBJECTIVE
  To functionally evaluate the benefits of long-term oral treatment with a phosphodiesterase type 5 inhibitor on the potential capacity of intracavernosal cell therapy to recover erectile function after CNI.
  
  
  METHODS
  Bilateral crush CNI (BCNI) was produced in anesthetized male rats. After BCNI, rats were treated with the phosphodiesterase type 5 inhibitor tadalafil (TAD; 5 mg/kg/d orally; BCNI + TAD), a single intracavernosal injection of bone marrow-derived mesenchymal stem cells (BMSCs; BCNI + BMSC), or dual therapy (BCNI + BMSC + TAD). Ex vivo function of the corpus cavernosum (CC) and in vivo intracavernosal pressure responses to CN electrical stimulation were evaluated 4 weeks after BCNI. Trichrome staining and terminal 2'-deoxyuridine-5'-triphosphate nick-end labeling assay were used for fibrosis and apoptosis determination, respectively, in the CC.
  
  
  METHODS
  In vivo erectile responses in anesthetized rats, ex vivo evaluation of endothelium-dependent relaxation, neurogenic relaxation and neurogenic contraction in CC strips, and histologic evaluation of fibrosis and apoptosis in cavernosal tissue.
  
  
  RESULTS
  BCNI resulted in a marked decrease of erectile responses that were partly recovered in the BCNI + TAD and BCNI + BMSC groups. Complete recovery of erectile function was achieved only in the BCNI + BMSC + TAD group. Endothelium-dependent and nitric oxide donor-induced relaxations of the CC were not altered by BCNI or the treatments. BCNI resulted in enhanced neurogenic adrenergic contractions and impaired nitrergic relaxations of the CC. The BCNI + TAD group displayed diminished neurogenic contractions, whereas the BCNI + TAD and BCNI + BMSC groups showed partly recovered nitrergic responses. In the BCNI + BMSC + TAD group, neurogenic contractions were decreased and nitrergic relaxations were normalized. Cavernosal apoptosis and fibrosis were similarly prevented in the BCNI + TAD, BCNI + BMSC, and BCNI + BMSC + TAD groups.
  
  
  CONCLUSIONS
  A dual strategy combining the intracavernosal injection of BMSCs and oral administration of TAD was superior to individual approaches in normalizing neurogenic control of cavernosal tone and preserving erectile function after CNI, suggesting the potential of this dual strategy in the future management of erectile dysfunction after radical prostatectomy.
authors.affiliation: Servicio de Urología, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Martínez-Salamanca
authors.affiliation: Servicio de Neurocirugía, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Zurita
authors.affiliation: Department of Biochemistry, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Costa
authors.affiliation: Unidad de Investigación Cardiovascular (IRYCIS/UFV), Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martínez-Salamanca
authors.affiliation: Unidad de Investigación Cardiovascular (IRYCIS/UFV), Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: Argentina
authors.initials: A
authors.lastname: Fernández
authors.affiliation: Department of Biochemistry, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Institute for Molecular and Cell Biology of the University of Porto (IBMC-UP), Porto, Portugal.
authors.forename: Angela
authors.initials: A
authors.lastname: Castela
authors.affiliation: Servicio de Neurocirugía, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Vaquero
authors.affiliation: Servicio de Urología, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Carballido
authors.affiliation: Unidad de Investigación Cardiovascular (IRYCIS/UFV), Hospital Universitario Ramón y Cajal, Madrid, Spain. Electronic address: javier.angulo@hrc.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Angulo
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009409:Nerve Crush; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000473:pathology*; D059348:Peripheral Nerve Injuries / Q000473:pathology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D011468:Prostatectomy / Q000009:adverse effects; D051381:Rats; D000068581:Tadalafil / Q000494:pharmacology*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil
keywords: Cavernous Nerve Injury; Cell Therapy; Corpus Cavernosum; Endothelium-Dependent Relaxation; Erectile Dysfunction; Nitrergic Relaxation; Phosphodiesterase Type 5; Radical Prostatectomy