digoxin and Pre-Eclampsia

Recent studies suggest that drugs affecting prostacyclin and thromboxane production may be able to affect the development of preeclampsia. In order to use these agents effectively, we must be able to select properly women at high risk. This review evaluates a number of historic and physical factors and laboratory tests that may aid in the prediction of preeclampsia. Family history, parity, and the roll-over test are currently the most efficient methods that are widely available. Two relatively new laboratory tests, plasma fibronectin concentration and urinary calcium/creatinine ratio, hold the greatest promise for the near future.

Topics: Angiotensin II; Antithrombin III; Atrial Natriuretic Factor; beta-Thromboglobulin; Blood Pressure; Blood Proteins; Calcium; Cardenolides; Digoxin; Female; Humans; Iron; Pre-Eclampsia; Pregnancy; Saponins; Serum Albumin; Uric Acid

We evaluated the efficacy, safety, and biological mechanisms of digoxin immune Fab (DIF) treatment of severe preeclampsia. Fifty-one severe preeclamptic patients were randomized in double-blind fashion to DIF ( N = 24) or placebo ( N = 27) for 48 hours. Primary outcomes were change in creatinine clearance (CrCl) at 24 to 48 hours and antihypertensive drug use. Serum sodium pump inhibition, a sequela of endogenous digitalis-like factors (EDLF), was also assessed. CrCl in DIF subjects was essentially unchanged from baseline versus a decrease with placebo (-3 +/- 10 and -34 +/- 10 mL/min, respectively, P = 0.02). Antihypertensive use was similar between treatments (46 and 52%, respectively, P = 0.7). Serum sodium pump inhibition was decreased with DIF compared with placebo at 24 hours after treatment initiation (least squares mean difference, 19 percentage points, P = 0.03). DIF appeared to be well tolerated. These results suggest DIF prevents a decline in renal function in severe preeclampsia by neutralizing EDLF. Sodium pump inhibition was significantly improved. Further research is warranted.

Topics: Adult; Antihypertensive Agents; Cardenolides; Digoxin; Double-Blind Method; Female; Humans; Immunoglobulin Fab Fragments; Kidney Function Tests; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Saponins; Sodium-Potassium-Exchanging ATPase; Treatment Outcome; Young Adult

Elevated Na(+)/H(+) exchanger activity and intracellular acidosis have previously been demonstrated in white blood cells isolated from women who have suffered from a pre-eclamptic pregnancy. The mechanisms underlying this abnormality and the implications in pre-eclamptic pregnancies are, at present, unclear. In this study, we used neutrophils from third trimester pre-eclamptic patients and third trimester normotensive pregnant controls to determine Na(+)/H(+) exchanger isoform-1 (NHE-1) activity and intracellular pH. This was performed using a well-validated technique involving flurometry and a pH sensitive dye, 2,7'Bis-(carboxyethyl) 5.6 carboxyfluorescein acetomethyl ester (BCECF-AM). Time course experiments were performed to assess the contribution of plasma factors to intracellular pH measurements. Plasma digoxin-like factor (DLF) was assessed in both patients and normotensive controls. Neutrophil intracellular pH was significantly lower in the pre-eclamptic patients (7.15 +/- 0.050) compared with the normotensive pregnant controls (7.36 +/- 0.027; P<.001). NHE-1 activity (in mmol/L/min) was significantly higher in the pre-eclamptics (32.4 +/- 1.9) compared with the normotensive neutrophils (27.1 +/- 1.6; P =.038). Times course experiments showed that mean pre-eclamptic intracellular pH increased from 7.11 +/- 0.049 to 7.25 +/- 0.043 after 2 hours of incubation. DLF, measured as amount of inorganic phosphate liberated from adenosine triphosphate (ATP), was significantly lower when plasma from the pre-eclamptic patients was incubated with the enzyme compared with plasma from the normotensive pregnant women (54.9 +/- 2.6 nmol/mL plasma v 63.91 +/- 1.7 nmol/mL plasma, n = 6, P =.018 unpaired Student's t test). The results suggest that elevated NHE-1 activity and intracellular acidosis are intermediate phenotypes in women who have pre-eclampsia. Intracellular pH may have been affected by plasma as shown in the time course experiments. DLF, an inhibitor of Na(+)/K(+)ATPase, may contribute to this intracellular acidosis in pre-eclamptic neutrophils.

