title: Metformin treatment improves erectile function in an angiotensin II model of erectile dysfunction.
abstract: BACKGROUND
  Increased angiotensin II (AngII) levels cause hypertension, which is a major risk factor for erectile dysfunction (ED). Studies have demonstrated that increased AngII levels in penile tissue are associated with ED. A recent study showed that metformin treatment restored nitric oxide synthase (NOS) protein expression in penile tissue in obese rats; however, whether metformin treatment can be beneficial and restore erectile function in a model of ED has not yet been established.
  
  
  OBJECTIVE
  The goal of this study was to test the hypothesis that AngII induces ED by means of increased corpus cavernosum contraction, and that metformin treatment will reverse ED in AngII-treated rats.
  
  
  METHODS
  Male Sprague-Dawley rats were implanted with mini-osmotic pumps containing saline or AngII (70 ng/minute, 28 days). Animals were then treated with metformin or vehicle during the last week of AngII infusion.
  
  
  METHODS
  Intracavernosal pressure; corpus cavernosum contraction and relaxation; nNOS protein expression; extracellular signal-regulated kinase (ERK1/2), AMP-activated protein kinase (AMPK), and eNOS protein expression and phosphorylation.
  
  
  RESULTS
  AngII-induced ED was accompanied with an increase in corpus cavernosum contractility, decreased nitrergic relaxation, and increased ERK1/2 phosphorylation. Metformin treatment improved erectile function in the AngII-treated rats by reversing the increased contraction and decreased relaxation. Metformin treatment also resulted in an increase in eNOS phosphorylation at ser1177.
  
