Maternal sildenafil impairs the cardiovascular adaptations to chronic hypoxaemia in fetal sheep

Inocencio, Ishmael M.; Polglase, Graeme R.; Nitsos, Ilias; Miller, Stephanie; Allison, Beth J.

doi:10.1113/jp279248

Cited by 15 publications

(10 citation statements)

References 56 publications

(118 reference statements)

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“…However, one could speculate that the induction of in utero pulmonary vasodilatation may create a new normal for regulation of pulmonary vascular tone and thus predispose to the persistent pulmonary hypertension that the Dutch arm of the STRIDER consortium reported. Nevertheless, this study and others performed by the same research group (Miller et al 2009;Inocencio et al 2019;Inocencio et al 2020) have provided strong evidence for the necessity of not only utilising a large animal model of human pregnancy complications in perinatal research but also in having these preclinical studies inform the choice to commence clinical trials.…”

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confidence: 63%

“…In this issue of Journal of Physiology , Inocencio et al (2020) performed an elegant study utilising a well‐characterised sheep model of FGR (single umbilical artery ligation, SUAL) in combination with chronic fetal instrumentation and a sheep equivalent SC STRIDER trial dosing regimen to determine how clinically relevant SC exposure impacted on both maternal and fetal haemodynamics in pregnancies complicated by FGR (Inocencio et al . 2020). In this model of FGR, SUAL fetuses are chronically hypoxaemic and smaller than their appropriately grown counterparts.…”

mentioning

confidence: 99%

“…2019; Inocencio et al . 2020) have provided strong evidence for the necessity of not only utilising a large animal model of human pregnancy complications in perinatal research but also in having these preclinical studies inform the choice to commence clinical trials.…”

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confidence: 99%

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Sildenafil: how to make a bad situation worse

Darby

2020

The Journal of Physiology

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confidence: 63%

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confidence: 99%

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Sildenafil: how to make a bad situation worse

Darby

2020

The Journal of Physiology

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“…This clinical trial investigating the benefits of prenatal sildenafil for IUGR was halted in one of the participating countries because of increased neonatal mortality in the treatment arm, urging caution in the use of prenatal sildenafil [13, 19, 39]. Further vigilance was urged by experimental studies using a single umbilical artery ligation fetal lamb model of IUGR, demonstrating interference of sildenafil with chronic cardiovascular adaptation causing worsening hypoxia, reduction of growth and production of higher lactate levels, as well as exacerbation of IUGR-related vascular dysfunction [20, 21]. It should be pointed out however that these single umbilical artery ligation-models create a chronic fetal hypoxic state by inducing placental insufficiency.…”

Section: Discussionmentioning

confidence: 99%

Transplacental Transfer and Fetal Pharmacodynamics of Sildenafil in the Pregnant Sheep Model

et al. 2021

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Background: Sildenafil is a phosphodiesterase-5 inhibitor considered for antenatal use for a variety of indications. We sought to assess sildenafil pharmacokinetics in the pregnant ewe and fetus and evaluate its physiological fetal effects. Methods: Twelve fetal lambs (127–133 days GA, term 145) were chronically catheterized in utero. Ewes received different doses of sildenafil, either via subcutaneous injection (1.6, 2.0 mg/kg/day) or intravenous (IV) infusion (3, 5, 7, 10, and 12 mg/kg/day). Maternal and fetal sildenafil concentrations and metabolic status (blood gas analysis) were measured at given intervals. The fetal heart rate, pulmonary blood flow, systemic and aortic pressure, and maternal uterine artery pressure were continuously monitored. Results: The transplacental sildenafil transfer was 2.9% (range: 1.4–7.8%), preventing attainment of fetal target concentrations without toxic maternal levels. IV sildenafil infusion induced an immediate, temporary, dose-dependent reduction of pulmonary vascular resistance (38–78%) and increased both pulmonary blood flow (32–132%) and heart rate (13–49%), with limited nonlinear dose-dependent effects on systemic and pulmonary pressures. Fetal and maternal blood gases and maternal uterine artery pressures were unaffected by sildenafil infusion. Conclusion: In sheep, transplacental transfer of sildenafil is extremely low. Though, minimal fetal sildenafil concentrations induce an acute transient pulmonary vasodilation, well-tolerated by the fetus and ewe.

