Abstract 017: Effect of Sildenafil on Nitric Oxide-Mediated Vasodilation in the Human Placenta: an Ex-Vivo Placental Perfusion Study

Abstract

Preeclampsia (PE) is a serious pregnancy complication characterized by suboptimal placentation, leading to increased vascular resistance and generalized endothelial dysfunction. A promising treatment is sildenafil, a phosphodiesterase-5 (PDE5) inhibitor that enhances nitric oxide (NO) mediated vasodilation. Although there are currently sildenafil trials ongoing in pregnant women, the effects of sildenafil on the placenta are still unknown. Placentas of healthy (n=17), early-onset (Eo)PE (n=6) and late-onset (Lo)PE (n=5) pregnancies were dually perfused, pre-constricted with serotonin, and subsequently exposed to the NO donor SNP in the absence or presence of 1 μmol/L sildenafil. Two healthy placentas were perfused with sildenafil on the maternal side to study placental transfer. Placental protein expression of PDE5, PDE1A, eNOS and iNOS was assessed using Western blot. Mean baseline pressure ±SEM was significantly lower (p<0.05) in EoPE (22.3±2.8 mmHg) and LoPE (22.8±1.7 mmHg) vs. healthy placentas (33.1±2.2 mmHg). There was no effect of sildenafil on baseline pressure or serotonin-induced pre-constriction. Sildenafil tended to enhance vasodilatory response to 10 -6 M SNP in healthy (mean pressure decrease 4.3±0.8 vs. 8.1±1.9 mmHg, p=0.1) and LoPE placentas (3.0±1.0 vs. 7.3±3.2 mmHg), while no improvement was seen in EoPE placentas (6.0±2.0 vs. 5.0±1.0 mmHg). When sildenafil was added at the maternal side, average fetal-maternal concentration ratio was 0.22 after 3 hours of perfusion, as compared to 0.86 for antipyrine, a freely diffusing molecule. Placental levels of PDE1A tended to be higher in PE (p=0.08), while no differences in expression of PDE5, eNOS and iNOS were observed between PE and healthy placentas. Our study reveals that PE placentas have a significantly lower baseline pressure compared to healthy placentas, possibly due to lower resistance in the feto-placental vasculature as a compensation mechanism for the increased resistance in the spiral arteries. Although sildenafil tended to enhance vasodilation in healthy and LoPE placentas, it did not have those beneficial effects in EoPE. Possibly PDE1A-selective inhibitors should be applied in PE, or PDE is not the appropriate target for restoring disturbed vasodilation.