Buhimschi C, Buhimschi I, Yallampalli C, Chwalisz K, Garfield R E
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston 77555-1062, USA.
Am J Obstet Gynecol. 1997 Sep;177(3):690-701. doi: 10.1016/s0002-9378(97)70166-2.
The aim of the study was to investigate the in vitro (on tension) and in vivo (on intrauterine pressure) effects of a spontaneously releasing nitric oxide adduct, diethylenetriamine-nitric oxide, on rat uterine contractility.
Contractile responses to the nitric oxide donor diethylenetriamine-nitric oxide on isometric tension of rat uterine strips (in vitro) and on intrauterine pressure (in vivo) in anesthetized and conscious animals were quantified at late gestation and during preterm and term labor. Preterm labor was induced with the administration of a single injection of the antiprogestin onapristone (10 mg). All control animals were injected with diethylenetriamine, the parent compound, without nitric oxide.
The nitric oxide donor diethylenetriamine-nitric oxide relaxes rat uterine tissues when given in vitro during gestation (median effective dose 0.30 +/- 0.09 mmol/L) but fails to have an effect on uterine tissues from laboring term and preterm animals in the muscle bath. Intraperitoneal injection of the nitric oxide adduct in doses of 5 mg and 50 mg produced a significant and sustained decrease in intrauterine pressure in both delivering and nondelivering animals compared with intrauterine pressure values before administration. Analysis of intrauterine pressure levels at different time frames (before injection, immediately after injection, and after 30, 60, and 90 minutes) in anesthetized rats between days 19 and 21 of gestation shows that the dose of 5 mg diethylenetriamine-nitric oxide significantly (p < 0.05) decreased contractility starling at 30 minutes after administration. Similarly, during labor diethylenetriamine-nitric oxide (5 mg intraperitoneally) decreased contractility (p < 0.05) but only starting at 60 minutes after injection. However, with the dose of 50 mg diethylenetriamine-nitric oxide contractility was reduced 30 minutes (p < 0.05) after treatment during pregnancy (days 19 to 21). The same dose of diethylenetriamine-nitric oxide produced a greater relaxation immediately after intraperitoneal injection (p < 0.05) in the laboring group. Diethylenetriamine-nitric oxide (50 mg) also induced an earlier onset and greater relaxation in animals delivering preterm compared with nondelivering animals at the same stage of gestation. The intrauterine pressure maintained constant contractility levels throughout the 100-minute recording period in the control groups of anesthetized and conscious animals that were injected with diethylenetriamine at the equivalent doses. In the preterm laboring group the effects were similar in both anesthetized and conscious animals.
Although in vitro studies of uterine muscle show decreased inhibitory responses to nitric oxide donors during spontaneous term labor and preterm labor compared with tissues collected during late pregnancy (day 19), studies in vivo demonstrate that nitric oxide donors can decrease uterine contractility even more effectively during delivery. The results suggest that nitric oxide donors may act indirectly or that the fetal-placental unit increases the availability of nitric oxide in vivo. Therefore, despite what in vitro studies alone suggest, nitric oxide donor drugs may be very effective in suppressing either term or preterm labor.
本研究旨在探讨自发释放一氧化氮的加合物二乙烯三胺 - 一氧化氮对大鼠子宫收缩力的体外（张力方面）和体内（子宫内压方面）影响。
在妊娠晚期、早产和足月分娩期间，对麻醉和清醒动物的大鼠子宫条带等长张力（体外）和子宫内压（体内）对一氧化氮供体二乙烯三胺 - 一氧化氮的收缩反应进行定量。通过单次注射抗孕激素奥那司酮（10毫克）诱导早产。所有对照动物注射不含一氧化氮的母体化合物二乙烯三胺。
一氧化氮供体二乙烯三胺 - 一氧化氮在体外给予妊娠大鼠时可使子宫组织松弛（半数有效剂量0.30±0.09毫摩尔/升），但对足月和早产分娩动物的子宫组织在肌肉浴中无作用。与给药前的子宫内压值相比，腹腔注射5毫克和50毫克剂量的一氧化氮加合物可使分娩和未分娩动物的子宫内压显著且持续降低。对妊娠第19至21天麻醉大鼠不同时间框架（注射前、注射后即刻、注射后30、60和90分钟）的子宫内压水平分析表明，5毫克二乙烯三胺 - 一氧化氮剂量在给药后30分钟显著（p<0.05）降低收缩力。同样，在分娩期间，二乙烯三胺 - 一氧化氮（腹腔注射5毫克）降低收缩力（p<0.05），但仅在注射后60分钟开始。然而，50毫克二乙烯三胺 - 一氧化氮剂量在妊娠期间（第19至21天）治疗后30分钟降低收缩力（p<0.05）。相同剂量的二乙烯三胺 - 一氧化氮在腹腔注射后即刻在分娩组产生更大的松弛（p<0.05）。与相同妊娠阶段未分娩动物相比，二乙烯三胺 - 一氧化氮（50毫克）在早产动物中也诱导更早发作且更大的松弛。在注射等效剂量二乙烯三胺的麻醉和清醒动物对照组中，子宫内压在整个100分钟记录期内保持恒定的收缩力水平。在早产分娩组中，麻醉和清醒动物的效果相似。
尽管子宫肌肉的体外研究表明，与妊娠晚期（第19天）收集的组织相比，在足月自然分娩和早产期间对一氧化氮供体的抑制反应降低，但体内研究表明一氧化氮供体在分娩期间可更有效地降低子宫收缩力。结果表明一氧化氮供体可能间接起作用，或者胎儿 - 胎盘单位在体内增加了一氧化氮的可用性。因此，尽管单独的体外研究表明情况并非如此，但一氧化氮供体药物在抑制足月或早产方面可能非常有效。
