Hiding in Plain Sight: Nebivolol Exhibits Compelling Tocolytic Properties.

Preterm birth before 37 weeks of completed gestation results in numerous health consequences for the foetus. Preterm labour leads to preterm birth in over 50% of cases, and no FDA‐approved treatment can prevent labour or help a foetus remain in the womb until term. Examination of nitric oxide mediated relaxation signaling in the uterine smooth muscle reveals a role for protein S‐nitrosation. The recent discovery of upregulated S‐nitrosoglutathione reductase (GSNOR) in spontaneously preterm labouring women has emphasized the need to explore the function of S‐nitrosation regulation in the maintenance of uterine quiescence. Here we have examined the ability of nebivolol to relax uterine smooth muscle and tested recent claims that nebivolol is a GSNOR inhibitor. In uterine smooth muscle strips from both mouse and human, nebivolol relaxes oxytocin‐induced contractions in a dose dependent manner. Our data indicates that nebivolol has no effect on GSNOR activity, nor does nebivolol inhibit thioredoxin reductase, two of the major protein denitrosylases. The ability of nebivolol to relax uterine smooth muscle is likely the combined effects of increased nitric oxide synthase activity and β3‐adregnegic stimulation.

妊娠满37周前早产会给胎儿带来诸多健康问题。在超过50%的病例中，早产临产会导致早产，且没有美国食品药品监督管理局（FDA）批准的治疗方法能够预防临产或帮助胎儿在子宫内维持至足月。对子宫平滑肌中一氧化氮介导的舒张信号传导的研究揭示了蛋白质S - 亚硝基化的作用。最近在自发性早产临产妇女中发现S - 亚硝基谷胱甘肽还原酶（GSNOR）上调，这强调了有必要探索S - 亚硝基化调节在维持子宫静止状态中的作用。在此我们研究了奈必洛尔舒张子宫平滑肌的能力，并对近期有关奈必洛尔是一种GSNOR抑制剂的说法进行了验证。在来自小鼠和人类的子宫平滑肌条中，奈必洛尔以剂量依赖的方式舒张由催产素诱导的收缩。我们的数据表明奈必洛尔对GSNOR活性没有影响，也不抑制硫氧还蛋白还原酶（两种主要的蛋白质脱亚硝基酶）。奈必洛尔舒张子宫平滑肌的能力可能是一氧化氮合酶活性增加和β3 - 肾上腺素能刺激共同作用的结果。