Effects of anti-hypertensive drugs on production of soluble FMS-like tyrosine kinase 1 and soluble endoglin from human normal and pre-eclamptic placentas in vitro

Increases in soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) contribute to the pathogenesis of preeclampsia. Soluble Flt-1 binds to circulating free vascular endothelial growth factor and placenta growth factor and this is associated with endothelial dysfunction. Soluble endoglin, a transforming growth factor (TGF)-β coreceptor, was reported to synergize with sFlt-1 to amplify endothelial dysfunction by inhibiting TGF-β1-mediated vasorelaxation. The aim of the present study was to examine whether the antihypertensive drugs clonidine (0.08–1.3 μg/mL), diazoxide (25–300 μg/mL), frusemide (60–1000 μg/mL) and hydralazine (6.3–100 μg/mL) have any effect on placental production of sFlt-1 and sEng in placentas from normal and pre-eclamptic pregnancies. Explants were taken from non-laboured term placentas of normal pregnancy (n=5) and women with pre-eclampsia (n=5). Villous explants were cultured with increasing doses of antihypertensive drugs. Placental sFlt-1 and sEng production was examined using ELISA. Baseline sFlt-1 production was higher in placentas from women with pre-eclampsia than from normal pregnancy (4.5 ± 1.4 vs 3.2 ± 0.6 ng/mg of total protein, respectively; P<0.001), as was sEng production (9.0 ± 2.3 vs 4.1 ± 0.6 ng/mg of total protein, respectively; P<0.001). With the exception of frusemide, none of the antihypertensive drugs tested had any effect on sFlt-1 and sEng production from placental explants of normal pregnancy and women with pre-eclampsia. Increasing frusemide concentrations were correlated with increased sEng production in normal pregnancy (P<0.005). In conclusion, placental sFlt-1 and sEng production was higher in pre-eclampsia and antihypertensive drugs had no effect on placental production of sFlt-1 and sEng in vitro.