marinobufagenin and Fetal-Growth-Retardation

Previous studies from this laboratory have demonstrated that the bufodienolide, marinobufagenin, causes a syndrome in the pregnant rat that resembles human preeclampsia. Furthermore, marinobufagenin urinary excretion is elevated in approximately 85% of preeclamptic patients. Resibufagenin, an antagonist to marinobufagenin, completely prevents the syndrome (hypertension, proteinuria, and intrauterine growth restriction) if given from early pregnancy.. We investigated the effects of another bufodienolide, cinobufatalin, to determine if it, likewise, could induce the rat "preeclamptic" syndrome, which it did. We then examined whether resibufagenin could prevent the syndrome due to cinobufatalin.. Resibufagenin improved hypertension but not proteinuria, and did not prevent uterine growth restriction.. We conclude that more than one bufodienolide may induce the preeclamptic syndrome and that each may require a specific antagonist to prevent (or treat) the syndrome.

Topics: Animals; Bufanolides; Disease Models, Animal; Female; Fetal Growth Retardation; Hypertension; Pre-Eclampsia; Pregnancy; Proteinuria; Rats

Preeclampsia (PE) is a disorder that results in significant fetomaternal morbidity and mortality with yet no definitive pharmacological intervention. It involves the development of de novo hypertension and proteinuria after 20 weeks of pregnancy. All too often, intrauterine growth restriction (IUGR) occurs. Evidence has accrued that implicates the cardiac glycosides (the cardenolides and the bufadienolides) as potentially involved in the pathophysiology of PE. These compounds act by inhibiting Na(+)/K(+) ATPase. Digibind (digoxin immune Fab) antagonizes this action of the cardenolides. It also has cross-reactivity against the bufadienolides, including marinobufagenin. This study investigated the effects of Digibind in a rat model of PE. We induced a syndrome in rats, which includes many of the phenotypic characteristics of human PE. Digibind, in escalating doses, was given on days 10 to 20 of pregnancy. Digibind produced significant lowering of the blood pressure and reduced proteinuria in our rat model of PE. However, it also did not avert IUGR. In view of these findings, in our experimental model of human PE, further studies in the quest for effective treatment of PE need to focus on pharmaceuticals that can remedy the syndrome without compromising the fetus.

Topics: Animals; Animals, Newborn; Blood Pressure Determination; Bufanolides; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fetal Growth Retardation; Immunoglobulin Fab Fragments; Injections, Intraperitoneal; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Probability; Proteinuria; Random Allocation; Rats; Reference Values; Risk Assessment; Treatment Outcome; Urinalysis

The bufodienolides are cardiac glycosides which have the ability to inhibit the enzyme, Na(+)/K(+) ATPase (sodium potassium adenosine triphosphatase). They are cardiac inotropes, cause vasoconstriction (and, potentially, hypertension) and are natriuretic. Evidence has accrued over time which supports the view that they are mechanistically involved in volume expansion-mediated hypertension. In this communication, the authors summarize data which support the view that the bufodienolides and, in particular, marinobufagenin (MBG) are involved in the pathogenesis of preeclampsia. In a rat model of the syndrome, MBG causes hypertension, proteinuria, intrauterine growth restriction and increased weight gain. All of these phenotypic characteristics are prevented by an antagonist to MBG, resibufogenin (RBG). The "preeclamptic" animals also develop a vascular leak syndrome, resulting in hemoconcentration. Abnormalities in the MAPK (mitogen-activated protein kinase) system play a role in the mechanism by which MBG produces the abnormalities in the pregnant rat. Studies to discover the relevance of these findings to human preeclampsia are currently underway in several laboratories and clinics.

Topics: Animals; Bufanolides; Disease Models, Animal; Female; Fetal Growth Retardation; Humans; Mitogen-Activated Protein Kinase Kinases; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Sodium-Potassium-Exchanging ATPase