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19: Maternal and fetal effects of bay 41-2272, a direct soluble guanylate cyclase activator, in a model of preeclampsia and intra uterine growth restriction

      Objective

      Preeclampsia and intra uterine growth restriction (IUGR) are strongly associated with reduced uterine perfusion and abnormal placentation. Increased production of nitric oxide (NO) by the endothelium contributes to the hemodynamic changes associated with normal pregnancy. Conversely, a reduction in NO production has been observed in preeclampsia and IUGR. BAY 41-2272 (BAY) is a novel NO-independent direct activator of soluble guanylate cyclase (sGC) that causes vasodilation in systemic and local circulations. However, BAY has not been studied during the pregnancy. We hypothesized that BAY may reduce maternal blood pressure and improve fetal growth in an animal model of preeclampsia and IUGR.

      Study Design

      To test this hypothesis, we studied the effects of BAY in pregnant rats after NO synthase inhibition with N(omega)-Nitro-L-arginine methyl ester (LNAME). Osmotic minipumps were inserted subcutaneously into timed pregnant wistar-han rats on day 17 of pregnancy. The pumps were loaded to continuously deliver either vehicle or LNAME 50 mg/d, either alone or with BAY 1mg/kg/d. Maternal arterial pressure and uterine resistance index were measured at 16 and 20 days. A c-section was performed on day 21. Pup weight and length, litter size and placental weight were recorded.

      Results

      Compared to control animals, pregnant rast with chronic NO synthase inhibition had increased arterial blood pressure, reduced pup weight and length and decreased placental weight. In comparison with LNAME-treated rats, BAY attenuated maternal arterial blood pressure (138±2.5 vs 120±2.1 for systolic pressure and 100±1.9 vs. 95±2.1 for diastolic pressure; p<0.05) and improved pup weight (3.67±0.11g vs 4.42±0.06 g; p<0.01) and length (3.55±0.05cm vs 3.88±0.03cm; p<0.01). In addition, placental weight was increased in BAY + LNAME group vs. LNAME alone (0.55±0.03g vs 0.49±0.02g; p<0.01).

      Conclusion

      We concluded that BAY reverses the maternal and fetal effects of LNAME-induced placental insufficiency in pregnant rats. We speculate that BAY may provide a novel treatment for preeclampsia and/or IUGR.