Evaluation of Sildenafil and Tadalafil for Reversing Constriction of Fetal Arteries in a Human Placenta Perfusion Model

Abstract

Fetal growth restriction resulting from reduced placental blood perfusion is a major cause of neonatal morbidity and mortality. Aside from intense surveillance and early delivery, there is no treatment for fetal growth restriction. A potential treatment associated with placental vasoconstriction is the class of PDE5 (phosphodiesterase type 5) inhibitors such as sildenafil, which is known to cross the placenta. In contrast, tadalafil, a more potent and selective PDE5 inhibitor has not been studied in pregnancy or experimental models of fetal growth restriction. Therefore, we compared the efficacy of these 2 PDE5 inhibitors for reversing vasoconstriction in an ex vivo human placental model and evaluating molecular and physiological responses. Sildenafil and tadalafil were infused into the intervillous space in a preconstricted human placental dual cotyledon, dual perfusion assay for the comparison of arteriole pressures and molecular indicators of drug inhibition. Results indicate a decrease arterial pressure with sildenafil citrate compared with controls, whereas tadalafil showed no difference. PDE5 and endothelial nitric oxide synthase activity were altered with sildenafil but not tadalafil. Sildenafil citrate improved preconstricted placental arterial perfusion in a human placental model, whereas tadalafil showed no response. It is possible that tadalafil did not cross the human placental barrier or was degraded by trophoblasts. This study supports human clinical trials exploring sildenafil as a potential treatment for improving fetal blood flow in fetal growth restriction associated with vasoconstriction.

Neonatal Morbidities of Fetal Growth Restriction: Pathophysiology and Impact

“…To date, the best studied of these has been sildenafil citrate. Sildenafil is a potent phosphodiesterase type 5 (PDE5) inhibitor that is an effective smooth muscle relaxant where the PDE5 enzyme is present in an organ or tissue, as is the case for the human placenta (174). The effects of sildenafil on smooth muscle are mediated via an enhanced and prolonged nitric oxide release leading to vasodilatation.…”

“…Although initial preclinical evidence for the multinational STRIDER trial suggested improved outcomes for FGR infants, this trial has now been aborted due to unexpected baby deaths (179), leading to a call for increased preclinical studies underpinning clinical trials (180), and improved understanding of the effects of sildenafil on the fetus given that it crosses the placenta (181). The longer acting tadalafil remains an active clinical experimental treatment of interest as an antenatal therapy for FGR and, given that tadalafil does not cross placenta (174), it may be more favorable as a targeted placental treatment.…”

Safety Evaluation of Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER): Results from the Phase II Trial

“…First, tadalafil is a different medicine from sildenafil. Walton RB et al reported that sildenafil citrate improved preconstricted placental-fetal arterial perfusion in a human placental model, whereas tadalafil produced no response [28]. This indicates that tadalafil does not cross the human placental barrier, or is degraded by trophoblasts.…”

Mechanisms of vascular dysfunction in the interleukin-10–deficient murine model of preeclampsia indicate nitric oxide dysregulation

“…Of note, the use of sildenafil and resultant increase in cyclic GMP (a second messenger for NO) has proven beneficial in reversing vasoconstriction in an ex vivo human placental model. 47 In a subsequent step, we will decipher the role and relative contribution of NO dysregulation in vascular injury in the IL-10 deficient mouse model of PE. Of note, previous studies have indicated that IL-10 induces the production of NO 48 and that IL-10 infusion blunts the rise in blood pressure in response to angiotensin II.…”