Abstract
Preeclampsia is a multi-system disorder defined as new-onset hypertension with proteinuria developing after 20 weeks gestation. Preeclampsia remains a significant contributor to maternal morbidity and mortality, with great impact in perinatal morbidity. Research efforts throughout the world have focused on alternative therapies for the treatment of preeclampsia to the mainstay treatment of delivery of the fetus and placenta. 17-alpha-hydroxyprogesterone caproate (17-OHP) is a synthetic metabolite of progesterone used effectively for the prevention of recurrent preterm birth in singleton pregnancies. Previously we identified potential role for 17-OHP as an anti-inflammatory that suppressed inflammatory cytokines, hypertension and endothelin-1 in response to placental ischemia in the RUPP rat model of preeclampsia. In the current study we examined a role 17-OHP to blunt the pathophysiological effects to elevated IL-6 during pregnancy. IL-6 induced hypertension during pregnancy occurs with increased renin activity, autoantibodies to the angiotensin II type I receptor (AT1-AA) and reduced kidney function. This experiment was performed in the following groups of normal pregnant rats: NP (n=5); NP+17-OHP (n=6); NP+IL-6 (n=10); NP+IL-6+17-OHP (n=10). To test our hypothesis IL-6 (5ng/day) was infused via miniosmotic pump into normal pregnant rats beginning on day 14 of gestation and 17-OHP (3.32mg/kg) was diluted in normal saline and injected on day 18. Blood pressure (MAP) determination and serum collection was performed on day 19 of gestation. MAP in NP was 100+3mmHg which increased with IL-6 to 112+4mmHg, p <0.05. Pregnant rats given 17-OHP alone had a MAP of 99+3mmHg and MAP only increased to 103+2mmHg in IL-6+17-OHP. AT1-AA was 1.2+0.5 bpm in NP rats and increased to 17+9 bpm with IL-6 infusion. Administration of 17-OHP significantly blunted AT1-AA to 4+0.8bpm in NP+IL-6+17-OHP. Importantly, this study illustrates that 17-OHP attenuates hypertension and AT1-AA in response to elevated IL-6 during pregnancy and could lend hope to a new potential therapeutic for preeclampsia.
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