Preeclampsia and other pregnancy-induced hypertensive states complicate 9% of all pregnancies in the United States. The cause of these abnormalities is not known. Associated with the hypertension of pregnancy are often derangements of salt and water homeostasis not directly related to the renin-angiotensin-aldosterone axis. The overall goal of the proposed research is to explore the possible role of circulating """"""""natriuretic factors"""""""", recently implicated in essential hypertension, in the inception or mediation of the hypertension of pregnancy and its related abnormalities. Our goals include the isolation and chemical identification of this fact. The studies proposed here will extend preliminary results showing significantly increased serum levels of a natriuretic factor as measured by a modified digoxin radioimmunoassay in hypertensive pregnant women at 38-42 weeks gestation who are free of digoxin. The digoxin-like substance also inhibits the ouabain-sensitive [Na,K]ATPase. Both enzymatically and immunologically determined circulating levels of natriuretic factor in the serum of 50 normotensive pregnant women at term will be compared to 50 hypertensive pregnant women at term. Differences in serum levels of this factor between these two groups as well as potential correlations between blood pressure and serum levels of this factor will be statistically tested. Similar studies will be carried out on 100 cord bloods and 100 amniotic fluids, half from hypertensive and half from normotensive pregnancies. Current efforts to purify this substance will be augmented through 1) increasing the initial concentrations of this factor by developing a method to remove the approximately 95% material which is normally bound in serum or by using amniotic fluid which contains higher concentrations of unbound factor and 2) using affinity columns specific for the immunologically or enzymatically measured natriuretic substance to complement the already effective methods of gel filtration chromatography and HPLC. The digoxin-like compound will be identified by amino acid analysis and sequencing (if a protein) and by mass spectrometry techniques. If quantities are sufficient, high resolutions NMR spectroscopy will also be carried out. Once the factor is isolated and identified future in vivo studies are envisioned to establish absolutely any pathogenic role of this compound in the hypertension of pregnancy.
| Graves, S W; Eder, J P; Schryber, S M et al. (1989) Endogenous digoxin-like immunoreactive factor and digitalis-like factor associated with the hypertension of patients receiving multiple alkylating agents as part of autologous bone marrow transplantation. Clin Sci (Lond) 77:501-7 |
| Graves, S W; Adler, G; Stuenkel, C et al. (1989) Increases in plasma digitalis-like factor activity during insulin-induced hypoglycemia. Neuroendocrinology 49:586-91 |
| Graves, S W; Sharma, K; Chandler, A B (1986) Methods for eliminating interferences in digoxin immunoassays caused by digoxin-like factors. Clin Chem 32:1506-9 |
