Antibody against Na/K-ATPase Inhibitor Lowers Blood Pressure and Increases Vascular Fli1 in Experimental Preeclampsia.

BACKGROUND: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). We demonstrated that MBG induces fibrosis via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. We hypothesized that PE blockade of increased MBG with antibody would lessen the fibrosis of umbilical arteries and lower the blood pressure in rats with PE. METHODS: We tested 36 pregnant Sprague-Dawley rats in which 12 were made hypertensive by 1.8% Na supplementation (days 6-19 of gestation), 12 pregnant rats served controls. At day 19, PE rats received one intraperitoneal injection of polyclonal anti-MBG-4 antibody (0.5 ug/ml) for 4 hours. RESULTS: PE was associated with higher blood pressure (117 ± 2 vs. 107 ± 2 mm Hg; P < 0.01), plasma MBG levels (1.54 ± 0.34 vs. 0.49 ± 0.11 nmol/L; P < 0.01), protein excretion (26 vs. 12 mg/24 hours), sFlt-1 (3-fold), decrease in Fli1 (7-fold) and increase in collagen-1 in aorta (4-fold) vs. control rats (all P < 0.01). In 12 rats treated with polyclonal anti-MBG-4 antibody blood pressure dropped (93 ± 3 mm Hg) and Fli1 was decreased much less (2-fold; P < 0.01 vs. nontreated rats). CONCLUSIONS: These results demonstrate that in experimental PE elevated MBG level is implicated in umbilical fibrosis via suppression of Fli1.

Addition of sildenafil citrate for treatment of severe intrauterine growth restriction: a double blind randomized placebo controlled trial.

Background: Severe intrauterine growth restriction complicates approximately 0.4% of the pregnancies. It increases the risk of perinatal morbidity and mortality.Subjects and methods: A double blind placebo controlled trial was conducted in Beni Suef University hospitals during 2017. It included 46 pregnant women with severe intrauterine growth restriction. Women were randomly allocated into two groups each included 23 patients. Intervention group received sildenafil citrate 20 mg orally three times a day, in addition to fish oil and zinc supplementation. Control group received tablets similar to sildenafil and the same treatment as intervention group. Primary outcomes included improvement in umbilical and middle cerebral arteries pulsatility indices and abdominal circumference.Results: Umbilical and middle cerebral arteries Doppler indices showed significant difference between groups after intake of sildenafil. Umbilical artery pulsatility index decreased significantly (p value = .001) while middle cerebral artery pulsatility index increased significantly in intervention group (p value0.001). Moreover, abdominal circumference growth velocity improved after two weeks of sildenafil intake (p value = .001).Conclusions: Sildenafil citrate may improve uteroplacental and fetal cerebral perfusion in pregnancies complicated by severe intrauterine growth restriction. It also improves abdominal circumference growth velocity. A wide scale randomized trials are needed for evaluation of neonatal and long term morbidity and mortality outcomes of pregnancies treated by sildenafil citrate.

Nifedipine increases fetoplacental perfusion.

AIM: Our aim is to evaluate the effect of nifedipine on fetoplacental hemodynamic parameters. METHODS: A retrospective study was conducted at a tertiary center with 30 patients for whom nifedipine treatment was used as a tocolytic therapy for preterm labor. Initiation of this treatment was at 31.6±2.5 weeks of gestation. We combined the pulse Doppler imaging parameters with grayscale imaging via the Bernoulli theorem, which is called the "continuity equation", to get the fetoplacental perfusion (FPP). Evaluated parameters were the resistance index (RI), the pulsatility index (PI), systole/diastole ratios (S/D), the velocity-time integral of the umbilical artery (VTI), the radius of the umbilical artery, the peak systolic velocity and the mean pressure gradient in the umbilical artery. From these parameters, the FPP was acquired. RESULTS: We found that the RI, the PI and the S/D ratio did not change after treatment with nifedipine. The mean pressure gradient, the VTI and the peak systolic velocity increased after treatment with nifedipine. Nifedipine increases FPP from 166±73.81 beat.cm3/min to 220±83.3 beat.cm3/min. DISCUSSION: Although nifedipine had no effect on the PI, the RI or the S/D, it increased the mean pressure gradient, the VTI and FPP.

