Dados do Trabalho

Título

RESVERATROL-NITRIC OXIDE DONOR HYBRID EFFECT ON PRIAPISM IN SICKLE CELL AND NITRIC OXIDE-DEFICIENT MOUSE

Resumo

Introduction: Children and adult with sickle cell disease (SCD) display priapism associated with low nitric oxide (NO) bioavailability and oxidative stress in penis. In SCD and endothelial NO synthase gene-deficient (eNOS-/-) mice corpus cavernosum, low NO-cGMP bioavailability is associated with PDE5 downregulation. Current pharmacological approaches are non-preventive for priapism;25 therefore, developments of preventive strategy are necessary. Preferably, pharmacological strategies should correct pathophysiologic basis of this disorder. Since low NO-cGMP bioavailability and oxidative stress are associated to priapism, we have developed the hybrid compound (E)-4-(4-(4-methoxystyryl) phenoxy)-3-methyl-1,2,5-oxadiazole 2-N-oxide (RVT-FxMe), derived from resveratrol bearing a NO-donor subunit. Aim: The aim of this study was to evaluate the effects of RVT-FxMe, on functional alterations of erectile function in murine models that display low NO-cGMP bioavailability and increased oxidative stress, SCD transgenic mice and eNOS-/- mice. We have focused on the dysregulated NO-cGMP in erectile tissue of SCD and eNOS-/- mice. Methods: Wild-type, SCD, and eNOS-/- mice were treated with RVT-FxMe (25 mg/kg/d, 2 weeks). Hematological parameters, concentration-response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), as well as to electrical field stimulation (EFS), were obtained in mice corpus cavernosum strips. Results: Corpus cavernosum relaxations to SNP and EFS were increased in eNOS-/- group, which were normalized by RVT-FxMe treatment. SCD mice exhibited an excessive corpus cavernosum relaxant response induced by ACh, EFS and SNP. RVT-FxMe treatment did not change the increased relaxant responses to ACh, EFS and SNP in corpus cavernosum from SCD group. Conclusion: Compound RVT-FxMe short-term treatment reversed enhanced NO-cGMP-mediated CC relaxations in eNOS-/- mice, but not in SCD mice. It is likely that excess of plasma hemoglobin in SCD mice act to inactivate NO before it reaches sGC, avoiding restoration of NO bioavailability in penis.

Palavras Chave ( separado por ; )

anemia; sickle cell disease, cGMP, hemoglobin, corpus cavernosum