Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats

Abstract

Objective To determine the effects of chronic administration of sildenafil citrateon healthy pregnant rats.Design In vivo animal experimental study.Setting Fundació n IVI-Instituto Universitario IVI, Valencia, Spain.Sample Pregnant and non-pregnant Wistarrats exposed to chronic administration of sildenafil.Methods Placental cross-barrier and feto-maternal relationship levels, maternal blood pressure, and haemodymamic effects on uterine arteries were evaluated. The effect of growth on weight and fetal tissues, and on perinatal outcome, was investigated.Main outcome measures Maternal blood pressure, blood viscosity, vascular indices of uterine arteries and fetal ductus venosus, plasmatic levels of sildenafil, embryo/fetal and litter weights, perinatal/postnatal survival rates.Results Sildenafil citrate crossed the placenta. The maternal and fetal levels of sildenafil, and its metabolite desmethyl-sildenafil, demonstrated a positive linear correlation in treated pregnant animals versus controls; a selective maternal hypotensive effect without changes in uterine vascular resistance was noted on days E8 and E11 (embryonic day). The lower pulsatility index of the ductus venosus on day E18 suggests fetal overflow at the end of the pregnancy. Effects on offspring were placental and liver enlargement, and increased fetal weight gain in the second half of pregnancy (irrespective of liver enlargement) and at birth. Perinatal and postnatal survival rates in the sildenafil group remained unaltered. No haemodynamic effects were evident in non-pregnant animals.Conclusions In normotensive rats, sildenafil appears to have a selective effect at the onset of pregnancy, implying increased fetal blood supply, and increased fetal weight, and placental and liver enlargement, but no increased perinatal mortality.

Sildenafil Citrate Increases Fetal Weight in a Mouse Model of Fetal Growth Restriction with a Normal Vascular Phenotype

“…Interestingly, SC treatment failed to increase fetal weight in the WT C57Bl/6J pups, in contrast with previous reports in sheep [14], mice [13] and rats [40], [41] which suggest an increased fetal weight in control fetuses from SC-treated mothers.…”

“…This is in contrast with studies suggesting that SC increased placental weight in control Wistar rats following long-term administration [40], [41] but in agreement with recent work in mice which failed to detect any differences in placental weight following SC treatment [13]. Most other published in vivo studies examining the effectiveness of SC in FGR failed to report placental weight, and this does require further investigation.…”

Sildenafil citrate improves perinatal outcome in fetuses from pre‐eclamptic rats

“…We have demonstrated the placental transfer of SC in a group of normotensive rats. We observed that SC appears to have a selective hypotensive effect at the onset of pregnancy, implying increased fetal blood supply, an effect that was not present in nonpregnant animal groups 11 . Moreover, the cellular mechanisms by which the inhibitors of phosphodiesterase‐5 improve endothelial function and cell survival in critical situations after ischaemia and reperfusion have been described 12 .…”

“…An animal PE model with hypertension, proteinuria and fetal growth restriction can be developed using a nonselective inhibitor of all isoforms of nitric oxide synthase (NOS) ( N ‐nitro‐ l ‐arginine methyl ester, l ‐NAME) 11,16–20 …”

“…Female Wistar rats were maintained under similar conditions to those reported previously 11,16 . Eighty‐six pregnant rats were randomly allocated to four groups from gestational day E0.…”