Topics: Adult; Buffers; Cardenolides; Digoxin; Environment; Female; Humans; Hydrogen-Ion Concentration; Neutrophils; Phosphates; Pre-Eclampsia; Pregnancy; Saponins; Sodium-Hydrogen Exchangers

An enzyme-linked immunosorbent assay is described for the measurement of ouabain in human plasma. This assay is specific for ouabain, strophanthidin, and ouabagenin, with other steroids, including digoxin and vasopressor hormones, exhibiting negligible cross-reactivity. Assay sensitivity was 0.06 nmol/L if 1 mL plasma was extracted and less than 0.005 nmol/L when 20 mL plasma was analyzed. Extracted plasma samples showed ouabainlike immunoreactivity that diluted in parallel with the ouabain standard curve. Repeated extraction and assay of single plasma samples, however, did not produce consistent results in the assay. Increased specificity was obtained by high-performance liquid chromatography of sample extracts before assay. When high-performance liquid chromatographic profiles of plasma spiked with ouabain standard or following bolus intravenous injections of ouabain into normal human volunteers were compared with profiles of unspiked plasma, there was no support for the immunoreactive material in the latter samples being ouabain. We propose that if ouabain is present in the human circulation, its concentration is less than 0.005 nmol/L.

Topics: Animals; Antibodies; Antibody Specificity; Chromatography, High Pressure Liquid; Cross Reactions; Digoxin; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Heart Failure; Humans; Kidney Failure, Chronic; Ouabain; Pre-Eclampsia; Pregnancy; Rabbits; Sensitivity and Specificity; Steroids; Strophanthidin; Vasopressins

Preeclampsia is a major cause of maternal and fetal mortality, and its pathogenesis is not fully understood. Endogenous digitalis-like cardiotonic steroids (CTS) have been implicated in the pathophysiology of preeclampsia; this is illustrated by clinical observations that Digibind, a therapeutic digoxin antibody fragment which binds CTS, lowers blood pressure and reverses Na/K-ATPase inhibition in patients with preeclampsia. Recently we reported that plasma levels of marinobufagenin (MBG), a bufadienolide vasoconstrictor CTS, are increased four-fold in patients with severe preeclampsia.. In the present study, we compared levels of MBG in normal and preeclamptic placentae, as well as the interactions of Digibind and antibodies against MBG and ouabain with material purified from preeclamptic placentae using high-performance liquid chromatography (HPLC).. Levels of endogenous MBG, but not that of endogenous ouabain, exhibited a four-fold elevation in preeclamptic placentae vs. normal placentae (13.6 +/- 2.5 and 48.6 +/- 7.0 nmoles/g tissue; P < 0.01). The elution time of endogenous placental MBG-like immunoreactive material from reverse-phase HPLC column was identical to that of authentic MBG. A competitive immunoassay based on Digibind exhibited reactivity to HPLC fractions having retention times similar to that seen with MBG and other bufadienolides, but not to ouabain-like immunoreactive material.. Our results suggest that elevated levels of endogenous bufadienolide CTS represent a potential target for immunoneutralization in patients with preeclampsia.

Topics: Adult; Binding, Competitive; Bufanolides; Cardiac Glycosides; Case-Control Studies; Cross Reactions; Digoxin; Female; Humans; Immunoglobulin Fab Fragments; In Vitro Techniques; Kinetics; Ouabain; Placenta; Pre-Eclampsia; Pregnancy

Exaggerated inflammatory response occurs in preeclampsia. Preeclampsia is also associated with elevated endogenous digoxin-like factors (EDLFs). Clinical data suggest that Digibind (a polyclonal sheep digoxin binding Fab fragment) binds to EDLF and may have the potential to attenuate vasoconstriction and other clinical symptoms of preeclampsia. This study was undertaken to determine if Digibind could attenuate increased endothelial inflammatory response induced by tumor necrosis factor-alpha (TNFalpha).. Confluent endothelial cells were treated with TNFalpha at different concentrations with or without Digibind in culture. Endothelial adhesion molecule ICAM, VCAM and E-selectin expressions were determined by an immunoassay directly detected on the endothelial surface. Effects of Digibind on TNFalpha-induced extracellular signal-regulated kinase and Na(+)/K(+)-ATPase expressions were also examined.. (1) TNFalpha induced dose-dependent increases in ICAM, VCAM and E-selectin expressions in endothelial cells; (2) Digibind could attenuate and reduce TNFalpha-induced upregulation of endothelial E-selectin, ICAM and VCAM expressions. The blocking effect was in a concentration dependent manner; (3) Digibind had no effects on TNFalpha-induced upregulation of extracellular signal-regulated kinase phosphorylation, but could block TNFalpha-induced downregulation of Na(+)/K(+)-ATPase beta1 expression.. Digibind may exert beneficial effects by preserving cell membrane Na(+)/K(+)-ATPase function and consequently to offset increased inflammatory response in endothelial cells.

