title: Hyperoxia stimulates endothelin-1 secretion from endothelial cells; modulation by captopril and nifedipine.
abstract: OBJECTIVE
  Retinopathy of prematurity (ROP) is a vasoproliferative condition that can result in severe visual impairment and blindness in preterm babies. Two conditions seen very early in radioimmunoassay (ROP) are vasoconstriction and vaso-obliteration. A potent vasoconstrictor secreted by endothelial cells is endothelin-1 (ET-1). Premature birth results in a relative systemic hyperoxia, compared to the in utero oxygen milieu. We tested the hypothesis that hyperoxia increases ET-1 expression as a possible mechanism for vasoconstriction in the retinal vasculature.
  
  
  METHODS
  Bovine retinal endothelial cells and adrenal capillary endothelial cells were isolated and maintained in culture. Cells were exposed to control or hyperoxic culture conditions for 24 h, with and without addition of captopril and nifedipine. Media was collected and assayed for ET-1 by ROP. In addition, cell counts and secreted LDH assays were performed.
  
  
  RESULTS
  Conditioned media from cultured bovine retinal and adrenal endothelial cells exposed to hyperoxic culture conditions for 24 h were found to have higher levels of ET-1 than conditioned media from normoxic control cells. Captopril (10(-6) M and 10(-4) M) and nifedipine (10(-6) M and 10(-4) M) inhibited ET-1 release from hyperoxia-exposed endothelial cells. Under normoxic conditions, ET-1 release was inhibited by 10(-4) M captopril or 10(-4) M nifedipine.
  
  
  CONCLUSIONS
  These results demonstrate that (1) hyperoxia stimulates in vitro ET-1 secretion in bovine retinal and adrenal capillary endothelial cells, and (2) captopril and nifedipine downregulate ET-1 secretion under normoxic and hyperoxic culture conditions, in a dose-dependent fashion. We speculate that ET-1 may be involved in retinal vessel vasoconstriction seen early in the development of ROP. Further, ACE inhibitors and calcium-channel blocking agents, such as captopril and nifedipine, may provide an avenue for blocking vasoconstriction in ROP.
authors.affiliation: Georgetown University Medical Center, Department of Pediatrics, Washington, DC 20007, USA. higginsr1@gunet.georgetown.edu
authors.forename: R D
authors.initials: RD
authors.lastname: Higgins
authors.forename: K D
authors.initials: KD
authors.lastname: Hendricks-Munoz
authors.forename: V V
authors.initials: VV
authors.lastname: Caines
authors.forename: R P
authors.initials: RP
authors.lastname: Gerrets
authors.forename: D B
authors.initials: DB
authors.lastname: Rifkin
mesh_terms: D000311:Adrenal Glands / Q000098:blood supply; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology*; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D018496:Hyperoxia / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D019332:Endothelin-1; D002216:Captopril; D007770:L-Lactate Dehydrogenase; D009543:Nifedipine