Evidence against a pathogenetic role for endothelin in pre‐eclampsia

Abstract

Objective To assess whether increased placental or systemic endothelin synthesis has a pathogenic role in pre‐eclampsia (gestational proteinuric hypertension). Design Prospective observations study. Subjects 19 women with pre‐eclampsia and 10 healthy pregnant women were studied. All were in the last trimester. Main outcome measures Preproendothelin‐1 gene expression by Northern blot analysis and generation of endothelin‐1 precursor, big‐endothelin‐1, and endothelin isoforms, namely endothelin‐1, 2 and 3, were assessed by specific radioimmunoassays, in placental tissue. Plasma endothelin‐1 levels and urinary excretion of big‐endothelin‐1 and endothelin‐1 were measured. Results Placental preproendothelin‐1 gene expression and immunoreactive bigendothelin‐1 and endothelin‐1, 2 and 3, were comparable in placental tissue from pre‐eclamptic and normal pregnant women. Plasma levels of endothelin‐1 did not differ between pre‐eclamptic and normal pregnancies. In contrast, urinary excretion of endothelin‐1, which is likely to reflect the renal synthesis of the peptide, was significantly decreased in pre‐eclamptic, as compared with normal pregnant women. This was not due to a decreased renal generation of endothelin‐1 precursor, since urinary excretion of big‐endothelin‐1 did not differ between pre‐eclamptic and normal pregnancies. These data suggest an increased renal endothelin‐1 breakdown in pre‐eclampsia. Conclusions Endothelin is unlikely to play a role in the pathogenesis of pre‐eclampsia. Instead, an increased renal breakdown may have a role in limiting the negative effects of other vasoactive factors on the renal circulation.

Differential localization of endothelin ETa and ETB binding sites in human placenta

“…The role of ET in pre-eclampsia is unclear, however, as contradictory reports exist concerning circulating ET levels in normotensive patients and those exhibiting this condition. Some reports have shown that prepro-ET-1 gene expression and plasma ET-1 levels are similar in both normal pregnancy and pre-eclampsia (Benigni et al, 1992;Otani et al, 1991), whilst others have reported elevated maternal plasma ET-1 levels in pre-eclampsia implicating ET in the impaired renal function and placental blood flow associated with the disease (Mastrogiannis et al, 1991;Nova et al, 1991;Clark et al, 1992). In the present study, we were unable to detect a difference in either the relative density or proportion of vascular and villous ET receptor imating the equilibrium dissociation constant from saturation data obtained under these conditions was therefore considered inappropriate.…”

“…Circulating ET levels have been shown to increase during pregnancy and labour (Mastrogiannis et al, 1991); however, conflicting evidence exists concerning the possible role of ET in the pathogenesis of pre-eclampsia. While some reports have indicated a further elevation of plasma ET levels in this condition (Nova et al, 1991;Clark et al, 1992), more recent studies have not found a significant difference in plasma ET levels between pre-eclamptic and normal pregnancies (Benigni et al, 1992) nor any correlation between plasma ET-1 concentration, blood pressure or renal function during toxaemic pregnancy (Otani et al, 1991).…”

Endothelin Type A Receptor Blockade Attenuates the Hypertension in Response to Chronic Reductions in Uterine Perfusion Pressure

“…11 Whether increased synthesis of endothelin occurs within the kidney during preeclampsia remains unknown, inasmuch as some studies have found a decrease in urinary excretion of endothelin, a measure of local renal synthesis, in preeclamptic women compared with normotensive pregnant women. 12,13 We recently reported that chronic reduced uterine perfusion pressure (RUPP) in pregnant rats resulted in significant elevations in MAP and reductions in kidney function. 14 Because the kidneys play a major role in the long-term regulation of arterial pressure, the first aim of the present study was to determine whether increases in renal preproendothelin mRNA expression were associated with the hypertension produced by chronic RUPP in pregnant rats.…”

Pathophysiology of hypertension in response to placental ischemia during pregnancy: A central role for endothelin?

“…Plasma concentration of ET-1 has been measured in normal pregnant and preeclamptic women (12). Some, but not all, investigators have found higher ET-1 plasma concentrations of approximately two-to threefold in women with preeclampsia (12,15) Typically, plasma levels of ET-1 are highest during the latter stage of the disease, suggesting that ET-1 may not be involved in the initiation of preeclampsia, but rather in the progression of disease into a malignant phase. Although the elevation in plasma levels of ET-1 during preeclampsia is only two or threefold above normal, previous studies have reported that this level of plasma ET-1 can have significant long-term effects on systemic hemodynamics and arterial pressure regulation (16) Thus long-term elevations in plasma levels of ET-1 comparable to those measured in women with preeclampsia could play a role in mediating the reductions in renal function and elevations in arterial pressure observed in women with preeclampsia.…”