Pre-eclampsia: the Potential of GSNO Reductase Inhibitors

Current Hypertension Reports, Mar 2017

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 pre-eclampsia 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. GSNOR inhibitors offer a potentially promising option for the management of pre-eclampsia.

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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)


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Thomas R. Everett, Ian B. Wilkinson, Christoph C. Lees. Pre-eclampsia: the Potential of GSNO Reductase Inhibitors, Current Hypertension Reports, 2017, pp. 20, Volume 19, Issue 3, DOI: 10.1007/s11906-017-0717-2