Phase 1 Study of Oral L-citrulline on ADMA/L-arginine and Endothelial-dependent Vascular Function in Pregnancy.

The pregnancy-specific syndrome preeclampsia is a leading cause of maternal and fetal morbidity and mortality. The underlying cause of preeclampsia is unknown, however several pre-existing maternal conditions are associated with an increased risk of preeclampsia including: diabetes, hypertension, renal dysfunction, and obesity. Among these conditions, obesity has been increasing in the population, such that 30% of the adult population in the US is now considered obese, and because of this obesity has the largest attributable risk for preeclampsia, accounting for 15 to 32% of the population attributable risk for preeclampsia. There is abundant evidence that pre-pregnancy obesity increases the risk of preeclampsia. However, it is unknown how pre-pregnancy obesity increases the risk of preeclampsia, how obesity-mediated metabolic aberrations interact with current hypotheses of the pathogenesis of preeclampsia, and why only a subset of obese women (~6-8%) develops preeclampsia. Several lines of evidence indicate that endothelial dysfunction is a central feature of the pathophysiology of preeclampsia, and endothelial dysfunction is a common endpoint of obesity. Asymmetric dimethylarginine (ADMA) is a methylated metabolite of the amino acid L-arginine and an endogenous inhibitor of nitric oxide synthase (NOS). High concentrations of ADMA contribute to endothelial dysfunction and ADMA inhibits angiogenesis and arteriogenesis, activities important in pregnancy and deficient in preeclampsia. ADMA is higher in obesity and ADMA concentrations are higher early in pregnancy among women who later develop preeclampsia. This protocol describes a randomized placebo-controlled trial of L-citrulline vs. placebo in 80 obese pregnant women from twelve to twenty weeks gestation, to determine whether L-citrulline supplementation decreases the plasma ADMA/L-arginine ratio, lowers maternal blood pressure, improves endothelial-dependent vascular function and peripheral vascular stiffness, and improvement in uterine artery Doppler resistance and flow. We will compare the data obtained from these obese pregnant women to the same measures obtained from 40 untreated lean pregnant women.