title: Corticotropin-releasing hormone-induced vasodilatation in the human fetal-placental circulation: involvement of the nitric oxide-cyclic guanosine 3',5'-monophosphate-mediated pathway.
abstract: 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 F2 alpha (0.7-2 mumol/L), KCl (50-100 mmol/L), or the thromboxane A2 mimetic, U46619 (0.05-0.5 mumol/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 F2 alpha (P < 0.05). Vasodilatory responses to CRH were attenuated by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (100 mumol/L; P < 0.05), and the guanylate cyclase inhibitor, LY 83583 (1 mumol/L; P < 0.05), but not by the cyclooxygenase inhibitor, indomethacin (3 mumol/L; 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.
authors.affiliation: Maternal Health Research Center, John Hunter Hospital, Newcastle, New South Wales, Australia.
authors.forename: V L
authors.initials: VL
authors.lastname: Clifton
authors.forename: M A
authors.initials: MA
authors.lastname: Read
authors.forename: I M
authors.initials: IM
authors.lastname: Leitch
authors.forename: W B
authors.initials: WB
authors.lastname: Giles
authors.forename: A L
authors.initials: AL
authors.lastname: Boura
authors.forename: P J
authors.initials: PJ
authors.lastname: Robinson
authors.forename: R
authors.initials: R
authors.lastname: Smith
mesh_terms: D000328:Adult; D001724:Birth Weight; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D006152:Cyclic GMP / Q000502:physiology*; D016640:Diabetes, Gestational / Q000503:physiopathology; D015237:Dinoprost / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology; D005333:Fetus / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D010920:Placenta / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D012016:Reference Values; D012044:Regression Analysis; D015398:Signal Transduction; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D009569:Nitric Oxide; D011189:Potassium Chloride; D003346:Corticotropin-Releasing Hormone; D015237:Dinoprost; D006152:Cyclic GMP