title: New approaches to the design and discovery of therapies to prevent erectile dysfunction.
abstract: BACKGROUND
  Nitric oxide (NO) is critically involved in erectile function. Since NO synthase (NOS) and arginase compete for the same substrate l-arginine, limiting arginase activity may provide more NO and thus be a beneficial therapeutic approach to erectile dysfunction (ED). In the corpora cavernosa, excessive arginase activity/expression has been implicated through studies of preclinical and clinical models of ED. Further, the inhibition of arginase has shown to increase vascular system relaxation and enhance blood flow in penile circulation. Further studies, therefore, looking at therapies targeting arginase could prove to be clinically useful.
  
  
  METHODS
  The authors review gene- and cell-based therapies, the involvement of RhoA/Rho-kinase (ROCK), MAPK and arginase in ED.
  
  
  CONCLUSIONS
  Extensive literature supports the view that upregulated arginase activity in cavernosal tissue can reduce NOS function and NO production. Excessive arginase activity has been shown to contribute to the progression of aging-, hypertension- and diabetes-induced vascular dysfunction as well as ED. Earlier studies have shown that RhoA/ROCK and subsequent activation of p38 MAPK mediate elevation of arginase expression/activity in diabetic and hypertensive mice. Reducing corporal arginase activity by gene-based or pharmacological therapy and/or inhibition of upstream regulators of arginase expression may provide novel therapeutic approaches in the management of ED.
authors.affiliation: Georgia Regents University, Medical College of Georgia, Department of Pharmacology and Toxicology , 1459 Laney Walker Blvd, Augusta, GA 30912-2308 , USA +1 706 721 6351 ; +1 706 721 2347 ; hflorestoque@gru.edu.
authors.forename: Haroldo A
authors.initials: HA
authors.lastname: Toque
authors.forename: Robert William
authors.initials: RW
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism; D001120:Arginine / Q000502:physiology / Q000627:therapeutic use; D055808:Drug Discovery; D007172:Erectile Dysfunction / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D006801:Humans; D008297:Male; D010410:Penile Erection / Q000502:physiology
chemical_list: D001120:Arginine; D001119:Arginase
keywords: arginase; cavernosal smooth muscle relaxation; erectile dysfunction; nitric oxide; penile erection