The vascular effects of sodium tanshinone IIA sulphonate in rodent and human pregnancy.

Danshen, in particular its derivative tanshinone IIA (TS), is a promising compound in the treatment of cardiovascular diseases and has been used for many years in traditional Chinese medicine. Although many actions of TS have been researched, its vasodilator effects in pregnancy remain unknown. There have been a few studies that have shown the ability of TS to reduce blood pressure in women with hypertensive pregnancies; however, there are no studies which have examined the vascular effects of TS in the pregnant state in either normal or complicated pregnancies. Our aim was to determine the vasoactive role of TS in multiple arteries during pregnancy including: rat resistance (mesenteric and uterine) and conduit (carotid) arteries. Further, we aimed to assess the ability of TS to improve uterine blood flow in a rodent model of intrauterine growth restriction. Wire myography was used to assess vascular responses to the water-soluble derivative, sodium tanshinone IIA sulphonate (STS) or to the endothelium-dependent vasodilator, methylcholine. At mid-pregnancy, STS caused direct vasodilation of rat resistance (pEC50 mesenteric: 4.47±0.05 and uterine: 3.65±0.10) but not conduit (carotid) arteries. In late pregnancy, human myometrial arteries responded with a similar sensitivity to STS (pEC50 myometrial: 3.26±0.13). STS treatment for the last third of pregnancy in eNOS-/- mice increased uterine artery responses to methylcholine (Emax eNOS-/-: 55.2±9.2% vs. eNOS-/- treated: 75.7±8.9%, p<0.0001). The promising vascular effects, however, did not lead to improved uterine or umbilical blood flow in vivo, nor to improved fetal biometrics; body weight and crown-rump length. Further, STS treatment increased the uterine artery resistance index and decreased offspring body weight in control mice. Further research would be required to determine the safety and efficacy of use of STS in pregnancy.

Uterine infusion of melatonin or melatonin receptor antagonist alters ovine feto-placental hemodynamics during midgestation.

Dietary melatonin supplementation from mid- to late gestation increases umbilical artery blood flow and causes disproportionate fetal growth. Melatonin receptors have been described throughout the cardiovascular system; however, there is a paucity of data on the function of placental melatonin receptors. The objectives of the current experiment were to determine fetal descending aorta blood flow, umbilical artery blood flow, and placental and fetal development following a 4-wk uterine infusion of melatonin (MEL), melatonin receptor 1 and 2 antagonist (luzindole; LUZ), or vehicle (CON) from Day 62 to Day 90 of gestation. After 4 wk of infusion, umbilical artery blood flow and umbilical artery blood flow relative to placentome weight were increased (P < 0.05) in MEL- versus CON- and LUZ-infused dams. Fetal descending aorta blood flow was increased (P < 0.05) in MEL- versus CON- and LUZ-infused dams, while fetal descending aorta blood flow relative to fetal weight was increased in MEL- versus CON-infused dams and decreased in LUZ- versus CON-infused dams. Following the 4-wk infusion, we observed an increase in placental efficiency (fetal-placentome weight ratio) in MEL- versus LUZ-infused dams. The increase in umbilical artery blood flow due to chronic uterine melatonin infusion is potentiated by an increased fetal cardiac output through the descending aorta. Moreover, melatonin receptor antagonism decreased fetal descending aorta blood flow relative to fetal weight. Therefore, melatonin receptor activation may partially mediate the observed increase in fetal blood flow following dietary melatonin supplementation.

Doppler velocimetry of the uterine, umbilical and fetal middle cerebral arteries in pregnant women undergoing tocolysis with oral nifedipine.

