Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, The Netherlands.
Department of Neonatology, National Maternity Hospital, Dublin, Ireland.
J Physiol Pharmacol. 2020 Oct;71(5). doi: 10.26402/jpp.2020.5.05. Epub 2021 Jan 16.
Prenatal treatment with magnesium sulfate (MgSO) has neuroprotective effects in very preterm infants but its use has been associated with an increased rate of patent ductus arteriosus (DA). MgSO is a vasodilator and thus may exert a direct relaxant effect in the DA. We aimed to investigate the vasoactive effects of MgSO in the DA using the chicken embryo as experimental model. DA rings from 15-d (E15), 17-d (E17) and 19-d (E19) chicken embryos (total incubation: 21-d) were mounted in a wire myograph for isometric tension recordings. Exposure of DA rings to 21% O induced a tonic contraction which was relaxed by MgSO (2.4 - 7.2 mmol L) in a concentration-dependent manner (mean maximal relaxation E19: 51.4%, SE 6.3; EC: 3.5 mmol L, SE 0.7). The relaxation evoked by MgSO was not significantly different between E15, E17 and E19 DA and was not affected by removal of the endothelium or by the presence of the nitric oxide synthase inhibitor L-NAME, the soluble guanylate cyclase inhibitor ODQ, or the cyclooxygenase inhibitor indomethacin. In contrast, when the DA rings were incubated in Ca-free solution, or in the presence of inhibitors of L-type Ca channels (nifedipine), or large-conductance Ca-activated K (BK) channels (iberiotoxin), MgSO-induced relaxation was impaired. Preincubation of the DA rings with MgSO concentrations ranging from 0 to 6.0 mmol L did not significantly affect O-induced contraction that was only impaired by a concentration of 7.2 mmol L. In conclusion, MgSO induced endothelium-independent relaxation of chicken DA and this relaxation appeared to be mediated through stimulation of BK channels and blockade of transmembrane flux of extracellular Ca. However, O-induced DA contraction was only impaired by suprapharmacological concentrations of MgSO (> 6.0 mmol L). Therefore, our data suggest that the higher incidence of patent DA in preterm infants exposed to MgSO is unlikely to be due to a direct pharmacological effect of the drug on the DA.
产前使用硫酸镁（MgSO）对极早产儿有神经保护作用，但它的使用与动脉导管未闭（DA）的发生率增加有关。MgSO 是一种血管扩张剂，因此它可能对 DA 产生直接的松弛作用。我们旨在使用鸡胚作为实验模型，研究 MgSO 对 DA 的血管活性作用。从 15 日龄（E15）、17 日龄（E17）和 19 日龄（E19）鸡胚的 DA 环（总孵育：21 天）中取出，安装在电生理记录仪上进行等长张力记录。将 DA 环暴露于 21% O 中会引起紧张性收缩，MgSO（2.4-7.2 mmol/L）以浓度依赖性方式使紧张性收缩松弛（E19 时最大松弛的平均值为 51.4%，SE 为 6.3%；EC 为 3.5 mmol/L，SE 为 0.7）。MgSO 引起的松弛在 E15、E17 和 E19 DA 之间没有显著差异，并且不受内皮去除、一氧化氮合酶抑制剂 L-NAME、可溶性鸟苷酸环化酶抑制剂 ODQ 或环氧化酶抑制剂吲哚美辛的影响。相比之下，当 DA 环在无钙溶液中孵育或存在 L 型钙通道抑制剂（硝苯地平）或大电导钙激活钾（BK）通道抑制剂（iberiotoxin）时，MgSO 诱导的松弛受到损害。DA 环用 0 至 6.0 mmol/L 的 MgSO 浓度预孵育不会显著影响仅被 7.2 mmol/L 浓度损害的 O 诱导收缩。总之，MgSO 诱导鸡 DA 产生内皮非依赖性松弛，这种松弛似乎是通过刺激 BK 通道和阻断细胞外 Ca 的跨膜通量来介导的。然而，只有超药理学浓度的 MgSO（>6.0 mmol/L）才会损害 O 诱导的 DA 收缩。因此，我们的数据表明，暴露于 MgSO 的早产儿中动脉导管未闭的发生率较高，这不太可能是由于药物对 DA 的直接药理作用。