  
  CONCLUSIONS
  Metformin treatment increased eNOS phosphorylation and improved erectile function in AngII hypertensive rats by reestablishing normal cavernosal smooth muscle tone.
authors.affiliation: Georgia Health Sciences University, Physiology Department, Augusta, GA, USA.
authors.forename: Hicham
authors.initials: H
authors.lastname: Labazi
authors.forename: Brandi M
authors.initials: BM
authors.lastname: Wynne
authors.forename: Rita
authors.initials: R
authors.lastname: Tostes
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D062186:Arterial Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D007172:Erectile Dysfunction / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D000804:Angiotensin II; D008687:Metformin; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases
keywords: Angiotensin II; Corpus Cavernosum; Erectile Dysfunction; Hypertension; Metformin; eNOS
references.citation: Mol Cell Endocrinol. 2009 Apr 29;302(2):128-39
references.pmid: 19150387
references.citation: Circ Res. 2007 Feb 16;100(3):328-41
references.pmid: 17307971
references.citation: Circ Res. 2009 Feb 27;104(4):422-4
references.pmid: 19246685
references.citation: Urology. 2001 Nov;58(5):805-10
references.pmid: 11711372
references.citation: Lancet. 1998 Sep 12;352(9131):854-65
references.pmid: 9742977
references.citation: J Androl. 2007 Jul-Aug;28(4):555-60
references.pmid: 17314235
references.citation: Clin Exp Pharmacol Physiol. 2008 May;35(5-6):535-45
references.pmid: 18177481
references.citation: Curr Opin Urol. 2006 Nov;16(6):435-43
references.pmid: 17053524
references.citation: Am J Cardiol. 2005 Dec 26;96(12B):8M-12M
references.pmid: 16387559
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R974-80
references.pmid: 17581838
references.citation: Brain Res. 2003 Jan 3;959(1):20-8
references.pmid: 12480154
references.citation: J Sex Med. 2009 Mar;6 Suppl 3:210-20
references.pmid: 19207270
references.citation: J Sex Med. 2005 Jan;2(1):26-39
references.pmid: 16422902
references.citation: Curr Opin Nephrol Hypertens. 2012 Mar;21(2):163-70
references.pmid: 22240443
references.citation: FEBS Lett. 1999 Jan 29;443(3):285-9
references.pmid: 10025949
references.citation: Biochem Biophys Res Commun. 2004 Nov 26;324(4):1204-9
references.pmid: 15504342
references.citation: J Intern Med. 1991 Feb;229(2):181-7
references.pmid: 1900072
references.citation: Nat Med. 2001 Jan;7(1):119-22
references.pmid: 11135626
references.citation: J Sex Med. 2008 Dec;5(12):2793-807
references.pmid: 18823320
references.citation: J Sex Med. 2011 Aug;8(8):2205-14
references.pmid: 20487243
references.citation: Am J Physiol. 1998 May;274(5):E867-76
references.pmid: 9612245
references.citation: Am J Physiol Renal Physiol. 2005 May;288(5):F871-80
references.pmid: 15821252
references.citation: Life Sci. 2006 Apr 25;78(22):2615-24
references.pmid: 16318863
references.citation: J Sex Med. 2008 Mar;5(3):544-51
references.pmid: 18208505
references.citation: Curr Opin Pharmacol. 2010 Apr;10(2):111-5
references.pmid: 20060780
references.citation: Am J Physiol Heart Circ Physiol. 2004 Oct;287(4):H1495-500
references.pmid: 15371261
references.citation: J Sex Med. 2011 Dec;8(12):3335-44
references.pmid: 21995824
references.citation: J Clin Invest. 1997 Nov 1;100(9):2158-69
references.pmid: 9410892
references.citation: Diabetes Care. 1993 Oct;16(10):1387-90
references.pmid: 8269798
references.citation: J Sex Med. 2012 Mar;9(3):837-43
references.pmid: 22304542
references.citation: J Urol. 1994 Jan;151(1):54-61
references.pmid: 8254833
references.citation: J Sex Med. 2008 Jun;5(6):1278-83
references.pmid: 18558990
references.citation: Gend Med. 2009;6 Suppl 1:4-16
references.pmid: 19318216
references.citation: J Intern Med. 1994 Apr;235(4):335-41
references.pmid: 8151265
references.citation: Diabetes. 2008 Feb;57(2):306-14
references.pmid: 17909097
references.citation: Curr Med Res Opin. 2004 May;20(5):607-17
references.pmid: 15171225
references.citation: Circ Res. 2009 Feb 27;104(4):496-505
references.pmid: 19131647
references.citation: Hypertension. 2006 Jun;47(6):1183-8
references.pmid: 16636195
references.citation: Diabetes. 2005 Apr;54(4):1123-31
references.pmid: 15793252
references.citation: Circulation. 2004 Jul 27;110(4):444-51
references.pmid: 15262850
references.citation: Cell. 2009 May 15;137(4):635-46
references.pmid: 19450513
references.citation: Eur J Pharmacol. 2002 Mar 29;439(1-3):173-4
references.pmid: 11937108
references.citation: J Sex Med. 2009 Mar;6 Suppl 3:302-10
references.pmid: 19267853
references.citation: Saudi Med J. 2009 Feb;30(2):184-90
references.pmid: 19198703
references.citation: Can J Physiol Pharmacol. 2008 Jun;86(6):320-8
references.pmid: 18516094
references.citation: Int J Impot Res. 2002 Aug;14(4):217-25
references.pmid: 12152110
references.citation: Pflugers Arch. 2010 May;459(6):923-39
references.pmid: 20306272
references.citation: Hypertension. 1996 Mar;27(3 Pt 2):619-25
references.pmid: 8613213
references.citation: J Sex Med. 2010 Nov;7(11):3620-34
references.pmid: 20807325
references.citation: Int J Clin Pract. 2005 Feb;59(2):225-9
references.pmid: 15854201
references.citation: Asian J Androl. 2008 Jan;10(1):6-13
references.pmid: 18087638
references.citation: J Pharmacol Exp Ther. 2006 Jul;318(1):288-95
references.pmid: 16569756
references.citation: Hypertension. 1999 May;33(5):1135-40
references.pmid: 10334800
references.citation: J Urol. 1997 May;157(5):1920-5
references.pmid: 9112563
references.citation: J Mol Med (Berl). 2008 Jun;86(6):615-21
references.pmid: 18414822
references.citation: Int J Impot Res. 2004 Oct;16 Suppl 2:S40-1
references.pmid: 15496856
references.citation: J Sex Med. 2011 Jun;8(6):1638-49
references.pmid: 21477013
references.citation: Diabetes. 2006 Mar;55(3):716-24
references.pmid: 16505235
references.citation: Biochem Pharmacol. 2006 Jul 14;72(2):176-83
references.pmid: 16730666
references.citation: Hypertension. 2000 Jan;35(1 Pt 1):108-12
references.pmid: 10642283
references.citation: Metabolism. 2005 Jun;54(6):829-34
references.pmid: 15931622
references.citation: J Pharmacol Exp Ther. 1994 Dec;271(3):1334-7
references.pmid: 7996443