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. MATERIALS AND 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)%. CONCLUSION: 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.