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-2 alpha (0.7-2 mu mol/L), KCl (50-100 mmol/L), or the thromboxane A(2) mimetic, U46619 (0.05-0.5 mu mol/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, alpha-helical CRH-(9-41)(200 pmol/L), and a polyclonal CRH antiserum significantly inhibited CRH-induced vasodilatation during constriction with prostaglandin F-2 alpha (P < 0.05). Vasodilatory responses to CRH were attenuated by the nitric oxide synthase inhibitor, N-omega-nitro-L-arginine (100 mu mol/L; P < 0.05), and the guanylate cyclase inhibitor, LY 83583 (1 mu mol/L; P < 0.05), but not by the cyclooxygenase inhibitor, indomethacin (3 mu mol/L; P > 0.05). In placentas of women with increased fetal vascular resistance, as demonstrated by DoppIer 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.