| p38 Mitogen-activated protein kinase (MAPK) increases arginase activity and contributes to endothelial dysfunction in corpora cavernosa from angiotensin-II-treated mice. | |
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MedLine Citation:
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PMID: 20807329 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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INTRODUCTION: 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. AIM: 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. MAIN OUTCOME MEASURES: 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. CONCLUSION: p38 MAPK inhibition corrects penile arginase activity and protects against erectile dysfunction caused by AngII. |
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Authors:
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Haroldo A Toque; Maritza J Romero; Rita C Tostes; Alia Shatanawi; Surabhi Chandra; Zidonia N Carneiro; Edward W Inscho; Robert Clinton Webb; Ruth B Caldwell; Robert William Caldwell |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-08-30 |
Journal Detail:
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Title: The journal of sexual medicine Volume: 7 ISSN: 1743-6109 ISO Abbreviation: J Sex Med Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-02 Completed Date: 2011-03-29 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 101230693 Medline TA: J Sex Med Country: United States |
Other Details:
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Languages: eng Pagination: 3857-67 Citation Subset: IM |
Copyright Information:
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© 2010 International Society for Sexual Medicine. |
Affiliation:
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Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta, GA 30912, USA. hflorestoque@mail.mcg.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Angiotensin II
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pharmacology* Animals Arginase / metabolism* Blood Pressure / drug effects Electric Stimulation Endothelium, Vascular / metabolism, physiopathology Enzyme Inhibitors / pharmacology Imidazoles / pharmacology Male Mice Mice, Inbred C57BL Muscle, Smooth, Vascular / metabolism Nitric Oxide Synthase / metabolism Penis / metabolism*, physiopathology Phenylephrine / pharmacology Phosphorylation Pyridines / pharmacology Vasoconstrictor Agents / pharmacology* p38 Mitogen-Activated Protein Kinases / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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EY-11766/EY/NEI NIH HHS; HL-70215/HL/NHLBI NIH HHS; R01 HL070215-04/HL/NHLBI NIH HHS; R01 HL070215-06/HL/NHLBI NIH HHS; R01 HL071138-08/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Imidazoles; 0/Pyridines; 0/SB 203580; 0/Vasoconstrictor Agents; 11128-99-7/Angiotensin II; 59-42-7/Phenylephrine; EC 1.14.13.39/Nitric Oxide Synthase; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 3.5.3.1/Arginase |
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