Sildenafil mechanism of action in the treatment of FGR

Currently, the use of sildenafil in pregnant women is limited to a few maternal indications, such as severe pulmonary hypertension and pre-eclampsia. At the same time, sildenafil can also be used as an adjunct to uterine-placental perfusion and severe early-onset FGR. As a selective inhibitor of PDE-5, sildenafil increases the level of intracellular second messenger guanosine 3' (5'-monophosphate, cGMP) by inhibiting PDE-5, increasing nitric oxide Yield, promote vascular smooth muscle relaxation.

A study of small arteries isolated from the myometrial tissues of pregnant women with FGR found that compared with normal pregnant women, the contraction of myometrial arterioles in FGR pregnant women increased, while endothelial cell-dependent vasodilation decreased. Sildenafil significantly relaxes the small arteries isolated from the myometrium of FGR pregnant women by improving the function of vascular endothelial cells, and significantly reduces the amount of contraction.

FGR models can now be established in animals such as rats, mice, sheep or rabbits by different methods. Some scholars have established an FGR animal model by limiting the supply of nutrients during pregnancy, and treated the animals in the FGR group with subcutaneous injection of sildenafil. It was found that sildenafil increased the number of blood vessels and the thickness of the vessel wall in the decidua of FGR pregnant rabbits, thereby promoting placental formation. Sildenafil increases the quality of FGR sheep placenta and reduces placental blood flow resistance. In addition, sildenafil can increase fetal body weight by increasing the amino acid and polypeptide content in the amniotic fluid of pregnant sheep and its fetal serum, which is present in both the FGR group and the control group.

After knocking out the placenta-specific insulin-like growth factor-2 gene, pregnant mice change the placental exchange capacity, leading to FGR, but does not affect placental perfusion. Treatment of these mice with sildenafil found that sildenafil improved FGR even in the absence of placental circulation disorders, which may have contributed to placental growth and improved placental material exchange with sildenafil. Functionally related. A pregnant rat that knocks out the catecholamine methyltransferase gene is another FGR animal model. In the application of sildenafil to these animal models, sildenafil was able to correct abnormal metabolomics in this type of FGR mice, reduce umbilical blood flow resistance in FGR mice, and improve neonatal growth.

A sub-eclampsia rat model induced by subcutaneous injection of sildenafil with N-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor) revealed that sildenafil improved eclampsia The blood pressure of the rats in the pre-stage group decreased the mortality of the fetus and the urine protein level of the pregnant rats, and increased the quality of the newborn rats and placenta.

This effect of sildenafil may be produced by reducing anti-angiogenic factors, soluble fms-like tyrosine kinase receptor-1 and soluble endothelin levels in the plasma of pre-eclampsia rats. However, other scholars have found that oral administration of sildenafil in FGR rats induced by N-nitro-L-arginine methyl ester does not improve FGR and even reduces the body weight of newborn rats. The appearance of such conflicting results may be related to the different modes of administration of the two groups. Therefore, it should be considered that the specific mechanism of sildenafil in the treatment of pre-eclampsia concurrent FGR requires further study.