Blood pressure control and adrenal steroid biosynthesis in preeclampsia

Erwin Schrödinger Fellowship J 1839 Blood pressure control and adrenal steroid biosynthesis in preeclampsia Lukas HEFLER 06.03.2000 Background: Preeclampsia is characterized by hypertension, decreased intravascular fluid volume, increased intervascular fluid volume, and proteinuria. This disorder of blood pressure homeostasis, proteinuna, and altered volume status affects up to 7% of gravid women and between 10-20% of women carrying their first pregnancy. Cures are affected through delivery of the fetus leaving family and physicians to cope with prematurity. If left untended to, the hypertension observed causes placental abruption, seizure, stroke and even death among women. Genes that regulate vascular smooth muscle activation have been implicated in this disorder. Our laboratory targeted the gene, which encodes endothelial nitric oxide synthase (Nos3). This results in a phenotype in pregnant mice, which is consistent with preeclampsia. Our laboratory has mice with 0, 1, 2, 3, and 4 copies of the angiotensinogen (Agt) gene driven by its wild type promoter. Higher serum levels of angiotensin II, which results from conversion of angiotensinogen, causes increased blood pressure and salt and water retention via increased adrenal gland output of aldosterone. The interaction between angiotensin II and aldosterone secretion has not been studied extensively during pregnancy. Adrenal gland production of aldosterone requires cholesterol as a substrate. Higher levels of total cholesterol and LDL cholesterol are observed among patients with preeclampsia. Aims: We speculate that significant reductions in cholesterol through dietary restriction, inhibition of cholesterol by an HMG-CoA reductase inhibitor, e.g., atorvastatin, or both could lead to blood pressure and water homeostasis more favorable for reproduction as compared to mice with a predisposition for hypertension. Methods: We plan to utilize the mice we have available (Nos3 and Agt) to explore blood pressure and water homeostasis during pregnancy. Blood pressure, renal function, serum electrolytes will be monitored across pregnancy. Maternal and fetal/neonatal reproductive out comes will be monitored closely. Adrenal gland steroidogenesis will be ascertained in association with these physiologic changes. These responses will be characterized on a background of high and low cholesterol diets, after exposure to an HMG-CoA reductase inhibitor, and diets plus an HMG-CoA reductase inhibitor.