title: Off-Target Effect of Sildenafil on Postsurgical Erectile Dysfunction: Alternate Pathways and Localized Delivery System.
abstract: There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury.
  
  
  
  To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI).
  
  
  
  The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H2O2were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures. The effects of phosphodiesterase type 4 inhibitor (PDE4I) and PDE5I on neuronal cell survival were evaluated. Male rats underwent BCNI and were untreated (BCNI), immediately treated with application of empty NSPs (BCNI + NSP), NSPs containing sildenafil (Sild + NSP), or NSPs containing rolipram (Rol + NSP).
  
  
  
  Viability of neuronal cells was measured. Intracavernous pressure changes after cavernous nerve electrostimulation and expression of neurofilament, nitric oxide synthase, and actin in mid-shaft of penis were analyzed 14 days after injury.
  
  
  
  Sildenafil and rolipram significantly decreased cell death after exposure to H2O2and hypoxia in PC12, SH-SY5Y, and NT2 cells. PC12 cells did not express PDE5 and knockdown of PDE4 significantly increased cell viability in PC12, SH-SY5Y, and NT2 cells exposed to hypoxia. The ratio of intracavernous pressure to mean arterial pressure and expression of penile neurofilament, nitric oxide synthase, and actin were significantly higher in the Sild + NSP and Rol + NSP groups than in the BCNI and BCNI + NSP groups. Limitations included analysis in only two PDE families using only a single dose.
  
  
  
  Sildenafil showed the most profound neuroprotective effect compared with tadalafil and vardenafil. Sildenafil- or rolipram-loaded NSP delivery to the site of nerve injury prevented erectile dysfunction and led to increased neurofilament, nitric oxide synthase, smooth muscle content in rat penile tissue after BCNI.
authors.affiliation: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Division of Urology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Amirali
authors.initials: A
authors.lastname: Salmasi
authors.affiliation: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
authors.forename: Geun Taek
authors.initials: GT
authors.lastname: Lee
authors.affiliation: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Division of Urology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Patel
authors.affiliation: New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ, USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Goyal
authors.affiliation: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Division of Urology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Dinizo
authors.affiliation: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Kwon
authors.affiliation: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Division of Urology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Parth K
authors.initials: PK
authors.lastname: Modi
authors.affiliation: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Division of Urology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Izak
authors.initials: I
authors.lastname: Faiena
authors.affiliation: Department of Neurology, College of Medicine, Hanyang University Medical Center, Seoul, Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Neurology, College of Medicine, Hanyang University Medical Center, Seoul, Korea; Department of Medicine, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Nara
authors.initials: N
authors.lastname: Lee
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Johanna L
authors.initials: JL
authors.lastname: Hannan
authors.affiliation: New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kohn
authors.affiliation: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Division of Urology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. Electronic address: kimiy@cinj.rutgers.edu.
authors.forename: Isaac Yi
authors.initials: IY
authors.lastname: Kim
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D006861:Hydrogen Peroxide; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000601:surgery; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D011468:Prostatectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate / Q000008:administration & dosage*; D020196:Trauma, Nervous System
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D006861:Hydrogen Peroxide; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP
keywords: Cavernous Nerve Injury; Iatrogenic Erectile Dysfunction; Penile Rehabilitation; Phosphodiesterase Inhibitors; Radical Prostatectomy