title: Role of neural NO synthase (nNOS) uncoupling in the dysfunctional nitrergic vasorelaxation of penile arteries from insulin-resistant obese Zucker rats.
abstract: OBJECTIVE
  Erectile dysfunction (ED) is considered as an early sign of vascular disease due to its high prevalence in patients with cardiovascular risk factors. Endothelial and neural dysfunction involving nitric oxide (NO) are usually implicated in the pathophysiology of the diabetic ED, but the underlying mechanisms are unclear. The present study assessed the role of oxidative stress in the dysfunctional neural vasodilator responses of penile arteries in the obese Zucker rat (OZR), an experimental model of metabolic syndrome/prediabetes.
  
  
  RESULTS
  Electrical field stimulation (EFS) under non-adrenergic non-cholinergic (NANC) conditions evoked relaxations that were significantly reduced in penile arteries of OZR compared with those of lean Zucker rats (LZR). Blockade of NO synthase (NOS) inhibited neural relaxations in both LZR and OZR, while saturating concentrations of the NOS substrate L-arginine reversed the inhibition and restored relaxations in OZR to levels in arteries from LZR. nNOS expression was unchanged in arteries from OZR compared to LZR and nNOS selective inhibition decreased the EFS relaxations in LZR but not in OZR, while endothelium removal did not alter these responses in either strain. Superoxide anion production and nitro-tyrosine immunostaining were elevated in the erectile tissue from OZR. Treatment with the NADPH oxidase inhibitor apocynin or acute incubation with the NOS cofactor tetrahydrobiopterin (BH4) restored neural relaxations in OZR to levels in control arteries, while inhibition of the enzyme of BH4 synthesis GTP-cyclohydrolase (GCH) reduced neural relaxations in arteries from LZR but not OZR. The NO donor SNAP induced decreases in intracellular calcium that were impaired in arteries from OZR compared to controls.
  
  
  CONCLUSIONS
  The present study demonstrates nitrergic dysfunction and impaired neural NO signalling due to oxidative stress and nNOS uncoupling in penile arteries under conditions of insulin resistance. This dysfunction likely contributes to the metabolic syndrome-associated ED, along with the endothelial dysfunction also involving altered NO signalling.
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sánchez
authors.forename: Cristina
authors.initials: C
authors.lastname: Contreras
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Martínez
authors.forename: Belén
authors.initials: B
authors.lastname: Climent
authors.forename: Sara
authors.initials: S
authors.lastname: Benedito
authors.forename: Albino
authors.initials: A
authors.lastname: García-Sacristán
authors.forename: Medardo
authors.initials: M
authors.lastname: Hernández
authors.forename: Dolores
authors.initials: D
authors.lastname: Prieto
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001158:Arteries / Q000503:physiopathology; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000378:metabolism; D007172:Erectile Dysfunction / Q000209:etiology; D006136:GTP Cyclohydrolase / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010413:Penis / Q000098:blood supply*; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000098:Acetophenones; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D001120:Arginine; C056165:acetovanillone; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D006136:GTP Cyclohydrolase; C003402:sapropterin; D002118:Calcium