Topics: Cell Adhesion Molecules; Cells, Cultured; Cohort Studies; Digoxin; Down-Regulation; Endothelial Cells; Female; Humans; Immunoglobulin Fab Fragments; Immunologic Factors; Pre-Eclampsia; Pregnancy; Sodium-Potassium-Exchanging ATPase; Tumor Necrosis Factor-alpha; Umbilical Veins

Levels of marinobufagenin (MBG), an endogenous bufadienolide Na/K-ATPase (NKA) inhibitor, increase in preeclampsia and in NaCl-sensitive hypertension.. We tested a 3E9 monoclonal anti-MBG antibody (mAb) for the ability to lower blood pressure (BP) in NaCl-sensitive hypertension and to reverse the preeclampsia-induced inhibition of erythrocyte NKA. Measurements of MBG were performed via immunoassay based on 4G4 anti-MBG mAb.. In hypertensive Dahl-S rats, intraperitoneal administration of 50 microg/kg 3E9 mAb lowered BP by 32 mmHg and activated the Na/K-pump in the thoracic aorta by 51%. NaCl supplementation of pregnant rats (n = 16) produced a 37 mmHg increase in BP, a 3.5-fold rise in MBG excretion, and a 25% inhibition of the Na/K-pump in the thoracic aorta, compared with pregnant rats on a normal NaCl intake. In eight pregnant hypertensive rats, 3E9 mAb reduced the BP (21 mmHg) and restored the vascular Na/K-pump. In 14 patients with preeclampsia (mean BP, 126 +/- 3 mmHg; 26.9 +/- 1.4 years; gestational age, 37 +/- 0.8 weeks), plasma MBG was increased three-fold and erythrocyte NKA was inhibited compared with that of 12 normotensive pregnant women (mean BP, 71 +/- 3 mmHg) (1.5 +/- 0.1 vs. 3.1 +/- 0.2 micromol Pi/ml/h, respectively; P < 0.01). Ex-vivo 3E9 mAb restored NKA activity in erythrocytes from patients with preeclampsia. As compared with 3E9 mAb, Digibind, an affinity-purified antidigoxin antibody, was less active with respect to lowering BP in both hypertensive models and to restoration of NKA from erythrocytes from patients with preeclampsia.. Anti-MBG mAbs may be a useful tool in studies of MBG in vitro and in vivo and may offer treatment of preeclampsia.

Topics: Adult; Animals; Antibodies, Monoclonal; Blood Pressure; Bufanolides; Digoxin; Disease Models, Animal; Female; Humans; Hypertension; Immunoglobulin Fab Fragments; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Pregnancy, Animal; Rats; Rats, Inbred Dahl; Sensitivity and Specificity; Sodium Chloride, Dietary; Sodium-Potassium-Exchanging ATPase

Although preeclampsia (PE) is a major cause of maternal and fetal mortality, its pathogenesis is not fully understood. Digitalis-like cardiotonic steroids (CTS) are believed to be involved in the pathophysiology of PE, as illustrated by clinical observations that DIGIBIND, a digoxin antibody which binds CTS, lowers blood pressure in PE. Recently we reported that plasma levels of marinobufagenin (MBG), a vasoconstrictor CTS, are increased fourfold in patients with severe PE. In the present study, we tested whether anti-MBG, or anti-ouabain antibodies, or DIGIBIND can reverse inhibition of erythrocyte Na/K-ATPase (NKA) from patients with mild PE (blood pressure, 149 +/- 3/93 +/- 3 mm Hg; age, 28 +/- 2 years; gestational age, 37 +/- 1 weeks). Development of PE was associated with twofold rise in plasma MBG levels (1.58 +/- 0.15 vs. 0.80 +/- 0.11 nmol/L; P<0.01). The activity of erythrocyte NKA in 12 patients with PE was lower than in 6 normotensive gestational age-matched subjects (1.56 +/- 0.18 vs. 3.11 +/- 0.16 micromol Pi/ml/hr; P<0.001). In vitro treatment of erythrocytes from PE patients with anti-MBG antibody fully restored the NKA activity (3.26 +/- 0.41 micromol Pi/ml/hr; P<0.01). The effects of DIGIBIND was marginally significant (2.53 +/- 0.32 micromol Pi/ml/hr), while the anti-ouabain antibody was not effective (2.25 +/- 0.25 micromol Pi/ml/hr, P>0.5). The present observations provide evidence for a role for MBG in the pathogenesis of PE, and suggest that antibodies against MBG may be useful in the treatment of this syndrome.

Topics: Adult; Antibodies; Blood Pressure; Bufanolides; Digoxin; Erythrocytes; Female; Humans; Ouabain; Pre-Eclampsia; Pregnancy; Sodium-Potassium-Exchanging ATPase

We report a case of a second trimester multifetal pregnancy with preeclampsia associated with an elevated digoxin-like immune factor. Due to the remoteness from viability the patient was offered therapy with digoxin-binding immunoglobulin. No untoward maternal effects were noted.

