title: Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action.
abstract: BACKGROUND
  The PDE5 inhibitor tadalafil is investigation for the treatment of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Several clinical studies of tadalafil and other PDE5 inhibitors have reported significant symptom reduction but limited urinary flow rate improvement. This manuscript reviews the published literature describing the pathophysiology of male LUTS, with an emphasis on mechanisms that may be modulated or improved by phosphodiesterase type 5 (PDE5) inhibition.
  
  
  METHODS
  Literature (through March 2010) was obtained via Medline searches and from the individual reviewers files. Articles were selected for review based on describing in vitro, preclinical, or clinical studies of pathological processes contributing to LUTS, or possible effects of PDE5 inhibition in the lower urinary tract.
  
  
  RESULTS
  Major mechanisms contributing to LUTS include: reduced nitric oxide/cyclic guanosine monophosphate signaling; increased RhoA kinase pathway activity; autonomic overactivity; increased bladder afferent activity; and pelvic ischemia. Tadalafil and other PDE5 inhibitors have demonstrated beneficial effects on smooth muscle relaxation, smooth muscle and endothelial cell proliferation, nerve activity, and tissue perfusion that may impact LUTS in men.
  
  
  CONCLUSIONS
  The pathophysiology of male LUTS is complex and not completely understood. LUTS may occur independently of BPH or secondary to BPH but in both cases involve obstructive or irritative mechanisms with substantial pathophysiological overlap. While the precise mechanism remains unclear, inhibition of PDE5 seems to have an effect on several pathways that may impact LUTS.
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. karl-erik.andersson@klinfarm.lu.se
authors.forename: Karl-Erik
authors.initials: KE
authors.lastname: Andersson
authors.forename: William C
authors.initials: WC
authors.lastname: de Groat
authors.forename: Kevin T
authors.initials: KT
authors.lastname: McVary
authors.forename: Tom F
authors.initials: TF
authors.lastname: Lue
authors.forename: Mario
authors.initials: M
authors.lastname: Maggi
authors.forename: Claus G
authors.initials: CG
authors.lastname: Roehrborn
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Wyndaele
authors.forename: Thomas
authors.initials: T
authors.lastname: Melby
authors.forename: Lars
authors.initials: L
authors.lastname: Viktrup
mesh_terms: D002243:Carbolines / Q000627:therapeutic use*; D019317:Evidence-Based Medicine; D006801:Humans; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D011470:Prostatic Hyperplasia / Q000150:complications* / Q000503:physiopathology; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D000068581:Tadalafil; D016896:Treatment Outcome; D014563:Urodynamics / Q000187:drug effects; D014570:Urologic Diseases / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
chemical_list: D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil