title: Endothelin-1 contributes to endothelial dysfunction and enhanced vasoconstriction through augmented superoxide production in penile arteries from insulin-resistant obese rats: role of ET(A) and ET(B) receptors.
abstract: OBJECTIVE
  We assessed whether endothelin-1 (ET-1) inhibits NO and contributes to endothelial dysfunction in penile arteries in a model of insulin resistance-associated erectile dysfunction (ED).
  
  
  METHODS
  Vascular function was assessed in penile arteries, from obese (OZR) and lean (LZR) Zucker rats, mounted in microvascular myographs. Changes in basal and stimulated levels of superoxide (O2 (-) ) were detected by lucigenin-enhanced chemiluminescence and ET receptor expression was determined by immunohistochemistry.
  
  
  RESULTS
  ET-1 stimulated acute O2 (-) production that was blunted by tempol and the NADPH oxidase inhibitor, apocynin, but markedly enhanced in obese animals. ET-1 inhibited the vasorelaxant effects of ACh and of the NO donor S-nitroso-N-acetyl-DL-penicillamine in arteries from both LZR and OZR. Selective ETA (BQ123) or ETB receptor (BQ788) antagonists reduced both basal and ET-1-stimulated superoxide generation and reversed ET-1-induced inhibition of NO-mediated relaxations in OZR, while only BQ-123 antagonized ET-1 actions in LZR. ET-1-induced vasoconstriction was markedly enhanced by NO synthase blockade and reduced by endothelium removal and apocynin. In endothelium-denuded penile arteries, apocynin blunted augmented ET-1-induced contractions in OZR. Both ETA and ETB receptors were expressed in smooth muscle and the endothelial layer and up-regulated in arteries from OZR.
  
  
  CONCLUSIONS
  ET-1 stimulates ETA -mediated NADPH oxidase-dependent ROS generation, which inhibits endothelial NO bioavailability and contributes to ET-1-induced contraction in healthy penile arteries. Enhanced vascular expression of ETB receptors contributes to augmented ROS production, endothelial dysfunction and increased vasoconstriction in erectile tissue from insulin-resistant obese rats. Hence, antagonism of ETB receptors might improve the ED associated with insulin-resistant states.
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sánchez
authors.forename: P
authors.initials: P
authors.lastname: Martínez
authors.forename: M
authors.initials: M
authors.lastname: Muñoz
authors.forename: S
authors.initials: S
authors.lastname: Benedito
authors.forename: A
authors.initials: A
authors.lastname: García-Sacristán
authors.forename: M
authors.initials: M
authors.lastname: Hernández
authors.forename: D
authors.initials: D
authors.lastname: Prieto
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism* / Q000503:physiopathology; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D018783:Impotence, Vasculogenic / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010413:Penis / Q000098:blood supply; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species; D013481:Superoxides / Q000378:metabolism*; D013851:Thinness / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D017382:Reactive Oxygen Species; D013481:Superoxides; D009569:Nitric Oxide; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
references.citation: Cardiovasc Res. 2001 Jan;49(1):146-51
references.pmid: 11121806
references.citation: Br J Pharmacol. 2008 Dec;155(7):974-83
references.pmid: 19029977
references.citation: J Sex Med. 2008 Dec;5(12):2793-807
references.pmid: 18823320
references.citation: Diabetes. 2002 Dec;51(12):3517-23
references.pmid: 12453909
references.citation: Am J Physiol Renal Physiol. 2007 Jan;292(1):F175-84
references.pmid: 16788136
references.citation: J Pharmacol Exp Ther. 2011 Apr;337(1):9-15
references.pmid: 21205912
references.citation: Br J Urol. 1995 Aug;76(2):203-7
references.pmid: 7663911
references.citation: Free Radic Biol Med. 2004 Jul 1;37(1):115-23
references.pmid: 15183199
references.citation: Hypertension. 2003 Sep;42(3):316-21
references.pmid: 12885792
references.citation: Clin Sci (Lond). 2002 Aug;103 Suppl 48:13S-15S
references.pmid: 12193045
references.citation: Diabetes. 2011 Aug;60(8):2061-7
references.pmid: 21677282
references.citation: Atherosclerosis. 2007 Feb;190(2):408-15
references.pmid: 16527283
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14367-72
references.pmid: 9826706
references.citation: Life Sci. 2012 Oct 15;91(13-14):723-8
references.pmid: 22483692
references.citation: Clin Sci (Lond). 2002 Mar;102(3):321-7
references.pmid: 11869173
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H281-8
references.pmid: 18487445
references.citation: Atherosclerosis. 2009 Jan;202(1):58-67
references.pmid: 18436224
references.citation: Br J Pharmacol. 2005 Jun;145(3):323-33
references.pmid: 15765100
references.citation: J Clin Invest. 2006 Apr;116(4):1071-80
references.pmid: 16528409
references.citation: Arterioscler Thromb Vasc Biol. 2005 Aug;25(8):1551-7
references.pmid: 15879305
references.citation: Hypertension. 2003 Oct;42(4):811-7
references.pmid: 12913063
references.citation: PLoS One. 2012;7(4):e36027
references.pmid: 22540017
references.citation: Acta Physiol (Oxf). 2009 Jun;196(2):193-222
references.pmid: 19220204
references.citation: Circulation. 2007 Feb 6;115(5):627-37
references.pmid: 17242275
references.citation: Exp Eye Res. 2009 Nov;89(5):693-9
references.pmid: 19576886
references.citation: Br J Pharmacol. 2013 Dec;170(8):1459-581
references.pmid: 24517644
references.citation: Pharmacol Res. 2011 Jun;63(6):496-501
references.pmid: 21185376
references.citation: Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H904-11
references.pmid: 17012356
references.citation: Atherosclerosis. 2010 Sep;212(1):78-85
references.pmid: 20553682
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D1098-106
references.pmid: 24234439
references.citation: Eur Heart J. 2013 Jul;34(27):2034-46
references.pmid: 23616415
references.citation: Life Sci. 2012 Oct 15;91(13-14):507-16
references.pmid: 22483688
references.citation: Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H689-95
references.pmid: 21666117
references.citation: Hypertension. 2004 May;43(5):1048-54
references.pmid: 15051669
references.citation: Br J Pharmacol. 2013 Dec;170(8):1797-867
references.pmid: 24528243
references.citation: Biochem Biophys Res Commun. 2000 Mar 24;269(3):713-7
references.pmid: 10720482
references.citation: J Sex Med. 2013 Sep;10(9):2141-53
references.pmid: 23875673
references.citation: Br J Pharmacol. 2010 Aug;160(7):1577-9
references.pmid: 20649561
references.citation: Hypertension. 2005 Feb;45(2):283-7
references.pmid: 15623539
references.citation: Diabetes. 2004 Aug;53(8):2060-6
references.pmid: 15277386
references.citation: Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H696-707
references.pmid: 19542483
references.citation: Life Sci. 2014 Nov 24;118(2):263-7
references.pmid: 24434796
references.citation: Br J Pharmacol. 2010 Feb 1;159(3):604-16
references.pmid: 20082610
references.citation: Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E568-77
references.pmid: 19491294
references.citation: J Cardiovasc Pharmacol. 2006 Mar;47(3):385-90
references.pmid: 16633080
references.citation: Am J Physiol Heart Circ Physiol. 2010 Sep;299(3):H915-24
references.pmid: 20581086
references.citation: J Androl. 2002 Jan-Feb;23(1):76-83
references.pmid: 11780926
references.citation: Am J Physiol Renal Physiol. 2008 Apr;294(4):F719-28
references.pmid: 18256310
references.citation: Br J Pharmacol. 2010 Aug;160(7):1573-6
references.pmid: 20649560
references.citation: J Pharmacol Exp Ther. 2005 Dec;315(3):1058-64
references.pmid: 16144972
references.citation: Diabetologia. 2012 Mar;55(3):600-7
references.pmid: 22200728
references.citation: J Urol. 1997 Nov;158(5):1966-72
references.pmid: 9334651
references.citation: Cardiovasc Res. 2007 Jan 15;73(2):368-75
references.pmid: 17166491
references.citation: Basic Clin Pharmacol Toxicol. 2012 Jan;110(1):87-94
references.pmid: 21883939
references.citation: Br J Pharmacol. 2010 Sep;161(2):350-64
references.pmid: 20735420
references.citation: Eur Heart J. 2010 Nov;31(22):2741-8
references.pmid: 20974801
references.citation: Free Radic Biol Med. 2005 Mar 1;38(5):589-96
references.pmid: 15683715
references.citation: BJU Int. 2006 Jul;98(1):116-24
references.pmid: 16831155
references.citation: J Urol. 1997 Nov;158(5):1770-4
references.pmid: 9334598
references.citation: Curr Vasc Pharmacol. 2014 May;12(3):412-26
references.pmid: 24846231