Topics: Adult; Cardenolides; Digoxin; Female; Humans; Immunoglobulin Fab Fragments; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Pregnancy, Multiple; Saponins

An endogenous sodium pump inhibitor, or digitalis-like factor (DLF), has been postulated to mediate essential hypertension. It may also play a role in preeclampsia. However, studies of this factor in hypertensive pregnancy have not provided consistent findings. Part of this may be due to the absence of subclassification of pregnant women with pregnancy-induced hypertension (PIH) when assessing these parameters. In this study we explored serum DLF and digoxin-like immunoreactive factor (DLIF) in insulin-dependent diabetic (IDDM) women with normotensive pregnancies or PIH, comparing them to each other and to nondiabetic pregnant women. Our results demonstrated that nondiabetic women with preeclampsia (PE, PIH with proteinuria) had significantly increased serum DLF and DLIF compared to normotensive pregnant women (NL BP). Women with transient hypertension of pregnancy (THP, PIH without proteinuria) had intermediate values (DLF. NL BP: 3.3 +/- 0.6, THP: 4.8 +/- 1.1, PE: 7.6 +/- 1.3% inhibition [Na,K]-ATPase, P < .05 ANOVA; DLIF. NL BP: 0.22 +/- 0.02, THP: 0.28 +/- 0.03, PE: 0.35 +/- 0.02 ng digoxin equivalents/mL, P < .05 ANOVA). Pregnant normotensive IDDM women had significantly higher serum DLF and DLIF activity than their nondiabetic counterparts (DLF. non-IDDM NL BP: 3.3 +/- 0.6 v IDDM NL BP: 8.8 +/- 1.2% inhibition [Na,K]-ATPase, P = .0008; DLIF. non-IDDM NL BP: 0.22 +/- 0.02 v IDDM NL BP: 0.31 +/- 0.02 ng digoxin equivalents/mL, P = .005).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Blood Proteins; Cardenolides; Creatinine; Diabetes Mellitus, Type 1; Digoxin; Female; Gestational Age; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Saponins

We measured plasma endogenous digitalis-like substances (EDLS), angiotensin II concentrations and plasma renin activity (PRA) by radioimmunoassay in 30 patients with pregnancy-induced hypertension (PIH), 30 normal pregnant women during the third trimester, and 23 non-pregnant women. Compared to the normal pregnant women, the concentration of plasma EDLS was significantly increased in patients with PIH (P < 0.05). There were significant positive correlations among plasma EDLS level, mean arterial pressure (r = 0.615; P < 0.01), the score index of PIH patients (r = 0.818; P < 0.01), hematocrit (r = 0.853; P < 0.01) and uric gravity (r = 0.764; P < 0.01). There was a significant negative correlation between plasma EDLS level and PRA in patients with PIH (r = -0.718; P < 0.01). Severe proteinuria and edema were related to a significant higher plasma EDLS level than the mild in patients with PIH (P < 0.001). After magnesium sulfate was administered in 9 severe patients of PIH, plasma EDLS levels were decreased (P > 0.05). These findings suggest that EDLS may play an important role in the pathogenesis of PIH and severe as an indicator of the severity of PIH. Its secretion may not be influenced after the administration of magnesium sulfate. There may be a close relationship between EDLS and renin-angiotensin system. When the medicine of digitalis type was administered in patients with PIH, the influence of EDLS must be considered to prevent digitalism.

Topics: Adult; Angiotensin II; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Pre-Eclampsia; Pregnancy; Renin; Saponins; Sodium-Potassium-Exchanging ATPase

To determine the potential use of a digoxin-immunoreactive substance in the prediction of preeclampsia, to study the relationship between serum levels of this substance and gestational age, and to evaluate the correlation between this substance and blood pressure findings in preeclamptic pregnancies.. Serum digoxin-immunoreactive substance concentrations were measured by RIA (double antibody radioimmunoassay) in normotensive (n = 14) and preeclamptic (n = 17) pregnant women in their third trimesters. Statistical evaluation was performed with the Mann-Whitney U-test and correlation-regression analysis.. The mean (+/- S.E.) digoxin-immunoreactive substance levels in the normal and preeclamptic patients were 0.29 +/- 0.06 and 0.31 +/- 0.05 ng/ml, respectively, the slightly higher level in the hypertensive group being statistically non-significant. Serum digoxin-immunoreactive substance levels did not demonstrate good correlation with gestational age and systolic blood pressure in preeclamptic pregnancies.. An endogenous digoxin-immunoreactive substance is present in the sera of third trimester pregnant women, but it does not contribute to the pathogenesis or prediction of preeclampsia.

Topics: Adolescent; Adult; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Female; Gestational Age; Humans; Pre-Eclampsia; Pregnancy; Prospective Studies; Saponins; Sodium-Potassium-Exchanging ATPase

Plasma and urinary digoxin-immunoreactive like substance (DILS) were measured in normal non-pregnant (NNP), normal pregnant (NP) and pregnancy-induced hypertensive women (PIH). The plasma DILS level of PIH, compared with NNP, was no significantly decreased (P > 0.05); but that of NP was significantly decreased (P < 0.01). While the urinary DILS levels of PIH and NNP were significantly higher than that in NNP (P < 0.01). In 24-72 hours after delivery the plasma and urinary DILS levels were all significantly lower than that in NNP (P < 0.05). These results indicate that DILS may play a role in homeostasis regulation in NP or PIH.

