Department of Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil.
Department of Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil.
Eur J Pharmacol. 2018 Mar 5;822:119-127. doi: 10.1016/j.ejphar.2018.01.010. Epub 2018 Jan 24.
Sildenafil has shown nitric oxide (NO)-independent pleiotropic effects, however the mechanisms involved are unclear. We investigated the protective effects of sildenafil against hypertension in pregnancy and feto-placental growth restriction induced by NO inhibition, and if sodium nitrite-derived NO formation influences sildenafil effects. We evaluated the plasmatic levels of NO metabolites, cyclic guanosine monophosphate (cGMP), oxidative stress and myeloperoxidase, which are involved in endothelial dysfunction during hypertension in pregnancy. Also, we performed in vitro experiments to examine cell viability and NO synthesis in human umbilical vein endothelial cells (HUVECs) cultures incubated with plasma from healthy or hypertensive pregnant rats treated (or not) with both drugs, either alone or in association. Sildenafil blunted hypertension in pregnancy and protected against feto-placental growth restriction induced by NO inhibition and these effects of sildenafil alone were similar to those presented by its association with sodium nitrite. Protective effects of sildenafil were observed even with low plasmatic NO levels and were not followed by increases in cGMP levels. Also, sildenafil, but not sodium nitrite, blunted the increases in myeloperoxidase activity. Both drugs (isolated or in association) presented antioxidant effects. Plasma from hypertensive pregnant rats treated with sildenafil, but not sodium nitrite alone, increased the viability of HUVECs. NO synthesis in HUVECs cultures was increased with plasma from rats treated with both drugs. We conclude that sildenafil effects are not dependent of circulating NO levels in hypertension and feto-placental growth restriction. These findings may reflect a protection against myeloperoxidase and pro-oxidant activation in hypertension in pregnancy.
西地那非具有非一氧化氮（NO）依赖性的多效作用，但具体机制尚不清楚。我们研究了西地那非对由 NO 抑制引起的妊娠高血压和胎-胎盘生长受限的保护作用，以及亚硝酸盐衍生的 NO 形成是否会影响西地那非的作用。我们评估了参与妊娠高血压期间内皮功能障碍的 NO 代谢物、环鸟苷单磷酸（cGMP）、氧化应激和髓过氧化物酶的血浆水平。此外，我们还进行了体外实验，以检查与健康或高血压妊娠大鼠的血浆孵育的人脐静脉内皮细胞（HUVEC）培养物中的细胞活力和 NO 合成，这些大鼠单独或联合使用两种药物（或不使用）进行了处理。西地那非可减轻妊娠高血压并预防由 NO 抑制引起的胎-胎盘生长受限，西地那非的这些作用与其与亚硝酸盐的联合作用相似。即使在低血浆 NO 水平下，西地那非也能发挥保护作用，且不会导致 cGMP 水平升高。此外，西地那非可减轻髓过氧化物酶活性的升高，但亚硝酸盐不行。两种药物（单独或联合使用）均具有抗氧化作用。与单独使用亚硝酸盐相比，仅用西地那非治疗的高血压妊娠大鼠的血浆可增加 HUVEC 的活力。用两种药物处理的大鼠的血浆可增加 HUVEC 培养物中的 NO 合成。我们得出结论，西地那非的作用不依赖于高血压和胎-胎盘生长受限中的循环 NO 水平。这些发现可能反映了对妊娠高血压中髓过氧化物酶和促氧化剂激活的保护作用。
