Programa de Pós-graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil; Laboratório de Farmacologia, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil.
Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil.
Eur J Pharmacol. 2017 Jun 5;804:82-93. doi: 10.1016/j.ejphar.2017.03.024. Epub 2017 Mar 15.
Ethanol consumption is associated with an increased risk of erectile dysfunction (ED), but the molecular mechanisms through which ethanol causes ED remain elusive. Reactive oxygen species are described as mediators of ethanol-induced cell toxicity/damage in distinctive tissues. The enzyme NADPH oxidase is the main source of reactive oxygen species in the endothelium and vascular smooth muscle cells and ethanol is described to increase NADPH oxidase activation and reactive oxygen species generation. This study evaluated the contribution of NADPH oxidase-derived reactive oxygen species to ethanol-induced ED, endothelial dysfunction and production of pro-inflammatory and redox-sensitive proteins in the rat cavernosal smooth muscle (CSM). Male Wistar rats were treated with ethanol (20% v/v) or ethanol plus apocynin (30mg/kg/day; p.o. gavage) for six weeks. Apocynin prevented both the decreased in acetylcholine-induced relaxation and intracavernosal pressure induced by ethanol. Ethanol increased superoxide anion (O) generation and catalase activity in CSM, and treatment with apocynin prevented these responses. Similarly, apocynin prevented the ethanol-induced decreased of nitrate/nitrite (NOx), hydrogen peroxide (HO) and SOD activity. Treatment with ethanol increased p47phox translocation to the membrane as well as the expression of Nox2, COX-1, catalase, iNOS, ICAM-1 and p65. Apocynin prevented the effects of ethanol on protein expression and p47phox translocation. Finally, treatment with ethanol increased both TNF-α production and neutrophil migration in CSM. The major new finding of this study is that NADPH oxidase-derived reactive oxygen species play a role on chronic ethanol consumption-induced ED and endothelial dysfunction in the rat CSM.
乙醇摄入与勃起功能障碍（ED）风险增加有关，但乙醇导致 ED 的分子机制仍不清楚。活性氧被描述为不同组织中乙醇诱导的细胞毒性/损伤的介质。NADPH 氧化酶是内皮细胞和血管平滑肌细胞中活性氧的主要来源，乙醇被描述为增加 NADPH 氧化酶的激活和活性氧的产生。本研究评估了 NADPH 氧化酶衍生的活性氧在乙醇诱导的 ED、内皮功能障碍和大鼠海绵体平滑肌（CSM）中促炎和氧化还原敏感蛋白产生中的作用。雄性 Wistar 大鼠用乙醇（20%v/v）或乙醇加 apocynin（30mg/kg/天；口服灌胃）处理 6 周。Apocynin 可预防乙醇引起的乙酰胆碱诱导的松弛和海绵体内压降低。乙醇增加了 CSM 中超氧阴离子（O）的产生和过氧化氢酶活性，而 apocynin 处理可预防这些反应。同样，apocynin 可预防乙醇诱导的硝酸盐/亚硝酸盐（NOx）、过氧化氢（HO）和 SOD 活性降低。乙醇处理增加了 p47phox 向膜的易位以及 Nox2、COX-1、过氧化氢酶、iNOS、ICAM-1 和 p65 的表达。Apocynin 可预防乙醇对蛋白表达和 p47phox 易位的影响。最后，乙醇处理增加了 CSM 中 TNF-α 的产生和中性粒细胞的迁移。本研究的主要新发现是，NADPH 氧化酶衍生的活性氧在慢性乙醇摄入引起的大鼠 CSM 中 ED 和内皮功能障碍中起作用。
