Inhibition of 20‐HETE Synthesis Attenuates Elevations in Blood Pressure and Uterine Artery Resistance Index in the RUPP Rat Model of Preeclampsia

Abstract

Preeclampsia (PE) is a hypertensive disorder of pregnancy afflicting 5-10% of US pregnancies. Recent data suggests the vasoactive cytochromeP450 metabolite, 20-hydroxyeicosatetraenoic (20-HETE), may play a role in hypertension in response to placental ischemia. Thus, we hypothesized that administration of HET0016, a specific 20-HETE synthesis inhibitor, would improve the pathophysiology in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia. RUPP procedure was performed on gestational day (GD) 14 and HET0016 (1mg/kg, i.p) was administered on GD14-18. Uterine Artery Resistance Index (UARI) was measured via sonography on GD18 and blood pressure (MAP) was measured on day GD19. UARI increased in RUPP compared to NP rats (0.71±0.04 vs 0.60 ±0.02), and was reduced in RUPP+HET0016 treated animals (0.56±0.07). Pup reabsorption (% of total pups at GD19) was significantly increased in RUPP versus NP rats (58±6 vs 7±6%, P<0.05). Treatment with HET0016 significantly reduced pup resorption in RUPP+HET0016 rats relative to control (21±7%, P<0.05). MAP was elevated in RUPP rats compared to NP rats (122±3 vs 104±3 mmHg, P<0.05), and was significantly decreased upon administration of HET0016 (112 ±3 mmHg, P<0.05). MAP remained unchanged in NP+HET0016 rats (106±5 mmHg). In conclusion, inhibition of 20-HETE synthesis prevented increases in UARI, fetal reabsorption, and blood pressure in the RUPP rat model of PE, thereby improving the pathology associated with hypertension in response to placental ischemia.