Sildenafil Treatment Ameliorates the Maternal Syndrome of Preeclampsia and Rescues Fetal Growth in the Dahl Salt–Sensitive Rat

Abstract

Preeclampsia, a hypertensive disorder of pregnancy, is detrimental to both mother and fetus. There is currently no effective treatment, but sildenafil, a phosphodiesterase-5 inhibitor, has been proposed as a potential therapy to reduce blood pressure and improve utero-placental perfusion in preeclamptic patients. We hypothesized that sildenafil would improve the maternal syndrome and fetal outcomes in the Dahl S rat model of superimposed preeclampsia. Dahl S rats were mated, and half received sildenafil (50 mg/kg/day, via food) from day 10 through day 20 of pregnancy. The untreated Dahl S rats had a significant rise in blood pressure and a 2-fold increase in urinary protein excretion from baseline to late pregnancy; however, sildenafil-treated Dahl S rats exhibited ~40 mmHg drops in blood pressure with no rise in protein excretion. Sildenafil also increased creatinine clearance and reduced nephrinuria and glomerulomegaly. Sildenafil treatment reduced the uterine artery resistance index during late pregnancy in the Dahl S rat and improved fetal outcomes (survival, weight, and litter size). Additionally, 19% of all pups were resorbed in untreated rats, with no incidence of resorptions observed in the treated group. Furthermore, TNF-α, endothelin-1, and oxidative stress, which are characteristically increased in women with preeclampsia and in experimental models of the disease, were reduced in treated rats. These data suggest that sildenafil improves the maternal syndrome of preeclampsia and blood flow to the fetoplacental unit, providing preclinical evidence to support the hypothesis that PDE-5 inhibition may be an important therapeutic target for the treatment of preeclampsia.

Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia

“…Several groups have also reported that sildenafil may be beneficial in other animal models of pregnancy complications, such as the rat model of placental ischemia, the Dahl salt-sensitive hypertensive rat, and the catechol-O-methyltransferase-deficient model of growth restriction (31,33,40). Bolnick et al have also reported that trophoblast invasion, a process that is defective in preeclampsia, may be promoted by sildenafil in culture studies (41).…”

Maternal Vascular Physiology in Preeclampsia

“…74 Sildenafil improved maternal and fetal outcomes and reduced oxidative stress and ET-1 in models of experimental preeclampsia. 28,75 Release of Ca 2+ from intracellular stores and entry of Ca 2+ from the extracellular space cause an increase in intracellular Ca 2+ concentrations, which trigger the contraction of vascular smooth muscle. 76 Incubation of human umbilical smooth muscle cells cocultured with umbilical endothelial cells with serum from women with preeclampsia increased intracellular Ca 2+ concentrations and PKC-α (second messenger) activation.…”

Mechanisms and Treatment of Halogen Inhalation–Induced Pulmonary and Systemic Injuries in Pregnant Mice

“…Interleukin-6 (IL-6) was increased in both non-pregnant and pregnant mice exposed to Br 2 . These cytokines have been shown to be associated with the onset of preeclampsia 12, 19–24 . Tadalafil therapy subsequently reduced these levels to those similar to air controls (Figure 5A–C).…”