Article

Effect of Antihypertensive Therapy with Alpha Methyldopa on Levels of Angiogenic Factors in Pregnancies with Hypertensive Disorders

Khon Kaen University, Thailand
PLoS ONE (Impact Factor: 3.53). 07/2008; 3(7):e2766. DOI: 10.1371/journal.pone.0002766
Source: PubMed

ABSTRACT Antihypertensive drugs are believed to lower blood pressure in pre-eclampsia by direct or central vasodilatory mechanisms. However, they could also act by decreasing production of anti-angiogenic proteins involved in the pathophysiology of hypertension and proteinuria in pre-eclampsia (PE). The aim of our study was to evaluate the impact of antihypertensive therapy with alpha methyldopa on maternal circulating levels and placental production of soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng), vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in hypertensive disorders of pregnancy.
In a study conducted at University College Hospital and the Homerton University Hospital in London, we recruited 51 women with PE, 29 with gestational hypertension (GH), and 80 matched normotensive controls. Eight (16%) of the women with PE had severe disease. Placental samples were obtained from a further 48 women (14 PE, 10 GH and 24 matched controls). Serum levels of angiogenic factors were measured before and 24-48 hours after commencing antihypertensive therapy with alpha methyldopa for clinical indications. The same parameters were measured in placental extracts. In both PE (P<0.0001) and GH (P<0.05), serum sFlt-1 was increased and PlGF reduced at all gestations (P<0.001) compared to controls. Serum sEng levels were also increased in PE. Placental concentration of sFlt-1 and sEng was significantly higher in women with PE compared to controls and women with GH (P<0.0001). The concentration of PlGF was significantly lower in the placental tissue of women with PE compared to GH (P = 0.008). Antihypertensive treatment was associated with a significant fall in serum and placental content of sFlt1 and sEng in PE only.
Our data suggest that alpha methyldopa may have a specific effect on placental and/or endothelial cell function in pre-eclampsia patients, altering angiogenic proteins.

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    • "Women with new-onset, nonproteinuric hypertension after 20 weeks of gestation are provisionally diagnosed as GH, however there is significant risk for the development of preeclampsia or chronic hypertension [6]. A recent study by Khalil et al., 2008, suggests that pathophysiology of GH and preeclampsia are different as treatment with antihypertensive drugs had an effect on levels of sFlt-1 and soluble endoglin in preeclamptic groups compared to GH group, although these biomarkers were significantly raised in untreated GH [7]. Furthermore, most published work on these biomarkers have not attempted to correlate this values to that of placental structural changes. "
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    ABSTRACT: 1. Increases in soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) contribute to the pathogenesis of pre-eclampsia. 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)-beta coreceptor, was reported to synergize with sFlt-1 to amplify endothelial dysfunction by inhibiting TGF-beta1-mediated vasorelaxation. 2. The aim of the present study was to examine whether the antihypertensive drugs clonidine (0.08-1.3 microg/mL), diazoxide (25-300 microg/mL), frusemide (60-1000 microg/mL) and hydralazine (6.3-100 microg/mL) have any effect on placental production of sFlt-1 and sEng in placentas from normal and pre-eclamptic pregnancies. 3. 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. 4. 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). 5. 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.
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