title: Penicillamine administration reverses the inhibitory effect of hyperhomocysteinaemia on endothelium-dependent relaxation in the corpus cavernosum in the rabbit.
abstract: OBJECTIVE
  To elucidate the role of copper in mediating the impact of homocysteine on vasculogenic erectile dysfunction (VED), by investigating the effect of dietary supplementation with the copper-chelator penicillamine to rabbits rendered hyperhomocysteinaemic (HHC) with a methionine-rich diet, as a raised plasma level of homocysteine might be a risk factor for VED.
  
  
  METHODS
  Homocysteine inhibits the nitric oxide (NO)-dependent relaxation of the corpus cavernosum (CC), an effect which appears to be mediated via the generation of superoxide (O2*-), and H2O2. Copper is a catalyst for the generation of H2O2 in the presence of homocysteine and in the presence of copper, H2O2 undergoes reactions resulting in the generation of O2*-, which reacts with NO to produce peroxynitrite (ONOO-), thereby reducing the bioavailability of NO and impairing NO-mediated relaxation of CC. Smooth muscle strips from CC were obtained from two groups of adult New Zealand White rabbits, one rendered HHC with a diet supplemented with methionine (group 1) and another HHC group that had additional dietary supplementation with penicillamine (group 2). Tissue O2*- levels were measured in each group. After pre-contraction with phenylephrine, relaxation responses of CC strips to carbachol were also assessed in both groups.
  
  
  RESULTS
  Methionine supplementation led to profound HHC in all rabbits. Penicillamine in group 2 reduced the total plasma Cu2+ compared to group 1. There was a markedly lower carbachol-stimulated relaxation of CC from HHC rabbits in group 1, with a mean (sem) maximum relaxation of 37 (4)% (six samples), than in group 2, at 58 (6)%.
  
  
  CONCLUSIONS
  These data show that elevated levels in vivo of homocysteine in the rabbit markedly impair NO-dependent relaxation of the CC. Furthermore, this effect appears to be augmented by copper. Further clinical studies on homocysteine and copper status in patients with VED are warranted.
authors.affiliation: Urology, Bristol Royal Infirmary, Bristol, UK. koupps@hotmail.com
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koupparis
authors.forename: Jamie
authors.initials: J
authors.lastname: Jeremy
authors.forename: Gianni
authors.initials: G
authors.lastname: Angelini
authors.forename: Raj
authors.initials: R
authors.lastname: Persad
authors.forename: Nilima
authors.initials: N
authors.lastname: Shukla
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D020138:Hyperhomocysteinemia / Q000503:physiopathology*; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D009126:Muscle Relaxation / Q000187:drug effects*; D010396:Penicillamine / Q000494:pharmacology*; D010413:Penis / Q000187:drug effects*; D011817:Rabbits
chemical_list: D002614:Chelating Agents; D008715:Methionine; D010396:Penicillamine