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“…2009a; Inocencio et al . 2020) and, more recently, maternal hypoxia chambers in combination with continuous fetal monitoring (Brain et al . 2015; Allison et al .…”

Section: Discussionmentioning

confidence: 99%

The reliance on α‐adrenergic receptor stimuli for blood pressure regulation in the chronically hypoxaemic fetus is not dependent on post‐ganglionic activation

Darby

Varcoe

Holman

et al. 2020

The Journal of Physiology

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Key points Chronic hypoxaemia is associated with intrauterine growth restriction (IUGR) and a predisposition to the development of hypertension in adult life. IUGR fetuses exhibit a greater reliance on α‐adrenergic activation for blood pressure regulation. The fetal blood pressure response to post‐ganglionic blockade is not different between control and IUGR fetuses. The decrease in mean arterial pressure is greater in the IUGR sheep fetus after α‐adrenergic receptor blockade at the level of the vasculature and this is inversely related to fetal PnormalO2. The increased reliance that the IUGR fetus has on α‐adrenergic activation for maintenance of mean arterial pressure is not a result of increased post‐ganglionic sympathetic activation. Abstract Intrauterine growth restriction (IUGR) is associated with an increased risk of cardiovascular disease in adult life. Placental restriction (PR) in sheep results in chronic hypoxaemia and early onset IUGR with increased circulating plasma noradrenaline concentrations. These IUGR fetuses exhibit a greater decrease in mean arterial pressure (MAP) during α‐adrenergic blockade. We aimed to determine the role of post‐ganglionic sympathetic activation with respect to regulating MAP in IUGR fetal sheep. PR was induced by carunclectomy surgery prior to conception. Fetal vascular catheterization was performed at 110–126 days gestational age (GA) (term, 150 days) in nine control and seven PR‐IUGR fetuses. The fetal blood pressure response to both a post‐ganglionic and an α‐adrenergic receptor blocker was assessed at 116–120 days GA and/or 129–131 days GA. The effect of both post ganglionic and α‐adrenergic blockade on fetal blood pressure was then compared between control and IUGR fetuses at both GAs. There was no difference in the effect of post‐ganglionic blockade on MAP in control and IUGR fetal sheep at either 116–120 days GA or 129–131 days GA. α‐adrenergic receptor blockade decreased MAP to the same extent in both control and IUGR fetuses at 116–120 days GA. At 129–131 days GA, the drop in MAP in response to α‐adrenergic receptor blockade was greater in IUGR fetuses than controls. There was a significant inverse relationship between the drop in MAP in response to α‐adrenergic receptor blockade at both GAs with fetal PnormalO2. Thus, the increased dependence on α‐adrenergic activation for blood pressure regulation in the chronically hypoxaemic IUGR fetus is not a result of increased post‐ganglionic sympathetic activation.

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Maternal sildenafil impairs the cardiovascular adaptations to chronic hypoxaemia in fetal sheep

Abstract: Fetal growth restriction induces a haemodynamic response that aims to maintain blood flow to vital organs such as the brain, in the face of chronic hypoxaemia r Maternal sildenafil treatment impairs the hypoxaemia-driven haemodynamic response and potentially compromises fetal development.

Cited by 15 publications

References 56 publications

Sildenafil: how to make a bad situation worse

Sildenafil: how to make a bad situation worse

Transplacental Transfer and Fetal Pharmacodynamics of Sildenafil in the Pregnant Sheep Model

The reliance on α‐adrenergic receptor stimuli for blood pressure regulation in the chronically hypoxaemic fetus is not dependent on post‐ganglionic activation

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