Ivy D D, Parker T A, Kinsella J P, Abman S H
The Pediatric Heart Lung Center, University of Colorado School of Medicine and The Children's Hospital, Denver 80218, USA.
Pediatr Res. 1998 Aug;44(2):175-80. doi: 10.1203/00006450-199808000-00006.
Endothelin (ET)-1 is a potent vasoconstrictor peptide that modulates basal pulmonary vascular resistance (PVR) in the normal ovine fetus and contributes to high PVR after chronic intrauterine pulmonary hypertension. Although high PVR is present in premature lambs with severe hyaline membrane disease (HMD), whether ET-1 plays a role in the pathophysiology of experimental HMD is unknown. To test the hypothesis that ET-1 activity contributes to high PVR in the premature lamb with HMD, we studied the hemodynamic effects of a selective ET(A) receptor antagonist, BQ 123, in 10 animals (gestational age 125 d; 147 d=term). After baseline measurements, animals were intubated, treated with surfactant (Infasurf), and mechanically ventilated with a fraction of inspired oxygen of 1.00 for 8 h. Animals were treated with continuous infusions of either BQ 123 (1 mg/h; treatment group, n=5) or 1% DMSO (control; n=5). Plasma ET-1 levels progressively increased during prolonged ventilation with hyperoxia (0.8+/-0.1 pg/mL, baseline to 6.8+/-2.5 pg/mL, 8 h, p < 0.05). In comparison with control lambs, BQ 123 treatment caused a sustained reduction in pulmonary vascular resistance (0.55+/-0.04 mm Hg mL-(-1) min(-1), control versus 0.18+/-0.04 mm Hg mL(-1) min(-1), BQ 123, p < 0.05), increased left pulmonary artery blood flow (70+/-12 mL/min, control versus 194+/-28 mL/min, BQ 123, p < 0.05), and increased arterial PaO2 (53+/-14 mm Hg, control versus 174+/-71 mm Hg, BQ 123, p < 0.05) 8 h after the onset of ventilation. We conclude that circulating levels of ET-1 increase after delivery of premature lambs with severe HMD, and that selective ET(A) receptor blockade causes sustained improvement in hemodynamics in severe experimental HMD. These studies suggest that ET-1 contributes to the hemodynamic abnormalities in this model of pulmonary hypertension and severe HMD.
内皮素（ET）-1是一种强效血管收缩肽，可调节正常绵羊胎儿的基础肺血管阻力（PVR），并在慢性宫内肺动脉高压后导致PVR升高。尽管患有严重透明膜病（HMD）的早产羔羊存在高PVR，但ET-1是否在实验性HMD的病理生理学中起作用尚不清楚。为了验证ET-1活性导致患有HMD的早产羔羊出现高PVR这一假设，我们研究了选择性ET（A）受体拮抗剂BQ 123对10只动物（胎龄125天；足月为147天）的血流动力学影响。在进行基线测量后，将动物插管，给予表面活性剂（固尔苏）治疗，并以吸入氧分数为1.00进行机械通气8小时。动物持续输注BQ 123（1毫克/小时；治疗组，n = 5）或1%二甲亚砜（对照组；n = 5）。在高氧通气延长期间，血浆ET-1水平逐渐升高（从基线时的0.8±0.1皮克/毫升升至8小时后的6.8±2.5皮克/毫升，p < 0.05）。与对照羔羊相比，BQ 123治疗导致肺血管阻力持续降低（对照组为0.55±0.04毫米汞柱·毫升-1·分钟-1，BQ 123组为0.18±0.04毫米汞柱·毫升-1·分钟-1，p < 0.05），左肺动脉血流量增加（对照组为70±12毫升/分钟，BQ 123组为194±28毫升/分钟，p < 0.05），通气开始8小时后动脉血氧分压升高（对照组为53±14毫米汞柱，BQ 123组为174±71毫米汞柱，p < 0.05）。我们得出结论，患有严重HMD的早产羔羊出生后循环中的ET-1水平升高，并且选择性ET（A）受体阻断可使严重实验性HMD的血流动力学持续改善。这些研究表明，ET-1在这种肺动脉高压和严重HMD模型中导致血流动力学异常。
