Pre-eclampsia: the Potential of GSNO Reductase Inhibitors
Curr Hypertens Rep
Pre-eclampsia: the Potential of GSNO Reductase Inhibitors
Thomas R. Everett 0 1 2 3 4 5 6
Ian B. Wilkinson 0 1 2 3 4 5 6
Christoph C. Lees 0 1 2 3 4 5 6
0 University of Leeds , Leeds , UK
1 Department of Fetal Medicine, Leeds Teaching Hospitals Trust , Leeds , UK
2 Thomas R. Everett
3 Department of Development and Regeneration, KU Leuven , Leuven , Belgium
4 Imperial College Healthcare NHS Trust , London , UK
5 Imperial College London , London , UK
6 Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital , Box 98, Cambridge , UK
Purpose of Review Pre-eclampsia remains a leading worldwide cause of maternal death and of perinatal morbidity. There remains no definitive treatment except delivery of the fetus. Recent Findings Recent insights into the cardiovascular changes that are evident prior to, during, and persist after preeclampsia have improved understanding of the underlying pathophysiology-disruption of normal endothelial function and decreased nitric oxide bioavailability. S-nitrosoglutathione (GSNO) is an endogenous S-nitrosothiol that acts as a NO pool and, by replenishing or preventing the breakdown of GSNO, endothelial dysfunction can be ameliorated. GSNO reductase inhibitors are a novel class of drug that can increase NO bioavailability. Summary GSNO reductase inhibitors have demonstrated improvement of endothelial dysfunction in animal models, and in vivo human studies have shown them to be well tolerated.
Pre-eclampsia; S-nitrosoglutathione; GSNO; GSNO reductase inhibitors
Introduction
Pre-eclampsia is a multisystem disorder, which manifests
clinically as hypertension and proteinuria after 20 weeks of
pregnancy. Pre-eclampsia occurring at or close to term is usually
treatable by delivery with minimal risk to mother or baby. However,
in approximately 1% of pregnancies the condition is early onset,
and this usually coincides with worse severity, particularly
before 32 weeks gestation. In this situation, expeditious
conservative management focusing on control of hypertension and
seizure prevention to gain fetal maturity is key. Although
antihypertensive medication is used, there is no current treatment that
targets the underlying pathophysiology [
1, 2
].
The underlying pathological processes of pre-eclampsia are
hypothesized to occur in two stages [
3
]. Abnormal
placentation is suggested to be the initiating event resulting in reduced
placental perfusion, in turn, leading to increased oxidative
stress, which, in combination with a maternal predisposition,
results in endothelial dysfunction. This manifest by changes in
a number of signaling pathways and homeostatic
mechanisms, but impaired nitric oxide (NO) bioavailability [
4
] is
thought to play a major role in the maternal manifestations
of pre-eclampsia such as hypertension and likewise platelet
activation, proteinuria, and oedema. More recently, abnormal
pre-pregnancy blood pressure has been shown to relate to risk
of pre-eclampsia [
5
], and abnormal arterial function in the first
trimester is associated with higher likelihood of PE [
6
]. So the
prevailing wisdom relating to the placenta’s central role in
preeclampsia is likely to be an over simplification.
Relationship of Pre-eclampsia and Endothelial
Dysfunction
Pre-eclampsia causes disruption of normal endothelial barrier,
structure, and function, resulting in a state of endothelial
dysfunction which is characterized by decreased NO
bioavailability. Arterial and cardiac function are abnormal before and
during the disease’s clinical manifestation [
7, 8 , 9
].
Consequently, there is an increase in vascular tone [
10, 11
],
hypertension [
12, 13
], increased permeability of the
vasculature and resultant proteinuria, and oedema [
14, 15
]. There is
also a shift towards a proinflammatory and prothrombotic
state [
4, 16
], particularly as a result of platelet activation [
17
].
Women who have had pre-eclampsia are at a higher
longterm risk of adverse cardiovascular outcomes including
stroke, myocardial dysfunction, and death due to a vascular
event [
18–21
]. Indeed, the major risk factors for pre-eclampsia
are those classically associated with endothelial dysfunction
and long-term cardiovascular morbidity including systolic
hypertension, obesity, diabetes mellitus, and
hypercholesterolaemia [
22–25
]. It is now suggested that there is pre-existing
prepregnancy endothelial dysfunction in women who go on to
develop pre-eclampsia. Studies starting prior to pregnancy and
following women throughout pregnancy have allowed an
insight into haemodynamic changes in normal pregnancy [
26,
27
]; abnormal cardiovascular adaptation in early pregnancy
may be associated with birth weight [28]. The degree to which
these risk factors affect endothelial function pre-pregnancy
and the degree to which they are exacerbated by pregnancy
and pre-eclampsia are currently under investigation.
Asymmetric dimethylarginine (ADMA) is an endogenous
eN (...truncated)