title: Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome.
abstract: BACKGROUND
  Hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS) is a congenital salt-losing tubulopathy with an induced expression of cyclooxygenase-2 (COX-2) in the macula densa probably leading to hyperreninemia. Inhibition of stimulated prostaglandin E2 (PGE2) formation with indomethacin results in a significant improvement of clinical symptoms and is therefore standard therapy. Using the COX-2 selective inhibitor rofecoxib, we investigated the role of COX-2 in the pathophysiology of HPS/aBS.
  
  
  METHODS
  Six clinically well-characterized patients with HPS/aBS (3 girls) were enrolled into the study. Four patients had mutations in the renal potassium channel ROMK, one patient in the furosemide-sensitive cotransporter NKCC2, whereas in one patient no molecular abnormality could be detected. Median age was 15.8 years (range: 9.1 to 19.0 years). Patients were evaluated on indomethacin treatment, 3 days after indomethacin withdrawal, and after 4 days of treatment with rofecoxib. Therapeutic drug monitoring was performed.
  
  
  RESULTS
  COX-2-selectivity of rofecoxib was confirmed in vivo and ex vivo. Both indomethacin and rofecoxib ameliorated clinical symptoms, the typical laboratory findings, and significantly suppressed PGE2 and PGE-M excretion to normal values while it was elevated under withdrawal conditions. Rofecoxib suppressed hyperreninemia to a similar extent as indomethacin.
  
  
  CONCLUSIONS
  In patients with HPS/aBS, excessive PGE2 synthesis and hyperreninemia is dependent on COX-2 activity. This observation proves the stimulatory role of COX-2 on renin-secretion in salt-depletion in humans. Clinical long-term efficacy and potential side effects of rofecoxib need to be evaluated in a larger cohort of HPS/aBS-patients.
authors.affiliation: Department of Pediatrics, Philipps-University Marburg, Deutschhausstrasse 12, D-35053 Marburg, Germany.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Reinalter
authors.forename: Nikola
authors.initials: N
authors.lastname: Jeck
authors.forename: Christoph
authors.initials: C
authors.lastname: Brochhausen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Watzer
authors.forename: Rolf M
authors.initials: RM
authors.lastname: Nüsing
authors.forename: Hannsjörg W
authors.initials: HW
authors.lastname: Seyberth
authors.forename: Martin
authors.initials: M
authors.lastname: Kömhoff
mesh_terms: D000293:Adolescent; D000328:Adult; D001477:Bartter Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D002648:Child; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D007783:Lactones / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011458:Prostaglandins E / Q000096:biosynthesis*; D012083:Renin / Q000097:blood; D013450:Sulfones; D013577:Syndrome
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D011458:Prostaglandins E; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D012083:Renin