Abstract
Preeclampsia (PE) is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and endothelin-1 (ET-1) levels. We and others have previously demonstrated that infusion of sFlt-1 into pregnant rodents causes hypertension, indicating an important role for sFlt-1 in mediating the pathophysiology of the disease. Currently there is no effective treatment for PE except for delivery of the fetal placental unit, making PE a leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of recurrent preterm birth, but not for treatment of PE. This study was designed to test the hypothesis that 17-OHPC improves hypertension and ET-1 in response to sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1 for 6 days, gestation days 13-19) in the presence or absence of 17-OHPC (3.32mg/kg) administered via intraperitoneal injection on gestational days 15 and 18. Mean arterial blood pressure (MAP), renal cortex endothelin-1 expression and Nitrate-Nitrite levels were measured on GD 19. Infusion of sFlt-1 into NP rats elevated mean arterial pressure (MAP) compared with control NP rats: 112+2 (n=11) vs. 98+2 mmHg (n=15, p<0.05). Administration of 17-OHPC attenuated this hypertension reducing MAP to 99+4 mmHg in sFlt-1 treated pregnant rats (n=8). Importantly, renal cortex PPET-1 expression was elevated 3 fold in NP+sFlt-1 rats compare to NP rats, which decreased with 17-OHPC administration. Plasma nitrate-nitrite levels were 26 μM in NP rats (n=6), 17 μM in NP+sFlt-1 (n=4), which increased to 27 μM NP+sFlt-1+17OHPC (n=5). Neither pup nor placental weight was affected by sFlt-1 or 17-OHPC. Administration of 17-OHPC improves hypertension in response to elevated sFlt-1 during pregnancy and should be considered further in the management of PE.
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