title: Increases in retinovascular prostaglandin receptor functions by cyclooxygenase-1 and -2 inhibition.
abstract: OBJECTIVE
  To determine the relative contribution of cyclooxygenase (COX)-1 and COX-2 in regulating prostaglandin (PG) E2 and PGF2alpha receptors (EP and FP, respectively) densities and their functions in retinal vasculature of neonatal pigs.
  
  
  METHODS
  Newborn pigs were treated intravenously every 8 hours for 48 hours with saline, 40 mg/kg nonselective COX inhibitor ibuprofen, 80 mg/kg COX-1 inhibitor valeryl salicylate, or 5 mg/kg DuP697 and 5 mg/kg NS398, COX-2 inhibitors. Retinal microvessel EP and FP receptor densities were measured by radioligand binding and receptor-coupled effects by determining second-messenger inositol 1,4,5-trisphosphate (IP3) and vasomotor responses. Retinal blood flow (RBF) response to incremental increases in blood pressure (BP) was measured by a microsphere technique.
  
  
  RESULTS
  Valeryl salicylate, DuP697, and NS398 reduced retinal PGE2 and PGF2alpha concentrations in the newborn by approximately half, whereas ibuprofen caused further reduction to levels observed in adults. Retinal vessel EP1, EP3, and FP receptor densities increased approximately threefold after treatments with COX-1 or COX-2 inhibitors, and five- to sixfold after ibuprofen treatment. EP and FP receptor upregulation was associated with corresponding increases in IP3 production and retinal vasoconstriction in response to PGF2alpha, fenprostalene (an FP agonist), PGE2, 17-phenyl trinor PGE2 (an EP1 agonist), and M&B28,767 (an EP3 agonist) and with enhanced RBF autoregulation of high BP (> or =125 mm Hg). Conversely, EP2 receptor density and coupled functions were minimally affected by COX inhibition.
  
  
  CONCLUSIONS
  Data suggest that increased COX-1- and COX-2-catalyzed prostaglandin synthesis contribute equivalently to the downregulation of retinovascular EP1, EP3, and FP receptors and their vasoconstrictor functions in newborn pigs; the EP2 receptor was not significantly influenced by ontogenic alterations in prostaglandin levels.
authors.affiliation: Department of Pediatrics, Research Center of Hôpital Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Hardy
authors.forename: M
authors.initials: M
authors.lastname: Bhattacharya
authors.forename: D
authors.initials: D
authors.lastname: Abran
authors.forename: K G
authors.initials: KG
authors.lastname: Peri
authors.forename: P
authors.initials: P
authors.lastname: Asselin
authors.forename: D R
authors.initials: DR
authors.lastname: Varma
authors.forename: S
authors.initials: S
authors.lastname: Chemtob
authors.forename: M
authors.initials: M
authors.lastname: Bhatthacharya
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001783:Blood Flow Velocity; D000242:Cyclic AMP / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D006706:Homeostasis; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000502:physiology*; D011458:Prostaglandins E / Q000819:agonists; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism*; D013552:Swine; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011458:Prostaglandins E; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; C034671:prostaglandin F2alpha receptor; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases