title: Cyclooxygenase-2-dependent prostacyclin formation and blood pressure homeostasis: targeted exchange of cyclooxygenase isoforms in mice.
abstract: BACKGROUND
  Cyclooxygenase (COX)-derived prostanoids (PGs) are involved in blood pressure homeostasis. Both traditional nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit COX-1 and COX-2 and NSAIDs designed to be selective for inhibition of COX-2 cause sodium retention and elevate blood pressure.
  
  
  OBJECTIVE
  To elucidate the role of COX-2 in blood pressure homeostasis using COX-1>COX-2 mice, in which the COX-1 expression is controlled by COX-2 regulatory elements.
  
  
  RESULTS
  COX-1>COX-2 mice developed systolic hypertension relative to wild types (WTs) on a high-salt diet (HSD); this was attenuated by a PGI(2) receptor agonist. HSD increased expression of COX-2 in WT mice and of COX-1 in COX-1>COX-2 mice in the inner renal medulla. The HSD augmented in all strains urinary prostanoid metabolite excretion, with the exception of the major PGI(2) metabolite that was suppressed on regular chow and unaltered by the HSD in both mutants. Furthermore, inner renal medullary expression of the receptor for PGI(2), but not for other prostanoids, was depressed by HSD in WT and even more so in both mutant strains. Increasing osmolarity augmented expression of COX-2 in WT renal medullary interstitial cells and again the increase in formation of PGI(2) observed in WTs was suppressed in cells derived from both mutants. Intramedullary infusion of the PGI(2) receptor agonist increased urine volume and sodium excretion in mice.
  
  
  CONCLUSIONS
  These studies suggest that dysregulated expression of the COX-2 dependent, PGI(2) biosynthesis/response pathway in the renal inner renal medulla undermines the homeostatic response to a HSD. Inhibition of this pathway may contribute directly to the hypertensive response to NSAIDs.
authors: Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 153 Johnson Pavilion, Philadelphia, PA 19104, USA.
authors: Ying
authors: Y
authors: Yu
authors: Jane
authors: J
authors: Stubbe
authors: Salam
authors: S
authors: Ibrahim
authors: Wen-liang
authors: WL
authors: Song
authors: Emer M
authors: EM
authors: Smyth
authors: Emer M
authors: EM
authors: Symth
authors: Colin D
authors: CD
authors: Funk
authors: Garret A
authors: GA
authors: FitzGerald
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000494:pharmacology; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D006973:Hypertension / Q000209:etiology / Q000378:metabolism; D007679:Kidney Medulla / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009318:Natriuresis / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage
chemical_list: D011982:Receptors, Prostaglandin; D017673:Sodium Chloride, Dietary; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D012083:Renin; C043867:cicaprost