Preeclampsia is a disorder which occurs only in human pregnancy. It consists of the development of hypertension, proteinuria and, often, excessive edema after 20 weeks of gestation in patients with previously normal blood pressure. It is the second most frequent cause of fetal wastage and maternal morbidity and mortality. Progress in understanding the pathophysiology of this disorder has been hampered by a lack of suitable animal models, especially of the early events in its pathogenesis. We have developed a rat model which reproduces many of the phenotypic characteristics of the human syndrome, including hypertension, proteinuria and intrauterine growth restriction. We have determined that the excretion of a circulating inhibitor of Na/K ATPase, marinobufagenin (MBG), a cardiotonic bufadienolide which has vasoconstrictive properties, is elevated in these animals even before hypertension develops. Resibufogenin (RBG) is a structurally related analogue that differs from MBG only by the absence of the 5 β-hydroxyl-grouping. Furthermore, this compound has been determined to have no effect on angiogenesis. We therefore injected this material intraperitonealy daily in a dose of 15.3 μg/kg in five pregnant animals which had been rendered “preeclamptic” by administering desoxycorticosterone (DOCA) and replacing their drinking water with 0.9% saline. Systolic blood pressure (BP), measured with a tail cuff method, which rose to 132 ± 5 mm Hg from an initial mean value of 109 ± mm Hg (p<0.001) due to the saline and DOCA treatment, fell to 117 ± 8 mm Hg after two days (p<0.01). This reduction in BP persisted throughout the treatment reaching a mean value of 115 ± 10 mm Hg (p = 0.02) after seven days. These data indicate that RBG is effective in reducing BP in this rat model of human preeclampsia. We postulate that its mechanism of action is that of competitive inhibition of the effect of MBG to inhibit Na/K ATPase. Studies to evaluate this possibility are under way.
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