DESCRIPTION (provided by applicant): Preeclampsia consists of hypertension and proteinuria in pregnancy and is the most common cause of maternal mortality if left untreated. Hypertension in preeclampsia is implicated in the constellation of symptoms including seizures, glomerular damage and intrauterine growth retardation. Inhibition of nitric oxide synthase (NOS) in pregnant rats is an established model of preeclampsia, as it replicates these symptoms. Magnesium sulfate is the standard treatment for preeclampsia. However, magnesium's anti-hypertensive effects remain poorly understood. Magnesium acts as a vasodilator, an action customarily attributed to its ability to antagonize calcium entry into vascular smooth muscle cells (VSMC). Emerging evidence suggests that magnesium may also regulate vascular nitric oxide (NO). Therefore, magnesium may mediate vascular relaxation and reduction of blood pressure by activating the vascular NO/cGMP/protein kinase G (PKG) signaling pathway. We hypothesize that magnesium and NO act synergistically at the level of the vasculature to cause vasodilation and a reduction in blood pressure. Specifically, magnesium's ability to reduce blood pressure in the nitric oxide-inhibited animal model of preeclampsia is due to its ability to upregulate vascular NO/cGMP/PKG signaling, effectively reducing total vascular resistance and consequently blood pressure. To test this hypothesis, we will use the NOS inhibitor, NGnitro-L-arginine methyl ester (L-NAME), to induce hypertension in pregnant rats. Then, graded doses of magnesium sulfate via chronic infusions in vivo, and acute treatment of vascular tissues ex vivo, will be used to address the following specific aims: 1) Determine if magnesium predictably reduces blood pressure and proteinuria and alters plasma/urinary NOS signaling metabolite levels, and whether these measures can be used therapeutically to predict and track hypertension; 2) Determine magnesium's effects on vascular inducible NOS (iNOS) and endothelial NOS (eNOS) expression; 3) Investigate magnesium's effects on vascular NOS signaling such as NOS activity, NO-mediated guanylate cyclase activity and PKG expression, and 4) Investigate magnesium's ability to regulate vascular reactivity in response to NO-generating stimuli. Data derived from these experiments will elucidate the anti-hypertensive effects of magnesium, its mode of action and the roles of NO and magnesium in preeclampsia and pregnancy-induced hypertension.
|Effective start/end date||8/15/03 → 8/31/06|
- National Institutes of Health: $127,360.00