title: Calcium channel blockers prevent endothelial cell activation in response to necrotic trophoblast debris: possible relevance to pre-eclampsia.
abstract: OBJECTIVE
  Pre-eclampsia is characterized by endothelial activation, which is triggered by placental factor(s). One such factor may be trophoblastic debris that is shed into the maternal blood to become trapped against the maternal pulmonary endothelium. Phagocytosis of necrotic trophoblastic debris (NTD) induces endothelial cell activation with increased secretion of interleukin-6 (IL-6) and transforming growth factor β1 (TGFβ1), which may induce systemic endothelial cell activation. In addition to its effects on vascular smooth muscle, evidence suggests that nifedipine may also affect the endothelium, contributing to the therapeutic benefits of the drug. We investigated whether nifedipine could reverse the endothelial cell activation induced by NTD.
  
  
  RESULTS
  Trophoblastic debris was collected from placental explants and exposed to endothelial cells with or without nifedipine, verapamil, or a nitric oxide (NO) donor for 24 h. Endothelial cell activation was measured by cell-surface intracellular adhesion molecule-1 and E-selectin, as well as monocyte adhesion. The activation of endothelial cells exposed to NTD or sera from pre-eclamptic women was significantly reduced by nifedipine or verapamil. In addition, the increases in the levels of IL-6 or TGFβ1 in conditioned media from endothelial cells following phagocytosis of NTD were significantly reduced by nifedipine. These actions of nifedipine were reversed by the NO synthetase inhibitor l-NAME and mimicked by a NO donor.
  
  
  CONCLUSIONS
  Our results suggest that calcium channel blockers may have a direct effect upon endothelial cells, reducing the endothelial cell activation that is a key pathogenic feature of pre-eclampsia. This action may be mediated, in part, by NO.
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, 85 Park Road, Grafton 1011, New Zealand. q.chen@auckland.ac.nz
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.forename: Shurong
authors.initials: S
authors.lastname: Liu
authors.forename: Jianping
authors.initials: J
authors.lastname: Xiao
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Saul
authors.initials: S
authors.lastname: Snowise
authors.forename: Peter R
authors.initials: PR
authors.lastname: Stone
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Chamley
mesh_terms: D000293:Adolescent; D000328:Adult; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008875:Middle Aged; D009336:Necrosis; D009543:Nifedipine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D013997:Time Factors; D046509:Tissue Culture Techniques; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism* / Q000473:pathology; D014700:Verapamil / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D002121:Calcium Channel Blockers; D017077:Culture Media, Conditioned; D019040:E-Selectin; D004791:Enzyme Inhibitors; C508600:IL6 protein, human; D015850:Interleukin-6; D020030:Nitric Oxide Donors; C546936:SELE protein, human; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D014700:Verapamil; D019001:Nitric Oxide Synthase; D009543:Nifedipine