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 me chanism by which CRH causes vasodilatation in the human fetal-placenta l circulation. In normal term placentas, vasodilatory responses to hum an CRH (24-7000 pmol/L) were examined during submaximal vasoconstricti on (100-120 mm Hg) of the fetal-placental vasculature induced by prost aglandin F-2 alpha (0.7-2 mu mol/L), KCl (50-100 mmol/L), or the throm boxane A(2) mimetic, U46619 (0.05-0.5 mu mol/L). Infusion of CRH cause d a concentration-dependent vasodilatation that was similar in the pre sence of each constrictor agent (P > 0.05). The CRH antagonist, alpha- helical CRH-(9-41)(200 pmol/L), and a polyclonal CRH antiserum signifi cantly inhibited CRH-induced vasodilatation during constriction with p rostaglandin F-2 alpha (P < 0.05). Vasodilatory responses to CRH were attenuated by the nitric oxide synthase inhibitor, N-omega-nitro-L-arg inine (100 mu mol/L; P < 0.05), and the guanylate cyclase inhibitor, L Y 83583 (1 mu mol/L; P < 0.05), but not by the cyclooxygenase inhibito r, indomethacin (3 mu mol/L; P > 0.05). In placentas of women with inc reased fetal vascular resistance, as demonstrated by DoppIer ultrasoun d waveforms in vivo, CRH-induced vasodilatation was significantly redu ced (P < 0.05). These results indicate that in the human fetal-placent al circulation, CRH causes a vasodilatory response via a nitric oxide- /cGMP-dependent pathway. CRH may play a role in the control of vascula r resistance to blood flow in the normal human placenta, and there may be a deficiency in the CRH signaling pathway of placentas with increa sed fetal vascular resistance.