Topics: Blood Proteins; Cardenolides; Digoxin; Female; Humans; Pre-Eclampsia; Pregnancy; Saponins

Digoxin-like immunoreactive substance (endoxin) was measured in pregnant patients with pregnancy-induced hypertension. The mean level was significantly higher than that in healthy control subjects (p less than 0.001). Patients with eclampsia had a significantly higher concentration than did women with preeclampsia (p less than 0.03). A positive significant correlation was found between concentration of digoxin-like immunoreactive substance and the value of the index of gestosis of von Goecke and Schwabe (p less than 0.03). Analysis of patterns during various kinds of therapy revealed that nitrendipine was most effective in lowering endoxin concentration. Although an insignificant correlation was found between maternal concentration and both birth and placental weights, the compartmental differences observed seem to suggest fetoplacental origin of this substance.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins

Recent studies have pointed to the existence of an endogenous digoxin-like immuno-active factor (DLIF), which may be associated with hypertension and pre-eclampsia. The DLIF levels in the umbilical venous and umbilical arterial blood of neonates, as well as the maternal serum of primigravidas and multigravidas with and without pre-eclampsia, were determined by means of a commercially available radioimmunoassay kit, which is cross-reactive with DLIF, in 44 mothers and their babies in search for a possible placental, fetal or maternal origin of the DLIF. The mean placental and neonatal masses were significantly lower in the pre-eclampsia group than in the control group (P less than 0.01). However, the DLIF levels in the maternal serum, umbilical cord venous and umbilical cord arterial serum were statistically significantly higher in the pre-eclampsia group than in the control pregnant group (P less than 0.05). A very strong correlation was found between umbilical cord venous and arterial DLIF levels (r = 0.90; P = 0.001, Spearman rank-correlation coefficient). Although the mean DLIF level in cord arterial serum was lower than that of cord venous serum, statistical significance was not reached if the Bonferroni adjustment was applied to the P value.

Topics: Adolescent; Adult; Blood Proteins; Cardenolides; Digoxin; Female; Gestational Age; Humans; Parity; Pre-Eclampsia; Pregnancy; Reference Values; Saponins; Umbilical Arteries; Umbilical Veins

The effects of Mg++ and the dihydropyridine calcium channel blocker isradipine on contractions induced by the thromboxane A2 mimetic U46619 were studied in isolated human uteroplacental arteries. In all preparations investigated U46619 10(-10) to 10(-6) mol/L induced concentration-related contractile responses. In maternal vessels U46619 produced a biphasic concentration-response curve, whereas the compound in fetal vessels produced a sigmoid concentration-response curve parallel to that of prostaglandin F2 alpha. Mg++ (1.0 to 6.0 mmol/L) and isradipine (10(-10) to 10(-5) mol/L) both relaxed U46619-induced contractions by up to about 40%. In preparations precontracted by U46619 and exposed to isradipine 10(-6) mol/L, addition of Mg++ 6.0 mmol/L consistently produced a further small relaxation. Removal of the endothelium or pretreatment with indomethacin 10(-6) mol/L or digoxin 10(-6) mol/L did not influence the inhibition produced by Mg++ or isradipine. In vessels pretreated in Ca(++)-free medium Mg++ 6.0 mmol/L depressed and isradipine abolished responses to Ca++ (0.01 to 4.0 mmol/L) after depolarization with K+ 124 mmol/L. In maternal and fetal arteries stimulated with U46619, however, Mg++ 6.0 mmol/L and isradipine 10(-6) mol/L produced a similar, partial inhibition of responses to Ca++ (0.01 to 4.0 mmol/L). Mg++ seems to inhibit transmembrane Ca++ influx, although less efficiently than the dihydropyridine calcium antagonist isradipine. In addition, Mg++ may interfere with Ca++ at intracellular binding sites. Provided that preeclampsia comprises enhanced vascular actions of thromboxane A2, the present results support the established use of Mg++ in the treatment of this condition and suggest that calcium antagonists are of potential benefit.

Topics: Antihypertensive Agents; Arteries; Calcium Channel Blockers; Digoxin; Female; Humans; Indomethacin; Isradipine; Magnesium; Placenta; Pre-Eclampsia; Pregnancy; Prostaglandin Endoperoxides, Synthetic; Pyridines; Uterus

To determine if there are abnormalities in cellular cation regulation in pregnancy-induced hypertension, erythrocyte intracellular levels of calcium, magnesium, sodium, and potassium and circulating parathyroid hormone and "endoxin" were examined in 13 women with pregnancy-induced hypertension and 34 control subjects matched for gestational age (greater than or equal to 35 weeks). Both endoxin and parathyroid hormone levels were higher in patients with pregnancy-induced hypertension than in control subjects (endoxin, 294 +/- 34 vs. 210 +/- 19 pg/ml, p less than 0.05; parathyroid hormone, 0.65 +/- 0.05 vs. 0.60 +/- 0.03 ng/ml); the increase was significant only for endoxin. Intracellular calcium was higher in the patients with pregnancy-induced hypertension (0.033 +/- 0.010 vs. 0.015 +/- 0.001 mEq/L, p less than 0.05, in the patients with pregnancy-induced hypertension and control patients, respectively) but intracellular sodium, potassium, and magnesium levels were not different. This intracellular calcium elevation may be caused directly by the increase in parathyroid hormone or indirectly by the observed elevation in endoxin. Our data indicate that the observed effect is specific because no changes in intracellular sodium, potassium, or magnesium levels were found.

