title: p38 Mitogen-activated protein kinase (MAPK) increases arginase activity and contributes to endothelial dysfunction in corpora cavernosa from angiotensin-II-treated mice.
abstract: BACKGROUND
  Angiotensin II (AngII) activates p38 mitogen-activated protein kinase (MAPK) and elevates arginase activity in endothelial cells. Upregulation of arginase activity has been implicated in endothelial dysfunction by reducing nitric oxide (NO) bioavailability. However, signaling pathways activated by AngII in the penis are largely unknown.
  
  
  OBJECTIVE
  We hypothesized that activation of p38 MAPK increases arginase activity and thus impairs penile vascular function in AngII-treated mice.
  
  
  METHODS
  Male C57BL/6 mice were implanted with osmotic minipumps containing saline or AngII (42 µg/kg/h) for 14 days and cotreated with p38 MAPK inhibitor, SB 203580 (5 µg/kg/day), beginning 2 days before minipump implantation. Systolic blood pressure (SBP) was measured. Corpus cavernosum (CC) tissue was used for vascular functional studies and protein expression levels of p38 MAPK, arginase and constitutive NO synthase (NOS), and arginase activity.
  
  
  METHODS
  Arginase expression and activity; expression of phospho-p38 MAPK, endothelial NOS (eNOS) and neuronal NOS proteins; endothelium-dependent and nitrergic nerve-mediated relaxations were determined in CC from control and AngII-infused mice.
  
  
  RESULTS
  AngII increased SBP (22%) and increased CC arginase activity and expression (∼twofold), and phosphorylated P38 MAPK levels (30%) over control. Treatment with SB 203580 prevented these effects. Endothelium-dependent NO-mediated relaxation to acetylcholine was significantly reduced by AngII and this effect was prevented by SB 203580 (P < 0.01). AngII (2 weeks) did not alter nitrergic function. However, SB 203580 significantly increased nitrergic relaxation in both control and AngII tissue at lower frequencies. Maximum contractile responses for phenylephrine and electrical field stimulation were increased by AngII (56% and 171%, respectively) and attenuated by SB 203580 treatment. AngII treatment also decreased eNOS phosphorylation at Ser-1177 compared to control. Treatment with SB 203580 prevented all these changes.
  
  
  CONCLUSIONS
  p38 MAPK inhibition corrects penile arginase activity and protects against erectile dysfunction caused by AngII.
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta, GA 30912, USA. hflorestoque@mail.mcg.edu
authors.forename: Haroldo A
authors.initials: HA
authors.lastname: Toque
authors.forename: Maritza J
authors.initials: MJ
authors.lastname: Romero
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.forename: Alia
authors.initials: A
authors.lastname: Shatanawi
authors.forename: Surabhi
authors.initials: S
authors.lastname: Chandra
authors.forename: Zidonia N
authors.initials: ZN
authors.lastname: Carneiro
authors.forename: Edward W
authors.initials: EW
authors.lastname: Inscho
authors.forename: Robert Clinton
authors.initials: RC
authors.lastname: Webb
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.forename: Robert William
authors.initials: RW
authors.lastname: Caldwell
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010413:Penis / Q000378:metabolism* / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D019001:Nitric Oxide Synthase; D048051:p38 Mitogen-Activated Protein Kinases; D001119:Arginase; C093642:SB 203580
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