Sildenafil Treatment Improves the Maternal Syndrome in the Preeclamptic Dahl Salt Sensitive (S) Rat

Abstract

Preeclampsia (PE), a hypertensive disorder of pregnancy, is detrimental to both mother and fetus; however, there is currently no effective treatment for PE. We hypothesized that sildenafil, a phosphodiesterase-5 inhibitor, would improve the maternal syndrome and fetal outcomes in the preeclamptic Dahl S rat. Baseline blood pressure (BP) was recorded (DSI Telemetry), and rats were placed in metabolic cages for 24 hr urine collection. After confirmation of pregnancy, rats were randomly divided into control and sildenafil treated groups. Sildenafil was administered via the food (50 mg/kg/d) beginning on day 10 of pregnancy. Uterine artery resistance index (UARI) was measured by Doppler ultrasound on day 18, and urine was collected again on day 19. Blood and tissues were harvested on day 20. BP dropped in treated rats during late pregnancy, but continued to increase in the controls (Table, n=2-9, *p<0.05). Urinary protein excretion (Bradford assay) did not differ between groups at baseline (96±19 vs 103±18 mg/d), but was significantly lower during late pregnancy in the sildenafil treated rats (n=6-9). TNF-α (R&D Systems ELISA) was decreased in the plasma and placenta of treated rats during late pregnancy (n=6-7). Additionally, sildenafil treatment normalized UARI in late pregnancy and improved fetal outcomes (n=3-9 dams). These data suggest that sildenafil improves the maternal syndrome of PE and improves blood flow to the fetoplacental unit, providing preclinical evidence to support the hypothesis that phosphodiesterase-5 inhibition is a therapeutic target for the treatment of PE. ΔBPDay9-18mmHg Proteinuria (mg/d) UARI Plasma TNF-α (pg/mL) Placental TNF-α (pg/mg) Pup weight (g) Fetal Demise (%) Control 9±2 209±42 0.7±0.02 2.5±0.57 6.6±0.58 2.1±0.06 19 Sildenafil -41±8* 103±17* 0.5±0.00* 1.1±0.33* 4.9±0.63* 2.5±0.06* 0