Topics: Black People; Blood Proteins; Cardenolides; Digoxin; Electrolytes; Erythrocytes; Female; Humans; Hypertension; Parathyroid Hormone; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Saponins; Sodium-Potassium-Exchanging ATPase; Spectrophotometry, Atomic

Topics: Blood Proteins; Cardenolides; Digoxin; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy, Multiple; Saponins

Topics: Digoxin; Female; Humans; Pre-Eclampsia; Pregnancy

The objective of this study was to measure maternal total digoxin-like immunoreactive factor levels in singleton pregnancies with or without hypertension and in twin pregnancies. Plasma digoxin-like immunoreactive factor was measured in 113 third-trimester patients: 51 normotensives, 20 preeclamptics, 19 with latent or chronic hypertension, and 23 with twin pregnancies. The concentration of total digoxin-like immunoreactive factor in the twin gestations (1143 +/- 249 pg/mL) was significantly higher than that in either the normotensive pregnancies (890 +/- 161 pg/mL) (P less than .001) or in the hypertensive pregnancies (903 +/- 256 pg/mL) (P less than .01). However, there were no significant differences in digoxin-like immunoreactive factor levels between the normotensive and hypertensive groups. A trend of higher, although not statistically significant, levels of digoxin-like immunoreactive factor was noted in the chronic hypertensive group as compared with the preeclamptic patients (957 +/- 212 versus 852 +/- 288 pg/mL). We therefore conclude that digoxin-like immunoreactive factor does not contribute significantly to the pathogenesis or prediction of preeclampsia. The increased amount of digoxin-like immunoreactive factor in twin pregnancies may reflect a contribution from multifetal origin, or might be a physiologic adaptive mechanism allowing higher cardiac output by a possible cardiotropic effect.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third; Pregnancy, Multiple; Prospective Studies; Saponins; Twins

1. A ouabain-displacing factor (ODF) was measured in the urine of non-pregnant, normotensive pregnant and hypertensive pregnant women by a receptor-binding assay with sodium, potassium-dependent adenosine triphosphatase. 2. Urinary ODF was significantly increased in normal pregnancy. 3. Greater increases were seen in pregnancy-induced hypertension and pre-eclampsia.

Topics: Adult; Aldosterone; Cardenolides; Catecholamines; Digoxin; Female; Humans; Hypertension; Natriuretic Agents; Plasma Volume; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Renin; Saponins; Sodium-Potassium-Exchanging ATPase; Uric Acid

Digoxin-like immunoreactive substance(s) has been measured in serum during pregnancy. Because of its presence in pregnancy, investigators have suggested that digoxin-like immunoreactive substance may play an etiologic role in the development of preeclampsia. The objectives of this study were to evaluate the relationship between maternal digoxin-like immunoreactive substance and gestational age and compare digoxin-like immunoreactive substance concentrations in patients with and without preeclampsia who were in the third trimester. Two hundred twenty patients were studied during either the first (n = 53), second (n = 56), or third (n = 111) trimester of pregnancy. Digoxin-like immunoreactive substance was undetectable in the serum of patients during the first trimester; however, 11% of second-trimester and 96% of third-trimester patients had measurable levels of serum digoxin-like immunoreactive substance (p less than 0.05). The mean +/- SEM concentration of digoxin-like immunoreactive substance in serum in third-trimester patients was 0.29 +/- 0.01 ng/ml (range 0 to 0.58 ng/ml). Gestational age at delivery was significantly lower in patients with preeclampsia than in those without preeclampsia (36.3 +/- 0.6 versus 38.8 +/- 0.4 weeks; p less than 0.001). In addition, there was no statistical difference in mean +/- SEM concentration of digoxin-like immunoreactive substance between 27 patients without preeclampsia (0.32 +/- 0.02 ng/ml) and 27 patients with preeclampsia (0.30 +/- 0.02 ng/ml; p = 0.47) matched for gestational age. We conclude that (1) digoxin-like immunoreactive substance appearance and increasing serum concentration during pregnancy are correlated with increasing gestational age and (2) there is no difference in digoxin-like immunoreactive substance values between patients with and without preeclampsia, which may exclude digoxin-like immunoreactive substance as a predictor of preeclampsia.

