Haskell Sarah E, Lo Cecilia, Kent Mitchell E, Eggleston Timothy M, Volk Kenneth A, Reinking Benjamin E, Roghair Robert D
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA.
J Cardiovasc Pharmacol. 2017 Aug;70(2):119-127. doi: 10.1097/FJC.0000000000000501.
Selective serotonin reuptake inhibitors are prescribed to 6%-10% of pregnant women in the United States. Using an intrauterine plus neonatal exposure model to represent exposure throughout human pregnancy, we hypothesized sertraline exposure would impact intracardiac serotonin signaling and lead to small left heart syndrome in the absence of maternal psychopathology. C57BL/6 adult female mice received sertraline (5 mg·kg·d IP) or saline throughout pregnancy to time of delivery. Pups maintained exposure on postnatal days 1-14 to encompass the developmental window analogous to human gestation. Sertraline-exposed mice had increased cardiac hydroxyproline content, decreased 5-HT2B receptor mRNA levels, and increased 5-HT2A receptor and serotonin transporter mRNA levels on postnatal day 21 (P < 0.05). These changes were associated with diminished exercise capacity at 6 weeks (P < 0.05) and decreased adult shortening fraction and stroke volume at 5 months. Isolated cardiomyocytes from neonatal sertraline-exposed mice had significantly decreased proliferation, cross-sectional area, and phosphorylation of Akt (P < 0.05 vs. neonatal control mice). Perinatal sertraline exposure alters neonatal cardiac development and produces long-standing changes in adult cardiac function and exercise capacity. Further studies are needed to assess whether similar findings are present in the growing population that has been exposed to selective serotonin reuptake inhibitors during development.
在美国，6%至10%的孕妇会被开选择性5-羟色胺再摄取抑制剂。我们采用子宫内加新生儿暴露模型来模拟人类孕期的暴露情况，推测在没有母体精神病理学的情况下，舍曲林暴露会影响心脏内5-羟色胺信号传导并导致左心发育不全综合征。C57BL/6成年雌性小鼠在整个孕期直至分娩都接受舍曲林（5毫克·千克·天，腹腔注射）或生理盐水注射。幼崽在出生后第1至14天持续暴露，以涵盖与人类妊娠期类似的发育窗口。在出生后第21天，暴露于舍曲林的小鼠心脏羟脯氨酸含量增加，5-HT2B受体mRNA水平降低，5-HT2A受体和5-羟色胺转运体mRNA水平增加（P<0.05）。这些变化与6周时运动能力下降（P<0.05）以及5个月时成年小鼠缩短分数和每搏输出量降低有关。来自新生儿期暴露于舍曲林的小鼠的离体心肌细胞增殖、横截面积和Akt磷酸化显著降低（与新生儿对照小鼠相比，P<0.05）。围产期舍曲林暴露会改变新生儿心脏发育，并对成年心脏功能和运动能力产生长期影响。需要进一步研究以评估在发育过程中暴露于选择性5-羟色胺再摄取抑制剂的不断增长的人群中是否存在类似发现。
