Laboratory of Multidisciplinary Research, São Francisco University Medical School, Bragança Paulista, SP, Brazil.
State University of São Paulo (UNESP), School of Pharmaceutical Science, Laboratory of Drug Discovery, Araraquara, SP, Brazil.
PLoS One. 2022 Jun 2;17(6):e0269310. doi: 10.1371/journal.pone.0269310. eCollection 2022.
Children and adult with sickle cell disease (SCD) display priapism associated with low nitric oxide (NO) bioavailability and oxidative stress in penis.
This study aimed to evaluate the effects of hybrid compound RVT-FxMe, derived from resveratrol bearing a NO-donor subunit, on two murine model that display priapism phenotype, SCD transgenic mice and endothelial NO synthase gene-deficient (eNOS-/-) mice.
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.
Corpus cavernosum relaxations to SNP and EFS were increased in eNOS-/- group, which were normalized by RVT-FxMe treatment. SCD mice exhibited an excessive CC 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.
Excess of plasma hemoglobin in SCD may interfere in pharmacological activity of NO donors compounds.
STRENGTH/LIMITATIONS: While mechanistic data with promising potential is showed, the current study is not without limitations. RVT-FxMe effects in the mid- and long-term warrant complementary studies.
Treatment with RVT-FxMe reversed the 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 soluble guanylyl cyclase, avoiding restoration of NO bioavailability in penis.
患有镰状细胞病（SCD）的儿童和成人表现出与阴茎中一氧化氮（NO）生物利用度降低和氧化应激相关的阴茎异常勃起。
本研究旨在评估源自具有 NO 供体部分的白藜芦醇的混合化合物 RVT-FxMe 对两种表现出阴茎异常勃起表型的小鼠模型，即 SCD 转基因小鼠和内皮型一氧化氮合酶基因缺失（eNOS-/-）小鼠的影响。
用 RVT-FxMe（25mg/kg/d，2 周）处理野生型、SCD 和 eNOS-/-小鼠。
获得了小鼠海绵体组织条的乙酰胆碱（ACh）和硝普钠（SNP）浓度反应曲线以及电刺激（EFS）的血液学参数。
eNOS-/-组的海绵体松弛对 SNP 和 EFS 的反应增加，RVT-FxMe 处理使其正常化。SCD 小鼠表现出 ACh、EFS 和 SNP 诱导的过度 CC 松弛反应，RVT-FxMe 处理并未改变 SCD 组海绵体对 ACh、EFS 和 SNP 的增加松弛反应。
SCD 中的血浆血红蛋白过多可能会干扰 NO 供体化合物的药理学活性。
虽然显示了有希望的潜在机制数据，但本研究并非没有局限性。RVT-FxMe 的中-长期效果需要补充研究。
RVT-FxMe 治疗逆转了 eNOS-/-小鼠中增强的 NO-cGMP 介导的 CC 松弛反应，但在 SCD 小鼠中没有；SCD 小鼠中的过量血浆血红蛋白可能在 NO 到达可溶性鸟苷酸环化酶之前使其失活，从而避免阴茎中 NO 生物利用度的恢复。