Topics: Adolescent; Adult; Blood Proteins; Cardenolides; Digoxin; Female; Gestational Age; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Saponins

Our aims were to determine the potential usefulness of digoxin-like immunoreactive substances in the prediction of preeclampsia, to study the relationship between fetal production of these substances and maternal serum levels, and to evaluate the association between digoxin-like immunoreactive substances and plasma volume findings in preeclamptic pregnancies. Serum digoxin-like immunoreactive substance concentrations were measured in normotensive and preeclamptic pregnant women and in umbilical artery and vein blood samples. None of the patients in the first trimester (n = 53) and 11% of those in the second (n = 56) had detectable levels of this substance. However, 91% of the patients in the third trimester (n = 161) had positive results. The concentrations of digoxin-like immunoreactive substances in the preeclamptic group (n = 78) were significantly (p less than 0.005) lower than those of third-trimester (n = 83) normotensive patients (0.22 +/- 0.12 versus 0.32 +/- 0.15 ng/ml). However, there were no significant differences between the two groups regarding digoxin-like immunoreactive substance concentrations when matched for gestational age (41 patients in each group). Digoxin-like immunoreactive substance concentrations in umbilical vessels were significantly higher (p less than 0.001) than the corresponding maternal levels. Umbilical vessel digoxin-like immunoreactive substance levels demonstrated good correlation with fetal gestational age and birth weight in both normotensive and preeclamptic pregnancies. On the other hand, there was a poor (r = 0.02; p = 0.91) correlation between plasma volume findings and digoxin-like immunoreactive substance concentration. We conclude that the digoxin-like immunoreactive substance level may be of very little value in the prediction of preeclampsia. The presence of digoxin-like immunoreactive substance at greater concentrations in the umbilical cord blood samples suggests the possibility of the fetus as the source of this substance. Digoxin-like immunoreactive substances may not play a major role in plasma volume expansion during pregnancy.

Topics: Blood Proteins; Cardenolides; Digoxin; Female; Fetal Blood; Humans; Plasma Volume; Pre-Eclampsia; Pregnancy; Saponins; Sodium-Potassium-Exchanging ATPase

The increase of peripheral resistance in pregnancy induced hypertension (PIH) and in preeclampsia (PE) is not yet explained since previous studies have found that renin-angiotensin-aldosterone system is actually depressed, that adrenergic system is inconstantly stimulated and that vasodilating prostaglandins are inconstantly decreased. In order to get a better insight in the pathogenesis of PIH and PE, we have measured the 24 h urinary excretion of digoxin-like natriuretic factor (DLF) in 15 normotensive pregnant women (NP), in 29 women with PIH and in 6 women with PE under normal salt diet, without treatment. DLF have been measured by radio receptor binding assay. Normal values were established in 14 normotensive non pregnant (NNP). In NP, 24 h urinary excretion of DLF was significantly higher than in NNP (respectively 14.9 +/- 7.5 and 9.5 +/- 2.5 nmol/mmol of creatininuria, p less than 0.01). Comparatively to NP, 24 h urinary excretion of DLF was significantly higher in PIH (31.7 +/- 19 nmol/mmol of creatininuria) and in PE (40.7 +/- 16.3 nmol/mmol of creatininuria). In PIH and PE, there were simultaneously a decrease of plasma renin activity and plasma volume but no difference for plasma catecholamines.. 1. the production of DLF is increased by normal pregnancy; 2. it is increased in PIH and PE in comparison with NP and may explain the increase of peripheral resistance.

Topics: Adult; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Middle Aged; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins

Some pregnant patients with toxemia, especially those with thrombocytopenia, liver or renal dysfunction have elevated serum DLF (digoxin like factor). Since antidigoxin serum reduces the hypertension of DOCA hypertensive rats, it is proposed that antidigoxin antibodies be tried in the treatment of these select patients with toxemia of pregnancy.

Topics: Antibodies; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Models, Biological; Pre-Eclampsia; Pregnancy; Saponins

A group of small, digitalislike compounds has been implicated in some forms of essential hypertension. Because of similarities between these forms of essential hypertension and pregnancy-induced hypertension, the presence of digitalislike factors in pregnancy-related fluids has been investigated. The factors are found in maternal sera with significantly higher levels of digitalislike activity, as monitored by digoxin radioimmunoassay, in the sera of third-trimester women with pregnancy-induced hypertension as compared to normotensive third-trimester controls (315 vs 195 pg digoxin equivalents/ml; p less than 0.001). Similarly, they are found in amniotic fluid, and significantly higher levels, as measured by radioimmunoassay (760 vs 540 pg digoxin equivalents/ml; p less than 0.0008) and by inhibition of ouabain-sensitive Na+,K+-adenosine triphosphatase (ATPase) (12.8 vs 2.7% inhibition; p less than 0.002), are found in those women whose pregnancies are complicated with hypertension. With purification, several digoxinlike immunoactive compounds are detected. Of these, some have a marked ability to inhibit ouabain-sensitive Na+,K+-ATPase. While as yet unidentified, these compounds have properties suggesting that they are not peptides, steroids, or fatty acids and lipids.