OBJECTIVES: To evaluate Doppler velocimetry (resistance index (RI) and peak systolic velocity (PSV)) in the maternal-fetal circulation before and 5 and 24 h after tocolysis with oral nifedipine. METHODS: This was a prospective, observational, analytic cohort study performed in 47 pregnant women undergoing nifedipine tocolysis, each subject acting as her own control. Doppler assessment of uterine, umbilical and fetal middle cerebral (MCA) arteries was performed before and 5 and 24 h after an initial 20-mg sublingual dose, which was repeated twice at 20-min intervals if contractions failed to diminish. The maintenance dose consisted of 20 mg orally every 6 h for 24 h up to a total of 100-120 mg nifedipine. We analyzed whether there was a time effect and compared values at the different time-points. RESULTS: The MCA-RI had decreased significantly after 24 h of tocolysis (0 h = 0.85; 5 h = 0.85; 24 h = 0.81; P = 0.001), with no differences in uterine or umbilical arteries or in the MCA to umbilical artery ratio. The MCA-PSV had reduced significantly after 5 h (0 h = 41.5 cm/s; 5 h = 34.7 cm/s; P = 0.001), returning close to baseline levels between 5 and 24 h. The PSV increased significantly between 5 and 24 h in the right uterine artery (5 h = 55.1 cm/s; 24 h = 65.0 cm/s; P = 0.037) and in the umbilical artery (5 h = 28.4 cm/s; 24 h = 33.1 cm/s; P = 0.038). CONCLUSIONS: Nifedipine tocolysis is associated with a reduction in RI in the MCA but not in the uterine or umbilical arteries, a reduction in PSV in the MCA after 5 h but returning to baseline within 24 h, and an increase in PSV between 5 and 24 h in the umbilical and right uterine arteries.

Acute and chronic modulation of placental chorionic plate artery reactivity by reactive oxygen species.

Control of vascular resistance and blood flow in the fetoplacental circulation is incompletely understood. Reactive oxygen species (ROS), physiological and pathophysiological regulators of vascular tone, are elevated in preeclampsia (PE), a disease of pregnancy characterized by increased fetoplacental vascular resistance. We tested the hypothesis that ROS modulate vascular reactivity in placental chorionic plate arteries. Wire myography was used to examine (1) the effects of acute exposure to ROS on arterial function in normal pregnancy and (2) the effects of maternal antioxidant supplementation on arterial reactivity in women at high risk for PE participating in the Vitamins in Pre-eclampsia (VIP) trial. ROS generated by xanthine plus xanthine oxidase enhanced basal tension, vasoconstriction in response to the thromboxane mimetic U46619, and relaxation in response to sodium nitroprusside. Hydrogen peroxide and peroxynitrite increased basal tone and relaxed preconstricted arteries (U44619), respectively. In women at risk for PE, chorionic plate artery constriction in response to U46619 was greater in the women receiving placebo compared to the women supplemented with the antioxidant vitamins C and E. ROS may regulate fetoplacental vascular resistance and blood flow in the short term, and chronic exposure to raised ROS could contribute to elevated fetoplacental vascular resistance in PE and fetal growth restriction (FGR).

Effects of oral L-arginine on the pulsatility indices of umbilical artery and middle cerebral artery in preterm labor.

OBJECTIVE: The objective of the study was the estimation of the influence of oral supplementation with low-dose l-arginine on feto-placental circulation in women with threatened preterm labor. STUDY DESIGN: Oral administration of 3g of L-arginine daily or placebo as a supplement to standard tocolytic therapy was tried in 70 women with threatened preterm delivery, randomly assigned to the L-arginine (n=37) or placebo (n=33) groups. Twenty-five and 20 completed the study, respectively. Doppler velocimetry of pulsatility indices (PI) of the umbilical (UA) and middle cerebral (MCA) arteries as well as pregnancy outcome and biochemical markers of nitric oxide synthesis (plasma amino acid and nitrite/nitrate levels, as well as 24 h nitrite/nitrate excretion with urine) were estimated. RESULTS: Starting from the second week of therapy, the UA PI values were significantly lower in the L-arginine group than in the placebo group. Moreover, treatment with L-arginine caused a significant increase in MCA PI and cerebro-placental ratio (CPR) values. The changes in feto-placental circulation in the L-arginine group were not associated with any signs of increased nitric oxide synthesis. CONCLUSION: Oral supplementation with low doses of L-arginine changed feto-placental blood flow distribution in patients with threatened preterm labor. The exact mechanism of L-arginine action on feto-placental circulation requires further investigation.

Effects of oral L-arginine on the foetal condition and neonatal outcome in preeclampsia: a preliminary report.

Estimation of the influence of oral supplementation with low dose of L-arginine on biophysical profile, foeto-placental circulation and neonatal outcome in preeclampsia. Randomized, placebo-controlled, double-blind, clinical trial. Oral therapy with 3 g of L-arginine daily or placebo as a supplement to standard therapy. Eighty-three preeclamptic women, randomly assigned to the L-arginine (n=42) or placebo (n=41) groups; [n=30 (L-arginine) and n=31 (placebo) ended the study, respectively]. Foetal gain chances due to ultrasound biometry, biophysical profile, Doppler velocimetry of pulsatility indices of umbilical and middle cerebral arteries, cerebro-placental ratio, as well as differences in duration of pregnancy and clinical data of newborn. L-arginine treatment transitory accelerated foetal gain and improved biophysical profile. Starting from 3rd week of therapy, the umbilical artery pulsatility indices values were significantly lower in L-arginine than in placebo group. Moreover, treatment with L-arginine caused significant increase of middle cerebral artery pulsatility indices and cerebro-placental ratio values. Latency was longer in L-arginine group. Neonates delivered in the L-arginine group revealed higher Apgar score. Supplementary treatment with oral L-arginine seems to be promising in improving foetal well-being and neonatal outcome as well as in prolonging pregnancy complicated with preeclampsia. However, these benefits require confirmation in more-powered, larger studies.

Nifedipine therapy for preterm labor: effects on placental, fetal cerebral and atrioventricular Doppler parameters in the first 48 hours.

OBJECTIVE: To assess the effect of nifedipine tocolysis on Doppler parameters of the uterine, umbilical and fetal middle cerebral arteries and atrioventricular valves in the first 48 h of therapy. METHODS: Doppler waveforms of uterine, umbilical and middle cerebral arteries and both atrioventricular valves were measured from 28 pregnant women and fetuses prior to and during nifedipine therapy for preterm labor. Maternal and fetal heart rates (FHR), maternal systolic and diastolic blood pressure, and the Doppler pulsatility index (PI) of the uterine, umbilical and middle cerebral arteries were measured. The cerebroplacental ratio (middle cerebral artery PI/umbilical artery PI) was calculated. The total time velocity integrals (TVIs) of tricuspid and mitral valves and their E- and A-wave peak velocity ratio (E/A) were measured. Friedman repeated-measures analysis of variance was used to compare the variables before and after nifedipine therapy. If significant differences were found, Wilcoxon's signed ranks test was used to analyze the difference between the two variables. A P-value of < 0.05 was considered significant. RESULTS: Nifedipine maintenance was associated with a significant decline in maternal systolic and diastolic blood pressure after 24 h, while maternal heart rate and FHR were unaffected. The uterine artery PI had decreased significantly at 24 and 48 h, while the umbilical artery PI did not change significantly. The middle cerebral artery PI had decreased significantly at 24 and again at 48 h. A significant fall in the cerebroplacental Doppler ratio was maintained beyond 24 h. The mean E/A values, TVIs and TVI x FHR values at 24 and 48 h were unchanged from the baseline values. CONCLUSIONS: Nifedipine maintenance tocolysis is associated with a significant decline in uterine artery and middle cerebral artery Doppler indices 24 h after the first dose. Fetal cardiac diastolic function is unaffected and the significant redistribution observed after 24 h is likely to be attributable to altered cerebral blood flow.

Effects of arecoline in relaxing human umbilical vessels and inhibiting endothelial cell growth.

This study investigated the effects of arecoline, an active ingredient of the areca nut, on the tone of human umbilical arteries and veins and on the eNOS expression and cell proliferation of human umbilical vein endothelial cells (HUVECs). We found that arecoline relaxes the human umbilical artery and vein rings in a concentration-dependent manner; the higher the concentration of arecoline, the greater the relaxation of the rings. However, the relaxation decreases after the endothelium was removed or pretreated with L-NAME, a nitric oxide synthase inhibitor. Moreover, arecoline increases in a dose-dependent way the cGMP levels of human umbilical arteries and veins. In HUVECs, arecoline also increases the eNOS expression. Therefore, the relaxant effects of arecoline on the umbilical artery and vein rings were endothelium-dependent through the NO-cGMP systems. In addition, arecoline at higher doses (100-1000 microM) inhibits endothelial cell proliferation; the exposure toarecoline (100-1000 microM) for 24 and 48 h induces G2/M cell cycle arrest of HUVECs. Our results indicate that arecoline would decrease vascular tone, in part mediated by NO. Higher doses of arecoline inhibit endothelial cell growth, which suggest that long-term use or high doses of areca nut might induce endothelial dysfunction and associated diseases.

Anti-hypertensive therapy and the feto-placental circulation: effects on umbilical artery resistance.

OBJECTIVE: To investigate and compare the direct effects of compounds used in the treatment of hypertensive disease in pregnancy on human umbilical artery resistance in vitro. METHODS: Isometric tension recordings were performed under physiological conditions on human umbilical arterial rings (n=30). The in vitro effects of labetolol, hydralazine, alpha-methyldopa, nifedepine and magnesium sulphate (at concentration ranges from 1 nanomolar to 1 millimolar), and their respective vehicle controls, were measured. Results were expressed as -logEC50 (pD2) and mean maximal inhibition values for each compound. RESULTS: All compounds investigated, except alpha methyldopa, exerted a significant relaxant effect on umbilical arterial tone. Alpha-methyldopa was significantly less potent when compared to all other compounds (mean maximal inhibition value [20.89+/-7.99%] versus all other agents [range 63.15+/-8.70-84.12+/-3.84%] (P<0.01)). The dose response curve of nifedipine yielded a significantly greater PD2 value when compared to that of hydralazine, labetalol, and magnesium sulphate (PD2 value [5.82+/-0.34] versus the above groups [range 3.10+/-0.09-3.52+/-0.14] (P <0.01)). CONCLUSION: These findings demonstrate that agents commonly used for the treatment of hypertensive disease in pregnancy, excluding alpha-methyldopa, have significant direct effects on the feto-placental circulation. These results suggest that alpha-methyldopa administration during pregnancy is less likely to produce significant direct effects on fetal vasculature then other agents used.

Contractile actions of thrombin receptor-derived polypeptides in human umbilical and placental vasculature: evidence for distinct receptor systems.

1. We studied the structure-activity profiles of four thrombin receptor-derived polypeptides (TRPs) (P5, SFLLR; P5-NH2, SFLLR-NH2; P7, SFLLRNP; P7-NH2, SFLLRN) in contractile human placental artery (PA), umbilical artery (UA) and umbilical vein (UV) preparations and in a human platelet aggregation assay. 2. The contractile actions of the TRPs in the two arterial preparations were endothelium-independent, whereas in the UV tissue a contractile response was observed only in an endothelium-denuded preparation; no endothelium-mediated relaxation responses were observed in any of the vascular preparations. 3. In the three vascular preparations, the contractile responses required extracellular calcium and were attenuated by the tyrosine kinase inhibitor, genistein. 4. The relative contractile orders of potencies of the TRPs in the three vascular preparations were distinct from each other (PA: P7-NH2 > P7 > P5-NH2 > P5; UA: P7-NH2 > or = P5-NH2 approximately = P7 > > P5; UV: P5-NH2 > > P7-NH2 = P7 > > P5) and these were in turn distinct from the potency order observed in the platelet aggregation assay (P5-NH2 > or = P7-NH2 > P7 > > P5). 5. Despite the markedly dissimilar TRP potency orders in the placental artery and umbilical vein preparations, the cDNA sequences for the thrombin receptor obtained by polymerase chain reaction cloning of cDNA from the two tissue sources were identical. 6. We conclude that the four tissues studied possess functionally distinct thrombin receptor systems that interact in a distinct way with agonist peptides. In view of the identity of the thrombin receptor cDNA in the two tissues displaying the most dissimilar structure-activity profiles, we suggest that in different tissues, differences in post-translational receptor processing or differences in receptor-effector coupling interactions may result in unique thrombin receptor systems that can display distinct structure-activity profiles.

Bidirectional regulation of smooth muscle cell proliferation by IFN-gamma.

We studied the effects of interferon gamma (IFN-gamma), a T-cell lymphokine, on the proliferation and chemotaxis of vascular smooth muscle cells (SMC). Recombinant human IFN-gamma dose-dependently inhibited the proliferation of SMC cultured in the presence of 20% fetal calf-serum. It also inhibited PDGF-induced chemotaxis of SMC. Similar concentrations of IFN-gamma induced DNA-synthesis of SMC cultured in mitogen-depleted medium for 5 days. The inhibition and the stimulation of SMC proliferation were accompanied by concomitant decrease and increase in the number of PDGF receptors. Our study indicated that IFN-gamma is a bidirectional regulator of SMC proliferation.

Action of alpha-methyldopa on human umbilical circulation in vitro.

To determine the possible effects of alpha-methyldopa on the motility of human umbilical artery, a total of 53 arterial segments were perfused with different concentrations of the drug as follows: 38 segments with 125, 250 and 500 ng/ml of the drug, 9 segments with 500 ng/ml alpha-methyldopa in combination with 10(-7) M yohimbine, and 6 segments with 10(-7) M yohimbine alone. alpha-Methyldopa had a vasoconstrictor effect at all doses employed, with a clear dose-effect correlation (p less than 0.01). The vasoconstrictor effect of 500 ng/ml alpha-methyldopa was fully inhibited in the presence of 10(-7) M yohimbine. These results suggest that alpha 2-adrenergic receptors are present in the umbilical circulation and that alpha-methyldopa may play a role in the control of this circulation.

The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia remote from term.

Twenty patients with preeclampsia at a gestational age of 26 to 35 weeks were treated with oral nifedipine until delivery. The mean oral daily dose was 45.1 +/- 11 mg/day (range, 40 to 80 mg/day). Fetal aorta, internal carotid artery, umbilical artery, and uteroplacental Doppler flow velocity waveforms were recorded before treatment and then serially. The mean nifedipine concentration at the time of the Doppler studies was 60.3 ng/ml (range, 10 to 90 ng/ml). The use of nifedipine therapy was associated with a significant decrease in both maternal systolic blood pressure (baseline, 154 to 135 mm Hg, p less than 0.001) and diastolic blood pressure (baseline, 100 to 88 mm Hg, p less than 0.001). However, there was no significant difference in the resistance index between baseline and postnifedipine Doppler studies in either the fetal or uteroplacental vessels. The use of oral nifedipine to control blood pressure in preeclampsia does not affect the resistance indices in fetal or uteroplacental vessels as measured by the Doppler technique.

Magnesium supplement in pregnancy-induced hypertension. A clinicopathological study.

The placenta and the umbilical cord obtained from 18 women with pregnancy-induced hypertension were investigated by light microscopy. The umbilical artery was studied by electron microscopy. 10 placentae and umbilical cords from normal pregnancies served as controls. The study was performed as a double-blind randomized controlled study in which 11 women were allocated to magnesium and 7 to placebo treatment. The treatment comprised a 48-hour intravenous magnesium/placebo infusion followed by daily oral magnesium/placebo intake until one day after delivery. Magnesium supplement increased birth weight and placental weight significantly. Light microscopic study of the placentae and the umbilical cord arteries showed no difference between the three groups concerning the occurrence of infarctions, cytotrophoblastic hyperplasia, vasculo-syncytial membranes, basement membrane thickening, stromal fibrosis or intervillous fibrin. Ultrastructurally, the endothelial cells of the umbilical arteries from women with pregnancy-induced hypertension showed a significant increase in the amount of dilated endoplasmic reticulum and basal laminae thickness when all 18 cases were compared with the controls. There was no significant difference when the magnesium group, the placebo group and the control group were compared separately. The present study suggests that magnesium supplement has a beneficial effect on fetal growth in pregnancy-induced hypertension. With regard to the light and electron microscopic changes we were unable to demonstrate any significant difference between the magnesium, placebo and control groups.

Effects of 3,4-dihydroxyacetophenone on the biosynthesis of TXA2 and PGI2 in human placental villus and umbilical artery segments in vitro.

In this paper, the effects of 3,4-dihydroxyacetophenone, DHAP (Qingxintong), an active constituent of traditional Chinese medicine, on the biosynthesis of TXA2 and PGI2 in human placental villi and umbilical artery segments of normal term pregnancy in vitro were studied by a perifusion technique. The collected fractions were assayed by radioimmunoassay for TXB2 and 6-keto-PGF1 alpha. The results showed that DHAP inhibited TXA2 and PGI2 production by umbilical artery segments in a dose dependent fashion and in both tissues TXA2 was more sensitive to inhibition than was 6-keto-PGF1 alpha. According to these data it is suggested that DHAP might be useful in treatment of pathologic pregnancies with chronic defective utero-placental circulation such as PIH and IUGR to improve this circulation.