他达拉非对子痫前期大鼠模型股动脉内皮功能的影响

Effect of tadalafil on endothelial function of femoral artery in preeclampsia rats

目的探讨他达拉非对子痫前期大鼠模型股动脉内皮功能的影响。方法 6~8周龄雌性Sprague-Dawley(SD)大鼠32只,随机分为对照组、左旋硝基精氨酸甲酯(l-NAME)造模组(l-NAME组)、l-NAME+低剂量他达拉非组(LT组),l-NAME+高剂量他达拉非组(HT组)4组,每组8只。测量孕鼠妊娠第0、5、10、15、20天的血压和妊娠第0、18天的24 h尿蛋白。妊娠第19天使用小动物超声检测并计算孕鼠股动脉血流介导的血管舒张功能(FMD)和管壁切应力(WSS)。妊娠第20天取材,测量胎鼠的顶臀长及体质量,留取血浆样本测量可溶性血管内皮生长因子受体1(sFlt-1)、胎盘生长因子(PlGF)、一氧化氮和内皮型一氧化氮合酶(eNOS)水平,计算sFlt-1与PlGF的比值(sFlt-1/PlGF)。结果他达拉非可以改善l-NAME诱导的妊娠期血压升高:l-NAME组妊娠第20天收缩压、舒张压和平均动脉压高于其余3组(均P<0.05)。妊娠第18天,l-NAME组尿蛋白显著升高,其与基线比较的升高幅度较对照组、LT组和HT组更大[(55.44±21.81)比(9.22±11.79),(27.69±15.47),(17.80±11.99)mg/24 h,均P<0.05]。对照组、LT组和HT组孕鼠FMD在120 s达到峰值,l-NAME组在240 s达到峰值。4组FMD峰值水平比较,对照组与HT组差异无统计学意义[(14.99±1.11)%比(13.69±1.60)%,P>0.05],且高于LT组[(11.81±1.57)%]和l-NAME组[(5.62±1.04)%],LT组高于l-NAME组(P<0.05)。4组孕鼠的WSS随时间增加而下降,l-NAME组WSS高于其余3组(均P<0.05)。l-NAME组孕期体质量增幅、胎仔顶臀长和胎仔体质量均小于其他3组(均P<0.05)。l-NAME组血浆sFlt-1水平和sFlt-1/PlGF较其他3组升高,血浆PlGF低于对照组和HT组,血浆一氧化氮水平低于其他3组,对照组血浆eNOS高于l-NAME组(均P<0.05)。结论预防性给予他达拉非可以改善l-NAME诱导的孕鼠的高血压,减少尿蛋白和胎儿生长受限,调节血管生长因子平衡,保护血管内皮功能,提示他达拉非对预防子痫前期可能具有潜在价值。

Objective To investigate the effect of tadalafil on endothelial function of femoral artery in rat model of preeclampsia. Methods Thirty-two female Sprague-Dawley(SD) rats aged 6-8 weeks were randomly divided into control group, N-nitro-L-arginine-methyl-ester(l-NAME) model group(l-NAME group), l-NAME+low-dose tadalafil group(LT group) and l-NAME+high-dose tadalafil group(HT group), with 8 rats in each group. The blood pressure of the pregnant rats was measured on day 0, 5, 10, 15 and 20 of pregnancy, and the 24 h urine protein was measured on day 0 and 18 of pregnancy. On the 19 th day of pregnancy, the small animal ultrasound was used to detect and calculate the femoral artery blood flow-mediated dilatation(FMD) and wall shear stress(WSS) of the pregnant rats. Rats were sacrificed on the 20 th day of pregnancy, body length and weight of fetuses were measured. Soluble vascular endothelial growth factor receptor 1(sFlt-1), placental growth factor(PlGF), nitric oxide(NO) and endothelial nitric oxide synthase(eNOS) levels in plasma were detected and the sFlt-1/PlGF ratio was calculated. Results Tadalafil improved l-NAME-induced gestational hypertension: the systolic, diastolic and mean arterial pressures in the l-NAME group were significantly higher than those in the other groups(P<0.05). On the 18 th day of pregnancy, compared with baseline, the urine protein of l-NAME group was significantly increased, and the increase was significantly higher in l-NAME group than that in control, LT and HT groups[(55.44±21.81)vs(9.22±11.79),(27.69±15.47),(17.80±11.99)mg/24 h, all P<0.05]. In the control, LT and HT groups, the FMD of the pregnant rats reached the peak at 120 s, and in the l-NAME group, it reached the peak at 240 s. The peak levels of FMD in the control [(14.99±1.11)%] and HT groups [(13.69±1.60)%] were higher than those in the LT [(11.81±1.57)%] and l-NAME groups [(5.62±1.04)%], and which in the LT group was higher than that in the l-NAME group(P<0.05). The WSS of the 4 groups of pregnant rats decreased with time, and the WSS of the l-NAME group was higher than other groups(P<0.05). The weight gain during pregnancy, the length and weight of the fetuses in l-NAME group were significantly lower than those of the other groups(P<0.05). The sFlt-1 and sFlt-1/PlGF in plasma of the l-NAME group were significantly higher than those in the other groups. The PlGF in plasma of the l-NAME group was lower than that in the control group and the HT group, and the plasma NO level was lower than the other groups(P<0.05). Plasma eNOS in the control group was significantly higher than that in the l-NAME group(P<0.05). Conclusion Prophylactic administration of tadalafil can improve hypertension, proteinuria and fetal growth restriction induced by l-NAME in pregnant rats, regulate the balance of vascular growth factors and protect vascular endothelial function, suggesting that tadalafil may have potential value in the prevention of preeclampsia.