Corticotropin-Releasing Hormone-Induced Vasodilatation in the Human Fetal-Placental Circulation - Involvement of the Nitric Oxide Cyclic Guanosine 3',5'-Monophosphate-Mediated Pathway

This study has used an in vitro perfusion method to investigate the mechanism by which CRH causes vasodilatation in the human fetal-placental circulation. In normal term placentas, vasodilatory responses to human CRH (24-7000 pmol/L) were examined during submaximal vasoconstriction (100-120 mm Hg) of the fetal-placental vasculature induced by prostaglandin F (0.7-2 µmol/L), KCl (50-100 mmol/L), or the thromboxane A mimetic, U46619 (0.05-0.5 µmol/L). Infusion of CRH caused a concentration-dependent vasodilatation that was similar in the presence of each constrictor agent (P > 0.05). The CRH antagonist, α-helical CRH-(9-41) (200 pmol/L), and a polyclonal CRH antiserum significantly inhibited CRH-induced vasodilatation during constriction with prostaglandin F (P 0.05). In placentas of women with increased fetal vascular resistance, as demonstrated by Doppler ultrasound waveforms in vivo, CRH-induced vasodilatation was significantly reduced (P < 0.05). These results indicate that in the human fetal-placental circulation, CRH causes a vasodilatory response via a nitric oxide-/cGMP-dependent pathway. CRH may play a role in the control of vascular resistance to blood flow in the normal human placenta, and there may be a deficiency in the CRH signaling pathway of placentas with increased fetal vascular resistance

Fetal placental vascular responses to corticotropin-releasing hormone in vitro. Effects of variation in oxygen tension

In this study, using the human placenta perfused in vitro with Krebs' bicarbonate solution, we have examined the effects of changes in oxygen tension on the vasoreactivity of fetal placental blood vessels to corticotropin releasing hormone (CRH). Vasodilatory responses to human synthetic CRH were measured during sub-maximal vasoconstriction of the fetal placental circulation with prostaglandin F(2alpha)(PGF(2alpha)) (1-100 micrometer). Decreases in fetal placental arterial perfusion pressure (FAP) were obtained with CRH under conditions of high oxygen or low oxygen tension, >/=450 mmHg and </=50 mmHg, respectively. Secretion of CRH into the maternal and fetal placental circulations was measured during changes in oxygen tension in normal placentae and placentae from abnormal pregnancies complicated by pre-eclampsia. The change from high to low oxygen perfusion resulted in a small increase in the basal perfusion pressure (21+/-3.6 to 28.3+/-2.6 mmHg; (P</= 0.001, Student's paired t -test). During high oxygen perfusion, CRH (0. 3-3000 p m) caused a concentration dependent reduction of the PGF(2alpha)induced increase in FAP. However, during low oxygen perfusion, the vasodilatory effects of CRH were completely inhibited (P</= 0.05, regression analysis, ANOVA). The effect of the NO synthase inhibitor l -nitro-omega-arginine methyl ester (l -NAME, 1-100 micrometer), on basal FAP during high and low oxygen conditions was also established. Low oxygen perfusion significantly attenuated l -NAME-induced increases in perfusion pressure (P</= 0.05, regression analysis, ANOVA). Low oxygen perfusion was associated with an increase in CRH secretion into the maternal but not fetal circulation. CRH release into either the maternal or fetal circulations of abnormal placentae were not significantly different from normal controls. In conclusion CRH-induced vasodilatation of the fetal placental vasculature in vitro is inhibited during low oxygen perfusion. This effect may be related to reduced NO production. Reduced CRH induced vasodilation is associated with increased secretion of the CRH into the maternal but not fetal circulation