A Double-Blind, Randomized, Pilot Study to Explore Whether Enhancing L-Arginine Bioavailability by Oral Supplementation Increases NO Production and Prevents Peroxynitrite Generation in the Pre-Eclamptic Placenta

INTRODUCTION

In the past few years evidence has accumulated strongly suggesting that nitric oxide (NO), a potent endothelial-derived vasodilator, might be implicated in gestational vasodilatation. NO is synthesized from the aminoacid L-arginine by a family of enzymes, the NO synthases (NOS). The endothelial isoform of nitric oxide synthase (ecNOS) has been found in the human placenta and immunohistochemically localized to the endothelium of the umbilical cord, chorionic plate and stem villous vessels. Locally formed ecNOS-dependent NO may serve to maintain low vascular resistance besides attenuating the action of vasoconstrictors. With its unique angiogenic/vasculogenic properties, NO can be instrumental for promoting cytotrophoblast endovascular invasion of uterine spiral arteries, an essential feature of normal placentation. Inadequate production of the vasodilator nitric oxide (NO) in the placenta has been recently suggested to explain the high resistance state and the ineffective placentation of pre-eclampsia, however the results to date are conflicting. We recently found that placental endothelial NO synthase (ecNOS) expression and activity were comparable in normal pregnancy and in pre-eclampsia, but in pre-eclamptic placenta NO is degraded to peroxynitrite, that is good candidate for mediating the oxidative damage of pre-eclampsia. Concentration of the NO precursor L-arginine was lower in pre-eclampsia, suggesting a defect in L-arginine bioavailability in the placentas. These results provide a biochemical explanation for the defective NO synthesis in pre-eclamptic placenta since NO production by endothelial NO synthase (ecNOS) is strongly dependent on the availability of the substrate L-arginine so that low L-arginine availability induces NOS to synthesize peroxynitrite at the expense of NO.

These results suggest that, in the normal placenta, adequate concentration of L-arginine selectively orients ecNOS toward NO, which is vital for a normal placentation.In the pre-eclamptic placenta, instead, a lower than normal L-arginine concentration re-directs ecNOS toward peroxynitrite which is generated in exuberant amounts at the expense of NO. This favors microvascular damage and impairs cytotrophoblast invasion.

Thus, whether increasing L-arginine bioavailability might restore physiological NO production in pre-eclamptic placenta is worth investigating in a pilot study that might represent the basis of a large, multicenter trial aimed to explore the impact of the above treatment on pregnancy outcome.

AIMS