title: Resveratrol Stimulates Hydrogen Sulfide (H2 S) Formation to Relax Murine Corpus Cavernosum.
abstract: BACKGROUND
  Resveratrol (RVT) found in red wine protects against erectile dysfunction and relaxes penile tissue (corpus cavernosum) via a nitric oxide (NO) independent pathway. However, the mechanism remains to be elucidated. Hydrogen sulfide (H2 S) is a potent vasodilator and neuromodulator generated in corpus cavernosum.
  
  
  OBJECTIVE
  We investigated whether RVT caused the relaxation of mice corpus cavernosum (MCC) through H2 S.
  
  
  METHODS
  H2 S formation is measured by methylene blue assay and vascular reactivity experiments have been performed by DMT strip myograph in CD1 MCC strips.
  
  
  METHODS
  Endothelial NO synthase (eNOS) inhibitor Nω-Nitro-L-arginine (L-NNA, 0.1 mM) or H2 S inhibitor aminooxyacetic acid (AOAA, 2 mM) which inhibits both cystathionine-β-synthase (CBS) and cystathionine-gamma-lyase (CSE) enzyme or combination of AOAA with PAG (CSE inhibitor) has been used in the presence/absence of RVT (0.1 mM, 30 min) to elucidate the role of NO or H2 S pathways on the effects of RVT in MCC. Concentration-dependent relaxations to RVT, L-cysteine, sodium hydrogen sulfide (NaHS) and acetylcholine (ACh) were studied.
  
  
  RESULTS
  Exposure of murine corpus cavernosum to RVT increased both basal and L-cysteine-stimulated H2 S formation. Both of these effects were reversed by AOAA but not by L-NNA. RVT caused concentration-dependent relaxation of MCC and that RVT-induced relaxation was significantly inhibited by AOAA or AOAA + PAG but not by L-NNA. L-cysteine caused concentration-dependent relaxations, which are inhibited by AOAA or AOAA + PAG significantly. Incubation of MCC with RVT significantly increased L-cysteine-induced relaxation, and this effect was inhibited by AOAA + PAG. However, RVT did not alter the effect of exogenous H2 S (NaHS) or ACh-induced relaxations.
  
  
  CONCLUSIONS
  These results demonstrate that RVT-induced relaxation is at least partly dependent on H2 S formation and acts independent of eNOS pathway. In phosphodiesterase 5 inhibitor (PDE-5i) nonresponder population, combination therapy with RVT may reverse erectile dysfunction via stimulating endogenous H2 S formation.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey.
authors.forename: Gunay
authors.identifier: http://orcid.org/0000-0002-7788-1657
authors.initials: G
authors.lastname: Yetik-Anacak
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey.
authors.forename: Mehmet V
authors.initials: MV
authors.lastname: Dereli
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey.
authors.forename: Gulnur
authors.initials: G
authors.lastname: Sevin
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey.
authors.forename: Ozge
authors.initials: O
authors.lastname: Ozzayım
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Erac
authors.affiliation: Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, UK.
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism / Q000502:physiology; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000187:drug effects / Q000473:pathology*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D013267:Stilbenes; D014665:Vasodilator Agents; D009569:Nitric Oxide; D001120:Arginine; D003545:Cysteine; D000077185:Resveratrol; D006862:Hydrogen Sulfide
keywords: Corpus Cavernosum; Erectile Dysfunction; Hydrogen Sulfide; Phosphodiesterase 5 Inhibitor; Resveratrol