Greenberg S G, Baker R S, Yang D, Clark K E
Department of Obstetrics and Gynecology, College of Medicine, University of Cincinnati, Ohio 45267-0526, USA.
Hypertension. 1997 Dec;30(6):1585-90. doi: 10.1161/01.hyp.30.6.1585.
Plasma concentration of endothelin-1, a potent vasoconstrictor produced by the vascular endothelium, has been observed to be significantly increased in a number of pathophysiological states, including preeclampsia. In the present study we have evaluated the effects of elevated plasma endothelin-1 in pregnant sheep by continuous exogenous endothelin-1 administration. Nine pregnant ewes (110+/-5 days' gestation) were instrumented for measurements of maternal mean arterial pressure, renal blood flow, and uterine blood flow. After recovery, endothelin-1 was infused intravenously for 4 hours at a dose that was adjusted to raise mean arterial pressure by approximately 20 mm Hg by the end of the first hour (range 5 to 20 ng/kg per minute). Mean arterial pressure, renal blood flow, uterine blood flow, urinary protein excretion, hematocrit, and plasma endothelin-1 concentration were measured hourly, and renal and uterine vascular resistances were calculated. Endothelin-1 produced significant increases (% change from baseline at t=4 hours) in mean arterial pressure (45+/-8%), renal vascular resistance (353+/-66 %), and uterine vascular resistance (59+/-21%). Endothelin-1 also increased microvascular permeability both systemically and within the kidney, as suggested by marked increases in hematocrit (0.27+/-0.01 to 0.32+/-0.01) and urinary protein concentration (0.95+/-0.1 to 7.9+/-3.2 mg/mL per mg creatinine). There was a highly significant correlation (P<.0001) between plasma endothelin-1 and mean arterial pressure, renal vascular resistance, uterine vascular resistance, hematocrit, and urinary protein content in all sheep studied. In addition, plasma endothelin-1 corresponded well with the time course of the changes in cardiovascular parameters and urinary protein excretion observed. These results provide evidence to suggest that elevation of circulating endothelin-1 in pregnant sheep can produce cardiovascular and hemodynamic changes that in many ways resemble the human disease preeclampsia. This supports the hypothesis that endothelial cell damage and/or dysfunction that is associated with increased production of endothelin-1 could directly contribute to the progression of preeclampsia.
内皮素-1是一种由血管内皮产生的强效血管收缩剂，在包括先兆子痫在内的多种病理生理状态下，其血浆浓度已被观察到显著升高。在本研究中，我们通过持续外源性给予内皮素-1来评估其在妊娠绵羊体内血浆浓度升高时的影响。选用9只妊娠母羊（妊娠110±5天），对其进行仪器安装以测量母体平均动脉压、肾血流量和子宫血流量。恢复后，以调整剂量静脉输注内皮素-1 4小时，使平均动脉压在第1小时末升高约20 mmHg（范围为每分钟5至20 ng/kg）。每小时测量平均动脉压、肾血流量、子宫血流量、尿蛋白排泄量、血细胞比容和血浆内皮素-1浓度，并计算肾血管阻力和子宫血管阻力。内皮素-1使平均动脉压（t = 4小时时相对于基线的变化百分比）显著升高（45±8%）、肾血管阻力显著升高（353±66%）以及子宫血管阻力显著升高（59±21%）。内皮素-1还使全身和肾脏内的微血管通透性增加，这可从血细胞比容显著升高（从0.27±0.01升高至0.32±0.01）和尿蛋白浓度显著升高（每毫克肌酐从0.95±0.1升高至7.9±3.2 mg/mL）得到提示。在所有研究的绵羊中，血浆内皮素-1与平均动脉压、肾血管阻力、子宫血管阻力、血细胞比容和尿蛋白含量之间存在高度显著的相关性（P<0.0001）。此外，血浆内皮素-1与所观察到的心血管参数和尿蛋白排泄变化的时间进程密切相关。这些结果提供了证据表明，妊娠绵羊体内循环内皮素-1升高可产生心血管和血液动力学变化，在许多方面类似于人类疾病先兆子痫。这支持了以下假说，即与内皮素-1产生增加相关的内皮细胞损伤和/或功能障碍可能直接导致先兆子痫的进展。
