A digoxin-like immunoreactive substance in preeclampsia

Gusdon, John P.; Buckalew, Vardaman M.; Hennessy, John F.

doi:10.1016/s0002-9378(84)80114-3

Cited by 69 publications

(23 citation statements)

References 5 publications

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“…Although several studies have shown a correlation between elevated endogenous cardiac glycosides and certain pathological conditions, the physiological function of endogenous cardiac glycoside-like compounds is still uncertain (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Plasma levels of endogenous cardiac glycosides are high in several animal models of hypertension, as well as in human essential hypertension and preeclampsia (10)(11)(12)(13)(14)(15)(16)(17).…”

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confidence: 99%

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The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

Dostanic-Larson

Huysse

Lorenz

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

173

190

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The Na,K-ATPase contains a binding site for cardiac glycosides, such as ouabain, digoxin, and digitoxin, which is highly conserved among species ranging from Drosophila to humans. Although advantage has been taken of this site to treat congestive heart failure with drugs such as digoxin, it is unknown whether this site has a natural function in vivo. Here we show that this site plays an important role in the regulation of blood pressure, and it specifically mediates adrenocorticotropic hormone (ACTH)-induced hypertension in mice. We used genetically engineered mice in which the Na,K-ATPase ␣2 isoform, which is normally sensitive to cardiac glycosides, was made resistant to these compounds. Chronic administration of ACTH caused hypertension in WT mice but not in mice with an ouabain-resistant ␣2 isoform of Na,K-ATPase. This finding demonstrates that the cardiac glycoside binding site of the Na,K-ATPase plays an important role in blood pressure regulation, most likely by responding to a naturally occurring ligand. Because the ␣1 isoform is sensitive to cardiac glycosides in humans, we developed mice in which the naturally occurring ouabain-resistant ␣1 isoform was made ouabain-sensitive. Mice with the ouabainsensitive ''human-like'' ␣1 isoform and an ouabain-resistant ␣2 isoform developed ACTH-induced hypertension to greater extent than WT animals. This result indicates that the cardiac glycoside binding site of the ␣1 isoform can also mediate ACTH-induced hypertension. Taken together these results demonstrate that the cardiac glycoside binding site of the ␣ isoforms of the Na,K-ATPase have a physiological function and supports the hypothesis for a role of the endogenous cardiac glycosides. adrenocorticotropic hormone ͉ hypertension ͉ endogenous cardiac glycosides

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confidence: 99%

“…Plasma levels of endogenous cardiac glycosides are high in several animal models of hypertension, as well as in human essential hypertension and preeclampsia (10)(11)(12)(13)(14)(15)(16)(17). In addition, marked increases in endogenous ouabain-like compounds occur in congestive heart failure, both in animal models and human patients (18)(19)(20).…”

mentioning

confidence: 99%

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

Dostanic-Larson

Huysse

Lorenz

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

173

190

View full text Add to dashboard Cite

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“…Although there is general agreement that a substance that cross reacts with digoxin antibodies is present in maternal blood during the third trimester of pregnancy, not all studies have shown that blood levels are higher in patients with preeclampsia when compared with patients with normal pregnancies. 5,6,[13][14][15][16][17][18] The strongest evidence for a causal role of EDLF in preeclampsia is the anecdotal reports that digoxin-binding immunoglobulin lowers blood pressure in preeclampsia. 9,10 The present trial represents the next step in formally evaluating the role of EDLF and attenuation of EDLF in the preeclamptic patient.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4] In 1984, two groups demonstrated increased circulating levels of an endogenous factor that crossreacted with digoxin antibodies in preeclampsia. 5,6 This observation, and the demonstration that digoxin antiserum lowered blood pressure in animal models of hypertension, 7 led Goodlin 8 to propose the use of a commercially available, ovine, digoxinbinding Fab fragment immunoglobulin (Digibind, Glaxo Wellcome/Smith Kline Beecham) (DIF) as a treatment for the elevated blood pressure of preeclampsia. Goodlin 9 reported that DIF lowered blood pressure in his index subject, and we reported similar results in one additional subject.…”

Section: Introductionmentioning

confidence: 99%

The hemodynamic effects of intravenous digoxin-binding fab immunoglobulin in severe preeclampsia: a double-blind, randomized, clinical trial

et al. 2009

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Objective: An endogenous digitalis-like factor (EDLF) has been implicated in the pathophysiology of preeclampsia (PE). This hypothesis is supported by two cases of preeclampsia in which administration of digoxin immune Fab (DIF) reduced mean arterial pressure (MAP). Study Design: To study this observation further, we performed a double-blind, placebo-controlled, randomized clinical trial to examine the effects on MAP of intravenous DIF given after delivery in 26 subjects with severe preeclampsia. Treating obstetricians were blinded to subject assignment and were allowed to use standard antihypertensive drugs during the trial. Results: The primary outcome, a significant difference in blood pressure between the two groups over the 24-h period of observation after the intervention, was not supported. However, mean MAP was significantly lower in the DIF-treated subjects for the first 4 h after therapy as compared with controls (P ¼ 0.05). Six subjects (46.2%) in the placebo arm were given conventional antihypertensive medications by their obstetrician for blood pressure >160 mm Hg systolic or >110 mm Hg diastolic, compared with zero subjects in the treatment arm (P ¼ 0.01). A trend towards increased creatinine clearance was observed in DIF-treated subjects (137.6 ± 42.6 versus 104.1 ± 43.4, P ¼ 0.07). Conclusion: These results support the hypothesis that EDLF contributes to the elevated blood pressure in preeclampsia and suggests a possible role for DIF as a treatment for this condition.

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“…Endogenous digitalis-like factors have been reported in the literature as a causative agent in the development of preeclampsia. [11][12][13][14][15][16] Although the mechanism of action of the digoxinfragmented antibody is not completely clear it is believed to work by releasing the inhibition of endogenous sodium pumps that have been associated with hypertension in pregnancy. 17,18 Two separate case reports attest to a possible clinical improvement with patients treated with the digoxin-fragmented antibody.…”

Section: Discussionmentioning

confidence: 99%