Vol. 281, Issue 2, H804-H812, August 2001
Mechanism of uterine vascular refractoriness to endothelin-1
in pregnant sheep
Sherrie
McElvy1,
Suzanne G.
Greenberg1,
John
L.
Mershon1,
Da Seng
Yang1,
Catherine
Magill2, and
Kenneth E.
Clark1
1 Department of Obstetrics and Gynecology, University of
Cincinnati College of Medicine, Cincinnati, Ohio 45267-0526; and
2 Axys Pharmaceuticals, San Francisco, California 94080
Endothelin-1 (ET-1) is a potent vasoconstrictor
and produces marked pressor responses when given systemically. Studies
in sheep have demonstrated that during pregnancy the uterine
vasculature is refractory to exogenously administered ET-1. We
hypothesize that this pregnancy-dependent refractoriness is due to an
upregulation of local uterine metabolism of ET-1 and/or ETB
receptors and/or downregulation of local uterine ETA
receptors. To investigate these possibilities, 21 nonpregnant and 17 pregnant sheep were used. Dose-response curves to intravenous infusion
of ET-1 and phenylephrine were generated for pregnant and nonpregnant
sheep. ET-1 infused systemically demonstrated vasoconstriction in the systemic and renal vasculature of pregnant and nonpregnant animals and
vasoconstriction in the uterine vasculature of nonpregnant animals. The
pregnant animals showed no uterine vascular response to ET-1. In
contrast, phenylephrine showed vasoconstriction in the systemic, renal,
and uterine circulations in both pregnant and nonpregnant sheep. After
experimentation, the animals were euthanized, and tissues were
harvested for Western blot and activity analysis of neutral
endopeptidase (NEP) or RT-PCR analysis of endothelin-converting enzyme
(ECE) and ETA and ETB receptors. The content
and activity of NEP in the uterine and renal vasculature of pregnant
and nonpregnant animals were similar. RT-PCR demonstrated the presence
of ECE in the uterine vasculature of pregnant and nonpregnant sheep.
ETA receptor mRNA was significantly reduced in pregnant
compared with nonpregnant sheep, whereas ETB receptor mRNA
remained unchanged. We conclude that the uterine vascular refractoriness seen in the pregnant sheep is due to a downregulation of
ETA receptors.
estrogen; placenta; kidney
