1. Academic Validation
  2. Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice

Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice

  • Br J Pharmacol. 2023 Apr 6. doi: 10.1111/bph.16087.
Miguel A Olivencia 1 2 3 Leticia Gil de Biedma-Elduayen 1 4 5 6 Pablo Giménez-Gómez 1 4 5 6 Bianca Barreira 1 2 3 Argentina Fernández 7 8 Javier Angulo 7 8 Maria Isabel Colado 1 4 5 6 Esther O'Shea 1 4 5 6 Francisco Perez-Vizcaino 1 2 3
Affiliations

Affiliations

  • 1 Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
  • 2 CIBER Enfermedades Respiratorias, Madrid, Spain.
  • 3 Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
  • 4 Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain.
  • 5 Red de Trastornos Adictivos del Instituto de Salud Carlos III, Madrid, Spain.
  • 6 Instituto Universitario de Investigación Neuroquímica (IUIN), Facultad de Medicina, Universidad Complutense, Madrid, Spain.
  • 7 Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.
  • 8 Servicio de Histología-Investigación, Unidad de Investigación Traslacional en Cardiología (IRYCIS-UFV), Hospital Universitario Ramón y Cajal, Madrid, Spain.
Abstract

Background and purpose: Alcohol abuse has been associated with erectile dysfunction (ED) but the molecular mechanisms implicated are unknown. This study analyses the role of alterations in soluble guanylyl cyclase (sGC) in ED.

Experimental approach: ED was analysed in adult male C57BL/6J mice subjected to the Chronic Intermittent Ethanol (CIE) paradigm. Erectile function was assessed in anesthetized mice in vivo by evaluating intracavernosal pressure (ICP) and in vitro in isolated mice corpora cavernosa (CC) mounted in a myograph. Protein expression and Reactive Oxygen Species were analysed by Western blot and dihydroethidium staining, respectively.

Key results: In CIE mice, we observed a significant decrease in the relaxant response of the CC to stimulation of NO release from nitrergic nerves by electrical field stimulation, to NO release from endothelial cells by acetylcholine, to the PDE5 Inhibitor sildenafil, and to the sGC stimulator riociguat. Conversely, the response to the sGC activator cinaciguat, whose action is independent on the oxidation state of sGC, was significantly enhanced in these CC. The responses to the adenylyl cyclase stimulation with forskolin were unchanged. We found an increase in Reactive Oxygen Species in the CC from CIE mice as well as an increase in CYP2E1 and NOX2 protein expression. In vivo pre-treatment with tempol prevented alcohol-induced erectile dysfunction.

Conclusions and implications: Our results demonstrate that alcoholic mice show ED in vitro and in vivo due to an alteration of the redox state of sGC and suggest that sGC activators may be effective in ED associated with alcoholism.

Keywords

alcohol; cinaciguat; erectile dysfunction; mice; soluble guanylyl cyclase.

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