Topics: Amniotic Fluid; Blood Proteins; Cardenolides; Chromatography, Gel; Chromatography, High Pressure Liquid; Digoxin; Female; Humans; Pre-Eclampsia; Pregnancy; Saponins; Ultrafiltration

The expanded toxemia syndrome or gestosis refers to polysymptomatic diseases that are associated with pregnancy. This report discusses those cases without initial hypertension or proteinuria that were "cured" by delivery and were associated with maternal and fetal morbidity (usually intrauterine growth retardation). A list of suggested tests is presented to document gestosis in pregnant women with medical illnesses. Unlike preeclampsia, gestosis may occur at almost any time in pregnancy.

Topics: Chorionic Gonadotropin; Digoxin; Female; Fetal Growth Retardation; Humans; Hypertension; Placenta; Plasma Volume; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Regional Blood Flow; Syndrome

An endogenous digitalis-like substance (DLS) may be involved in the pathogenesis of essential hypertension and pre-eclampsia. The digoxin levels in maternal and cord blood of 504 randomly selected patients were determined. Since none of the patients received digoxin, these levels indicated a cross-reacting substance (immunoreactive DLS). DLS levels were significantly higher in the cord blood of pre-eclamptic patients than in the cord blood of controls. DLS levels in cord blood increased with the severity of pre-eclampsia, and levels were higher in primigravidas than in multigravidas. The structure and biological activity of DLS must be determined before definite conclusions about its role in the pathogenesis of pre-eclampsia can be made.

Topics: Digitalis Glycosides; Digoxin; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy

Endogenous digoxin-like immunoactivity has been detected in the blood of adult patients in renal failure, newborn infants, and pregnant women in the third trimester. Blood levels of this activity increase in pregnant women as gestation progresses, and preliminary data suggest that the activity is increased in hypertensive pregnant women relative to normotensive pregnant women. Similar immunoactivity has also been detected in amniotic fluid and in the urine and serum of normal healthy subjects. The factors giving rise to this immunoactivity cross-react with antibodies used in many commercially available immunoassays for digoxin. The immunoactive factor isolated from human subjects is water soluble and exists tightly but reversibly bound to proteins in serum. The extent of this protein binding is altered in the clinical conditions studied relative to normal adults. This altered protein binding accounts for the detection of this factor by many of the commercially used immunoassays for digoxin. In this article I summarize recent findings related to detecting this activity in the blood of several clinical populations where the accurate measurement of digoxin may be compromised. I also summarize the preliminary isolation and characterization of the factor responsible for this immunoactivity.

Topics: Adult; Blood Proteins; Cardenolides; Creatinine; Cross Reactions; Digoxin; Female; Hot Temperature; Humans; Infant, Newborn; Kidney Failure, Chronic; Methods; Molecular Weight; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Reagent Kits, Diagnostic; Saponins; Ultrafiltration

Various functions of erythrocytic cation transport were studied in normotensive and hypertensive pregnancy (women with pre-eclampsia and essential hypertension). The results showed that in pregnancy there is an increase in the number of erythrocytic glycoside binding sites accompanied by a proportional increase in the active inward transport of rubidium (used as a substitute for potassium). There was no evidence of an effect of pregnancy on intraerythrocytic sodium concentrations. These changes were apparently entirely attributable to pregnancy and not affected by pre-eclampsia or essential hypertension. It is suggested that these alterations indicate an adaptive increase in sodium pump numbers and activity secondary to a tendency for the intraerythrocytic sodium concentration to rise during pregnancy and compensating for that tendency.

Topics: Adolescent; Adult; Biological Transport, Active; Digoxin; Erythrocytes; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Rubidium; Sodium

A study has been undertaken of levels of an endogenous substance which immunologically cross reacts with digoxin and may be the putative natriuretic hormone. The possibility that this substance may play a role in the pathophysiology of preeclampsia has been studied by measuring the plasma concentrations in clinically healthy and preeclamptic pregnant patients. A significant difference (p less than 0.001) between these two groups has been found.

Topics: Cross Reactions; Digoxin; Female; Humans; Natriuresis; Natriuretic Agents; Pre-Eclampsia; Pregnancy; Proteins

Topics: Aminophylline; Aspirin; Atropine; Cardiomyopathies; Cataract; Child, Preschool; Chloramphenicol; Chlorothiazide; Conjunctivitis; Digoxin; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Iatrogenic Disease; Infant; Infant, Newborn; Infant, Newborn, Diseases; Male; Ophthalmic Solutions; Pre-Eclampsia; Pregnancy; Purpura, Thrombocytopenic; Substance-Related Disorders; Suppositories