(Hypertension. 1997;30:1585-1590.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Continuous Infusion of Endothelin-1 in Pregnant Sheep
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Correspondence and reprint requests to Suzanne G. Greenberg, PhD, Department of Obstetrics and Gynecology, PO Box 670526, University of Cincinnati, Cincinnati OH 45267-0526. E-mail Suzanne.Greenberg{at}uc.edu
Abstract 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 
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.
Key Words: endothelin-1 • sheep • proteinuria • preeclampsia • kidney
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