The nitric oxide pathway and possible therapeutic options in pre‐eclampsia

Abstract

Pre-eclampsia is a serious multisystem disorder with diverse clinical manifestations. Although not causal, endothelial dysfunction and reduced nitric oxide bioavailability are likely to play an important role in the maternal and fetal pathophysiology of this condition. Lack of treatment modalities that can target the underlying pathophysiological changes and reverse the endothelial dysfunction frequently leads to iatrogenic preterm delivery of the fetus, causing neonatal morbidity and mortality, and the condition itself is associated with short-and longer term maternal morbidity and mortality. Drugs that target various components of the nitric oxide-soluble guanylyl cyclase pathway can help to increase NO bioavailability. The purpose of this review is to outline the current status of clinical research involving these therapeutic modalities in the context of pre-eclampsia, with the focus being on the following: nitric oxide donors, including organic nitrates and S-nitrosothiols; L-arginine, the endogenous precursor of NO; inhibitors of cyclic guanosine 3′,5′-monophosphate breakdown, including sildenafil; and other novel inhibitors of NO donor metabolism. The advantages and limitations of each modality are outlined, and scope for development into established therapeutic options for pre-eclampsia is explored.

Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated bySTOX1, a Pre-Eclampsia-Associated Gene

“…However, the most striking effect is the imbalance of ROS and RNS induced by STOX1 overexpression in cells and placentas. The capture of NO by STOX1 overexpressing placentas is proposed here as a mechanism to explain increased blood pressure in pre-eclampsia, consistently with existing literature (34,63). In human gestation, the blood flow in the placenta near term is around 600 ml/min, which is theoretically able to drive a rapid and strong decrease of NO in the whole maternal body during pre-eclampsia.…”

Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3′,5′-cyclic monophosphate signaling

“…Endothelial dysfunction, which is due largely to overproduction of soluble fms-like tyrosine kinase (sFLT1) and soluble endoglin (sENG) (22), and vasoconstriction, were prevented with L-arginine, correcting the dysregulation of nitric oxide synthase known to occur in pre-eclampsia. L-Arginine, a precursor of NO, can reduce blood pressure to prevent pre-eclampsia by increasing NO bioavailability and activating the cGMP pathway (23). Nitric oxide donors with or without antioxidants could also suppress other sequelae associated with the disease, including IUGR and preterm delivery (23).…”

“…L-Arginine, a precursor of NO, can reduce blood pressure to prevent pre-eclampsia by increasing NO bioavailability and activating the cGMP pathway (23). Nitric oxide donors with or without antioxidants could also suppress other sequelae associated with the disease, including IUGR and preterm delivery (23).…”

Prolonged uterine artery nitric oxide synthase inhibition modestly alters basal uteroplacental vasodilation in the last third of ovine pregnancy

“…The rise in UA NO synthesis is paralleled by Ͼ30-fold increases in uterine cGMP synthesis in pregnant ewes (35). Thus, existing evidence supports an association between uterine NO and cGMP synthesis and the rise in and maintenance of UPBF in pregnancy, as well as abnormalities in NO synthesis and decreased UPBF in women with preeclampsia (15). However, in the presence of systemic NOS inhibition and the absence of eNOS in eNOS Ϫ/Ϫ pregnant mice, the rise in basal UPBF is only modestly attenuated (1,17,19,20).…”